Expatriados Online

Sobre los tiroteos al aire durante la despedida de año en PR ...

2012-01-01T17:10:00.000-08:00

Preguntas que se me ocurren luego de ver el video escalofriante del tiroteo durante la despedida de año que grabaron unos muchachos en PR :

¿DÓNDE CARAJO está la fucking policía de Puerto Rico mientras eso ocurre?
¿Cuántas personas fueron arrestadas anoche por tirar tiros al aire en PR?
Mientras esos ANIMALES puedan seguir tiroteando IMPUNEMENTE, olvídense de que eso se arregle. Sigan creyéndose que "campañas de conscientización" van a funcionar con ANIMALES como esos.

Si el gobierno no ejerce el MONOPOLIO DE LA FUERZA que le concede la ley, y PERMITE que éstas cosas sucedan IMPUNEMENTE, pues entonces SÍ son accountables por ésto, aunque a los penepos no les guste admitirlo.

¿Y cómo es posible que los PRs TOLEREN eso? ¿uds TOLERAN y dan por normal que la policía SE ESCONDA de los cacos y les tenga miedo?

¿Uds no le EXIGEN al gobierno que le meta mano a esa situación, que BOTE PAL CARAJO a todos los Coroneles que han permitido un fiasco tan bochornoso?

Porque ok, digamos que ocurre UN año. En cualquier país civilizado, la policía se prepara para que el PRÓXIMO año los sitios donde hubo tiroteo parezcan un fucking CAMPO DE CONCENTRACIÓN, saturados de fuerza.

Pero es evidente que uds en esa Isla se han dado por vencidos. Acaben y compren el pasaje de IDA, y déjenle la isla a los cacos y los Melonchos.

No es al policía individual a quien se le esta responsabilizando, es a la policía como institución.

Ésto no es un asunto imprevisto en el que de repente un policía se encuentra con una pandilla de delincuentes armados con ametralladoras, NO. Ésto es algo que ocurre TODOS los años, en unos puntos específicos de PR. Exigirle a la policía de PR que tenga un PLAN preparado de antemano para meterle mano a ésto durante la despedida de año NO ES INJUSTO , es lo que DEBERÍA hacer la ciudadanía.

La responsabilidad empieza por el GOBERNADOR. Si eso implica declarar un Estado de Emergencia la noche del 31 entre 9pm - 3am, poner checkpoints de la policía en las carreteras donde se registren TODOS los carros que entren y salgan de algún sitio, concentrar masivamente policías y Guardias Nacionales precisamente en las áreas calientes, SE HACE.

La policía SABE que ésto ocurre. SABEN la fecha y hora en que ocurre. SABEN los sitios donde ocurre.

En cualquier sitio civilizado hubieran tenido un plan de saturación y despliegue de fuerza para suprimir éste salvajismo. Pero en PR no, en PR se esconden en los cuarteles.

En cualquier sitio civilizado el Presidente, Primer Ministro, Gobernador, o Primer Loquesea hubiera BOTADO COMO BOLSA no sólo al jefe de la Policía sino a TODOS, TODOS los Coroneles y demás altos oficiales que permiten éste tipo de anarquía totalmente anticipable.

Pero no en PR, porque la gente aparentemente ya se ha dado por vencida y han aceptado ésta aberración grotesca como la realidad.

Los sitios donde las mafias y pandillas campean por su respeto impunemente y las fuerzas de seguridad del estado son impotentes y no pueden o no se atreven a enfrentarlos tienen un nombre: ESTADO FALLIDO. Si PR no está en esas, está peligrosamente cerca.

Para los que no lo han visto, aquí está el video:

http://www.facebook.com/photo.php?v=10151092762705142

ELA, Gini Index y la brecha entre pobres y ricos

2011-12-22T11:07:00.000-08:00

ELA: sistema sociopolítico colonial que rige a PR.

El ELA se compone de:

(1) Un sistema económico socialistoide obsoleto, fracasado, mezcla de clientelismo gubernamental, paternalismo dictatorial y mercantilismo medieval; donde el más competitivo es aplastado por el gobierno o por la Secta...

(2) un sistema político trampeado y totalmente secuestrado por un puñado de ricachones parásitos conocidos como la Secta de San Patricio;

Gracias a ese sistema llamado ELA es que Puerto Rico, que tiene el potencial de ser uno de los lugares MÁS PRÓSPEROS y con MEJOR calidad de vida del mundo, lleva 30 años de colapso económico y social, y se ha convertido en una decepcionante letrina tercermundista de la que se ha largado y se siguen largando todos los que pueden.

La brecha entre ricos y pobres se mide con el índice Gini. Mientras más alto es el número, mayor es la brecha.

El Gini de USA es de 45, según el CIA World Factbook

El Gini del ELA (ANTES de llegar Fortuño al poder) era de 63.3 según un estudio del Dr Rafael Corrada Guerrero, de la Escuela de Planificación de la UPR

Según éste website, que cataloga los Gini Indices de todo el mundo, PR bajo el PPD estaría #2 en el MUNDO ENTERO en términos de lo grande que es la brecha entre ricos y pobres.

http://www.nationmaster.com/graph/eco_inc_equ_un_gin_ind-income-equality-un-gini-index

Ahí tienen la VERDADERA RAZÓN por la que el ELA sigue existiendo después de haber colapsado social y económicamente hace décadas: porque hay un puñado de ricachones parásitos beneficiándose de él, nadando en dinero mal habido, y comprando políticos y partidos para seguir en la jauja mientras uds siguen cada día MÁS xodíos ...

Nazionalistas yankifóbicos: antes de irse a criticar la paja en el ojo ajeno, miren la VIGA en el propio.

La Triste Realidad del Cubano de a Pie

2011-12-18T01:41:00.000-08:00

Un especial muy interesante sobre la difícil realidad de la vida en Cuba.

Realmente da pena que la gente tenga terror de que los metan presos por el "delito" de vender un yogurt o un pote de mantequilla, o de atreverse a criticar a su gobierno.

Parte 1
http://youtu.be/TVQ_2TWXikU

Parte 2
http://youtu.be/ClppMAqKbt8

Parte 3
http://youtu.be/Y2MAHGB0THE

Parte 4
http://youtu.be/8i3gcwRgtS8

Parte 5
http://youtu.be/zxvJMTq7TtE

What caused the Great Recession? Read on...

2011-12-13T12:28:00.000-08:00

A Primer: Understanding Derivatives
Heidi is the proprietor of a bar in Detroit ..

She realizes that virtually all of her customers are unemployed alcoholics and, as such, can no longer afford to patronize her bar.

To solve this problem, she comes up with a new marketing plan that allows her customers to drink now, but pay later.

Heidi keeps track of the drinks consumed on a ledger (thereby granting the customers loans).

Word gets around about Heidi's "drink now, pay later" marketing strategy and, as a result, increasing numbers of customers flood into Heidi's bar.

Soon she has the largest sales volume for any bar in Detroit .

By providing her customers freedom from immediate payment demands, Heidi gets no resistance when, at regular intervals, she substantially increases her prices for wine and beer, the most consumed beverages.

Consequently, Heidi's gross sales volume increases massively.

A young and dynamic vice-president at the local bank recognizes that these customer debts constitute valuable future assets and increases Heidi's borrowing limit. He sees no reason for any undue concern because he has the debts of the unemployed alcoholics as collateral!

At the bank's corporate headquarters, expert traders figure a way to make huge commissions, and transform these customer loans into DRINKBONDS.

These "securities" then are bundled and traded on international securities markets.

Naive investors don't really understand that the securities being sold to them as "AAA Secured Bonds" really are debts of unemployed alcoholics. Nevertheless, the bond prices continuously climb - and the securities soon become the hottest-selling items for some of the nation's leading brokerage houses.

One day, even though the bond prices still are climbing, a risk manager at the original local bank decides that the time has come to demand payment on the debts incurred by the drinkers at Heidi's bar. He so informs Heidi.

Heidi then demands payment from her alcoholic patrons. But, being unemployed alcoholics -- they cannot pay back their drinking debts.

Since Heidi cannot fulfill her loan obligations she is forced into bankruptcy.

The bar closes and Heidi's 11 employees lose their jobs. Overnight, DRINKBOND prices drop by 90%.

The collapsed bond asset value destroys the bank's liquidity and prevents it from issuing new loans,thus freezing credit and economic activity in the community.

The suppliers of Heidi's bar had granted her generous payment extensions and had invested their firms' pension funds in the BOND securities.

They find they are now faced with having to write off her bad debt and with losing over 90% of the presumed value of the bonds.

Her wine supplier also claims bankruptcy, closing the doors on a family business that had endured for three generations, her beer supplier is taken over by a competitor, who immediately closes the local plant and lays off
150 workers.

Fortunately though, the bank, the brokerage houses and their respective executives are saved and bailed out by a multibillion dollar no-strings attached cash infusion from the government.

The funds required for this bailout are obtained by new taxes levied on employed, middle-class, nondrinkers who have never been in Heidi's bar.

Now do you understand? There!

Verguenza Ajena

2011-12-10T15:03:00.001-08:00

Si los independentistas no fueran un club privado dedicado al incesto ideológico y a vivir del mantengo del fondo electoral, hubieran aprovechado éstos pasados 3 años en que el PPD ha estado en el momento más desacreditado, más jodío y más débil de TODA su historia para establecerse como el segundo partido de PR.

Pero en vez de eso se han dedicado a servirle de cheerleaders y lambeojos a la Pava.

¿Cómo compara el ELA vs la Libre Asociación?

2011-12-08T15:03:00.001-08:00

Comparación económica entre los Estados de EEUU, sus territorios no incorporados, y sus repúblicas asociadas

Para que comparen:

GDPs Per Capita

USA $47,200 (promedio)
Hawaii $49,214 (estado más cercano a Guam)
Florida $40,106 (estado más cercano a PR)
Mississippi $32,967 (más bajo de los estados)
Delaware $69,667 (más alto de los estados)
Rhode Island $45,000 (estado más chiquito que PR)

PR $16,300
Guam $15,000
Islas Vírgenes $14,500
American Samoa $8,000
Marianas $12,500

Palau $8,100
Micronesia $2,200
Marshall $2,500

Luego de varias décadas de Libre Asociación, las repúblicas asociadas son MUCHO MÁS POBRES que lo que PR ha sido en los pasados 50 años...

Ahí está la realidad, monda y lironda. Al que no le guste, que continúe con la cabeza firmemente enterrada en lo que se le perdió a Narciso ...

Petróleo ...

2011-12-04T18:23:00.001-08:00

Espero con ansias el día en que la humanidad logre perfeccionar las tecnologías de fusión nuclear (para producir electricidad) y de fuel cells (para vehículos); y así podamos decirle a los Saudis, los Ayatollahs, a Putin, al gorila de Caracas, y al resto de todos esos robber barons que pueden coger su oro negro y hacerse enemas con él .

¿Cuántos empleados gubernamentales REALMENTE necesita tener PR?

2011-11-13T01:02:00.000-08:00

Sigue la gente con la cantaleta de que si el gobierno actual botó 17 mil empleados... sí, la misma gente que también recita cantaletas sobre las muchas batatas políticas que hay en PR...

Lo que pasa es que en PR no se hace benchmarking para comparar al gobierno con el de otros países que hacen las cosas MEJOR para así mejorar también.

La EXAGERADA cantidad de empleados públicos que tiene el gobierno del ELA es la razón principal por la cual en PR la gente paga una cantidad ENORME de impuestos pero no se ve a dónde van; las carreteras siguen fastidiadas, las escuelas públicas en mal estado, las obras públicas sin mantenimiento y deterioradas... ¿Por qué? Porque todos esos cuchocientos millones que ustedes pagan en impuestos, en IVU y cuanta cosa más les cobra el gobierno se van en PAGAR LA NÓMINA de todo ese montón de empleados del gobierno que ustedes no quieren sacar.

El ELA tiene 3.7 millones de habitantes, y más de 300 mil empleados públicos, o sea aproximadamente 1 empleado público del gobierno por cada 12 personas. En comparación, Japón tiene 130 millones de habitantes y 1 millón de empleados públicos, o sea aproximadamente 1 empleado del gobierno por cada 127 habitantes. Con esa cantidad de gente el gobierno de Japón provee más y mejores servicios que el gobierno del ELA.

O sea, que PR tiene proporcionalmente 10.5 empleados del gobierno por cada uno que tiene Japón... y aún así el gobierno de Japón, con UNA DÉCIMA PARTE de los empleados que el de PR, provee MAS y MEJORES servicios.

Lo que hay que preguntarse es ¿Cómo es que los japoneses pueden correr BIEN su país con UNA DÉCIMA PARTE de los empleados públicos? O también, ¿cómo es posible que con DIEZ VECES MÁS empleados púbicos que Japón, la calidad de los servicios del gobierno de PR sea PÉSIMA?

Porque en PR los empleos del gobierno se usan como refugio de batatas. Y eso lo sabe todo el mundo.

Esa es una de las razones por las cuales Japón es una potencia mundial y un país del Primer Mundo, mientas que PR es una colonia tercermundista: porque los empleos en el gobierno son una forma de MANTENGO para batatas, y CADA VEZ que se intenta arreglar eso BOTANDO batatas, medio mundo protesta.

Así que JÓDANSE.

"Con la iglesia hemos dado, Sancho."

2011-11-13T00:46:00.000-08:00

Escribió un amigo hoy en un foto de Internet:"Si no llega a ser por la iglesia católica no hubiera ni las ciencias modernas, ni las matematicas, ni las universidades, las cuales fueron todas fundadas por la iglesia. "

WTF??!! Las matemáticas existían milenios antes que la Iglesia Católica, y a los que crearon las ciencias modernas la iglesia los quemaba en la hoguera por herejes y blasfemos.

Digamos, como mucho, que todas esas cosas existen A PESAR de la Iglesia; a cuenta de la Iglesia estuviéramos todavía afirmando que el sol orbita alrededor de la Tierra, que la lluvia y el viento eran causados por demonios (Sto Tomás de Aquino en Summa Theologica) y que los pararrayos son cosa del diablo.

Pero según digo eso, también tengo que decir que a pesar de su horroroso pasado, y a pesar de que aún hoy en día sostienen estupideces como oponerse al uso de stem cells y de métodos de control de natalidad, la Iglesia Católica está mucho más al día que gran parte de las Iglesias protestantes, donde el fanatismo anticientífico (sobre todo su acérrima, irracional y absurda guerra contra la evolución) es razón de orgullo demente para muchos de sus líderes.

A la verdad que hay que retorcer grotescamente la historia para alegar que tener a los papas como emperadores de Europa "salvó" la civilización occidental... cuando en realidad eso lo único que provocó fue el OSCURANTISMO (a.k.a. The Dark Ages) período durante el cual Occidente perdió CASI UN MILENIO debajo del talón de la Iglesia Católica Apostólica Romana.

Quienes salvaron la civilización occidental, irónicamente, fueron los MUSULMANES, que copiaron y tradujeron del griego al árabe las grandes obras culturales, médicas y científicas... todo eso mientras la Iglesia Católica mantenía a Europa sumergida en un pantano de ignorancia y salvajismo, cacerías de brujas e Inquisiciones, persecuciones y asesinatos contra los judíos, moros, cátaros, Waldensians; en las Cruzadas, etc.

Pero eso no es todo. Aún hoy que todo el mundo sabe que Galileo estaba en lo correcto y los religiosos ignorantes no, hubo alguien que en pleno 1990 JUSTIFICÓ las salvajadas de la Iglesia contra Galileo:

"The Church at the time of Galileo kept much more closely to reason than did Galileo himself, and she took into consideration the ethical and social consequences of Galileo's teaching too. Her verdict against Galileo was rational and just, and the revision of this verdict can be justified only on the grounds of what is politically opportune."

¿Adivinen quién fue el cavernícola que se disparó esa joya de discurso? Nada menos que el Cardenal Ratzinger, hoy Papa.

Márquez v Pacquiao, y el negocio del boxeo

2011-11-13T00:30:00.000-08:00

Mucha gente ofendida con la pelea de boxeo de hoy, la que le robaron al mexicano Márquez a pesar de la pela que le dió por ojos, boca y nariz al filipino Pacquiao. Dicen unos que hasta aquí llegó el boxeo. Otros que ya no tiene credibilidad como deporte. Etc etc...

Gente... really? ¿AHORA es que vienen uds a darse cuenta de que el boxeo es un ENTRETENIMIENTO como la WWF, y NO un deporte?

Para los que dicen que NUNCA habían visto una pelea en que un campeón ganara por decisión a pesar de haber cogido de arroz y de masa, me permito recordarles éstas dos:

1993: Whittaker le dió contra el piso a Julio César Chávez. Dieron la pelea EMPATE.

1999: Oscar de la Hoya le hizo CANTOS la cara a Tito Trinidad. Le dieron la pelea a Tito, que apenas consciente estaba luego de la zarza que cogió.

Gente, ésto es bien sencillo. A mí me da mucha pena con Márquez, porque le robaron la pelea. Pero la REALIDAD es que el boxeo NO ES un deporte. El boxeo es un show. Y las peleas importantiosas las gana el favorito de los promotores multimillonarios y las mafias.

Eso es así y SEGUIRÁ siendo así mientras TOOOOODA esa gente que se queja por las peleas robadas SIGA PAGANDO DINERO por ver los shows de boxeo.

Univisión y las conspiraciones imaginarias ...

2011-11-13T00:26:00.001-08:00

Alguien dijo hoy lo siguiente en un foro de internet donde pululo:

"te das cuenta que en Univision pretenden meternos la cultura mejicana por ojo, boca y nariz? Y programas de mediocridad para que el que vea el canal se embrutezca cada vez mas? Siempre nos han tenido envidia porque gozamos de la ciudadania americana. Y aqui no sabemos valorar lo que tenemos! Por tanto, se han metido aqui para destruir al pueblo"

Yo no creo que ésto sea un "complot" de Univisión para mexicanizar a la gente, de la misma manera que la programación de ABC, CBS, NBC, Fox, etc no es un complot para americanizar a nadie.

Simple y sencillamente Univisión de PR le pertenece a la cadena Univisión en USA. La inmensa mayoría de la audiencia de ésta cadena son mexicanos, y por lo tanto la mayoría de su personal, y el enfoque de su programación, es hacia esa audiencia. En pocas palabras, AHÍ es que están los CHAVOS $$$ de Univisión.

El mercado de PR es comparativamente bien pequeño, un puñado de millones, y ellos no van a hacer mucho esfuerzo en desarrollar programación específica para ese mercado solamente. Como cualquier cadena de televisión, ellos solamente van a meter $ en programación enfocada en la audiencia que les deja $$$.

La televisión NO ES un servicio público, no está ahí para ayudar a la gente, ni para educar, ni para informar, ni para alimentar la cultura; la televisión, al igual que la radio y los periódicos, es un NEGOCIO y esta ahí para hacer DINERO a sus dueños. Lo que pasa es que nos creemos los embustes que esos dueños nos meten. Lo que pasa es que nos gusta disfrazar la realidad de eufemismos, emocionalismos y wishful thinking.

Si los PRs quieren que se produzca televisión enfocada en PR, pues tienen que APOYAR la televisión local que se produce. A más audiencia más dinero de los anunciantes, y a más dinero pues más se puede producir. Si los PRs quieren una televisión que SI ayude a la gente, que SI eduque e informe, que SÍ sustente y promueva las expresiones culturales locales, pues tienen que PAGAR por ella, porque de gratis no hay NADA en el mundo.

My first attempt to update my iPhone to iOS5 : semi-disaster

2011-10-13T09:47:00.000-07:00

My first attempt to update my iPhone to iOS5 : semi-disaster

1. The update process crashed repeatedly.

2. I had to restore the phone to factory conditions and reinstall everything

3. The whole process took over 5 (yes, FIVE) hours... and those 5 hours do NOT count all the time I will have to spend FIXING the stuff that got BROKEN and messed up by the " update". Read on...

4. Icon arrangement came out all messed up. I have to spend time now rearranging all

the App icons in the screens and folders I had them

5. I LOST ALL the eBooks (100+ !!!) I had in the Stanza eBook reader app. Gone. I probably have them on my Windows 7 PC (which has NOT crashed even once in almost 2 years, it looks like MS *finally* learned how to write an OS...).

6. The Stanza bookreader app doesn't work with iOS5. I'll have to switch to Kindle or Nook because iBooks sucks. That means that once I search and locate my eBooks in the PC, I will have to CONVERT ALL of them from .ePub to .mobi so I can access them on Kindle. Drat... MORE time wasted...

7. I lost ALL my Safari bookmarks. ALL. GONE. Re-doing all this is going to take A LOT of time that I don't have.

8. I lost ALL my photos and videos. This one is MAJOR. Thankfully I back them up manually to an external drive and didn't lose them completely. But if I hadn't ...

9. I lost ALL the alarms I had set. Minor but annoying.

10. I lost ALL the world clocks I had set up. Minor but annoying.

11. I lost ALL my "Favorites" in the phonebook. Minor but annoying.

12. My voicemail lost its configuration, now I have to remember the damn password or call AT&T.

13. All the entries in my Calendar are now duplicated. That's more time I will have to spend fixing that.

14. the Weather app lost all the pre-set cities. Minor annoyance, more time wasted.

15. some apps, such as Weather Channel, got deleted. GONE. Now I will have to reinstall them. More time wasted.

16. I lost ALL the text messages I have sent or received over MANY years. Apparently there is NO WAY to recover that. Gee, thanks, Apple...

17. eMail accounts configuration was lost. Minor annoyance, more time wasted.

18. My phone's memory shows 4.3 Gb in "other". It looks like I will have to wipe out the phone AGAIN and reinstall everything.

Pirámides y astronomía antigua

2011-10-11T10:36:00.000-07:00

RE: pirámides y astronomía antigua

... La mayoría de la gente se cree que porque los antiguos humanos aún no habían desarrollado tecnología, eran brutos. No, señores, eran homo sapiens, tan inteligentes e ingeniosos como nosotros. Su vida dependía de la agricultura, así que aprendieron a discernir las estaciones y a medirlas con el sol y las estrellas. Total, de noche no había más ná que hacer !

No sólo los egipcios construyeron edificios y plazoletas alineadas con los astros. Por TODO EL MUNDO existen construcciones así. Era algo normal, y demuestra que la humanidad luego de haber observado los cielos durante siglos aprendió a discernir y medir muchas cosas. En Irlanda (Newgrainge) y Perú (Caral) existen complejos de edificios más antiguos que las pirámides, también alineados con los astros.

Los taínos, de hecho, también alineaban sus plazas y canchas de pelota con los astros; arqueólogos han encontrado plazas taínas alineadas con el punto donde el sol sale en el solsticio, con estrellas como Betelgeuse, etc. en Turks & Caicos. En Antigua hay rocas con glifos alineadas con los puntos donde sale el sol en fechas específicas, con estrellas particulares, etc. De hecho, Tibes en Ponce es el observatorio astronómico más antiguo de las Antillas:

http://ponce.inter.edu/tibes/ingles/historia.html

http://www.timespub.tc/2005/04/talking-taino-starry-starry-night/

http://uwispace.sta.uwi.edu/dspace/bitstream/handle/2139/11062/Article%206%20-%20astronomy_Cerami.pdf?sequence=1

Why Apple's Main Product was Steve Jobs image

2011-10-10T18:28:00.001-07:00

Les comparto algo que acabo de postear en el foro Veritas... :-)

El principal producto que Apple mercadeaba no eran ni los teléfonos ni los music players ni sus compus ni sus tablets. El principal producto que Apple mercadeaba era a Steve.

Raul Soto I mean, el tipo era un genio vendiendo.

El iPhone no hace nada que otros smartphones no hagan también. De hecho, mi iPhone se crashea mucho más a menudo que mi PC con Windows 7.

El iPad no tiene access a Flash (o sea que no puedes ver cuchocientos programas y películas gratis en los websites de las cadenas de televisión, ni jugar montones de juegos gratis en el web), no tiene slots para USB ni tarjetas SD para uno mover files del cacharro a la compu fácilmente, no; todo tiene que irse por la leña de programa ese iTunes. Lo mismo los iPods. Las compus hacen lo mismo que las de Guindous por el doble del precio. Con un Kindle de $200 puedes leer los mismos libros que con un iPad de $500.

Sin embargo mucha gente ve los productos de Apple como mejores que los de la competencia. No son malos, pero tienen serias limitaciones. Pero la gente los compra por montones, pagando el precio premium que Apple cobra - gracias al famoso Steve Jobs' Distortion Field.

El que la IMAGEN de Jobs era el principal producto de Apple se veía cada vez que lanzaban un producto "nuevo" que aunque no era otra cosa que un catch up con OTROS productos de la competencia, como quiera la gente lo compraba, aún los que tenían la versión que Apple había tirado 8 meses antes.

La gente JURA y PERJURA que Steve Jobs era un Da Vinci moderno, dando como ejemplos Apple y Pixar. ¿Pero es que uds se creen que Steve fue quien se inventó a Woody y a Buzz Lightyear y al iPad? Jobs era un CEO, él daba dirección high-level, y aprobaba o desaprobaba conceptos para productos. Pero Jobs no se inventó nada de eso. Zuckerberg se inventó Facebook, pero hace años que él no es el programador que lo actualiza. Larry Page y Sergei Brin se inventaron Google, pero hace años que ellos no son quienes inventan y programan ahí, Bill Gates escribió el MS-DOS original y junto a Jobs se pirateó el GUI de Xerox (Gates para hacer Windows, Jobs para hacer la Mac), pero nadie sostiene que Bill Gates se inventó Powerpoint ni el XBox.

Nadie en su sano juicio se cree que Kevin Sharer se mete en los laboratorios de nosotros en Amgen a inventarse las medicinas.

¿Por qué creen entonces que JOBS fue el inventor de todo eso? Porque Apple cultivó esa IMAGEN de genio rebelde, irreverente y contra cultura. Porque ESA imagen, no los cacharritos electrónicos, es el producto principal de Apple. Los gadgets son el símbolo.

About China's Naval Threat ...

2011-10-10T17:52:00.000-07:00

About China's Naval Threat ...

I just read this article, and posted the following rant at Veritas, one of my favorite Fbk discussion groups. ;-)

http://www.reuters.com/article/2011/10/10/us-usa-china-military-idUSTRE7990S620111010

That's how services compete among themselves in the Pentagon - by trying to grab as much of the budget pie as possible. At one point several years ago, when the USA started getting heavily involved in both Iraq and Afghanistan, plus in counterterrorism activities around the globe, the Navy found itself relegated to a secondary role as the Army's cargo drivers. With the once mighty Soviet fleet rusting in Kiev and Arkhangel, NO ONE in the world had a Navy that even got close to ours.

We were no longer fighting the vast armor columns of the Warsaw Pact, or the splendid supersonic naval bombers of the Soviet Atlantic fleet. Now we were fighting Ahmed the Towelhead with a Chinese-made AK-47 and 10kg of C4 strapped around his balls, and his 10 thousand cousins. The Army, once thought to be an obsolete left over from mid 20th century in an era of missiles, fighters and carriers, was once again king of the services and getting the lion's share of the budget. The Air Force, after doing away with its Iraqi counterpart in like the first 7 minutes of the 2003 invasion, morphed and settled into its close ground air support role and never looked back. Even the Marine Corps found itself at home in the sands and cliffs along with the Army, thousands of miles away from the nearest beach.

That whole state of affairs, of course, didn't sit well with the admirals. Yeah, they fired Tomahawks from ships and subs, yeah the SEALs are doing awesome things everywhere, yeah they get to launch drones every time Obama wants to execute an American-born terrorist without them pesky niceties such as due process. Sure, they got to blow up Qadaffi's butt and provide command & control while our esteemed Euro NATO allies were still sorting out which of them whose turn it was to bring the Grey Poupon.

But that's not what the Admirals got into the Navy for. It's SHIPS, big and scary and shiny, bristling with mighty missile launchers and mysterious antennae and full of white-clad sailors saluting them and polishing brass to a mirror and kissing their ass. Yeah, SHIPS. That's the ticket.

So... how do they keep the Navy from feeling irrelevant in the Brave New World of enemies with no navies to speak of? Hmmm...

Of course! The People's Republic of China! The big bad dragon replaces the big bad Soviet bear! They bought a floating pile of shit from Ukraine and spent 10 years scraping the rust off - they have a CARRIER !!! Forget that we have like 14 of them, and that ours are bigger and mightier, and that even countries like Brasil and Thailand have carriers... No! They.Are.THE.NEXT.BIG.Threat!

THAT's how the Navy gets its budget appropriations passed!

And now, after this not-so-frequent stroke of Generalísimo wisdom, I have to go design @#$%^ primers for PCR because this week I've got to clone genes.

Otra vez la burra al trigo ...

2011-09-25T23:16:00.000-07:00

Ninguna economía se puede sostener mediante muletas contributivas y mantengo corporativo. Ninguna.

El propuesto cambio a la sección 933 es para que se use la banca de PR como conducto para que empresas multinacionales puedan repatriar hacia USA sus ganancias obtenidas en el exterior. El que se crea que ésto va a traer plantas manufactureras u algún otro tipo de empleo a PR se llevará tremenda decepción.

Quienes realmente se benefician de ésta propuesta enmienda 933A son la banca local (que históricamente ha contribuído millones al Partido Popular y a mantener la colonia), los accionistas de los bancos locales (como los Ferré Rangel, Sila María Calderón, etc) y los grandes bufetes como McConnell-Valdés (¡que coincidencia, el bufete de donde salió Fortuño!) que perdieron muchísimo dinero cuando las ex-936 dejaron de usar sus servicios, y por supuesto el Partido Popular, que nuevamente recibirá ayuda multimillonaria de éstas empresas cada vez que haya que torpedear, obstaculizar y hundir procesos descolonizadores.

El neoPNP con ésta movida acaba de convertirse oficialmente en el hederedo del PPD como el partido de los Happy Colonials ligeramente pro-americanos.

Para que una economía prospere tiene que levantarse sobre sus propias ventajas comparativas, sobre características y fortalezas propias, inherentes, no sobre inventos y traquetelos leguleyos que pueden desaparecer con un plumazo del Congreso.

PR tiene que levantar sus propias empresas, echar a andar sus propios start-ups, tener disponible capital de riesgo para inversiones, invertir en incubadoras de tecnología, para que surjan empresas locales que puedan ser el fundamento de una economía propia que invierta aquí, no una economía prestada que viene y se va según sople el viento económico mundial.

Y para atraer inversiones Puerto Rico tiene que corregir sus eternos problemas, que joroban tanto al inversionista como al empresario local como a los residentes: el alto costo y pésimo servicio de electricidad y agua, el pésimo estado de la infraestructura, la espantosa criminalidad, el alto costo de la transportación, las leyes laborales prehistóricas y retrógradas, y la tramitología elefantiásica del gobierno estatal.

Arreglen todo eso y se reducen los costos de operar en Puerto Rico no sólo para las multinacionales sino para los empresarios locales, que viven asfixiados por el peso de todas esas cosas. Arreglen eso, inviertan en startups de tecnología tendrán un fundamento fuerte para la economía de la Isla que NO DEPENDERÁ del status político, ni de muletas contributivas, ni de mantengo corporativo.

Yo dudo que el Congreso, que está como loco buscando fuentes de ingresos en medio de un déficit cuasi-apocalíptico, vaya a aprobar un tax loophole tan enorme como éste. Probablemente aprobarán un tax holiday de 12 meses directo con el IRS, sin usar a PR como conducto. Pero de aprobarse éste embeleco, olvídense que lo que hay en PR es 100 años más de coloniaje.

2011-09-23T12:49:00.000-07:00

El que ACEPTE que lo traten como a un SÚBDITO COLONIAL en vez de como a un CIUDADANO, pues se merece los maltratos y las injusticias que le caigan encima.

- Yo
hoy.

Particles Found to Travel Faster than Speed of Light

2011-09-23T01:05:00.000-07:00

ésta noticia recorrió el mundo hoy ...

http://www.scientificamerican.com/article.cfm?id=particles-found-to-travel

This result is not yet conclusive. When something like this happens, a LOT of research, confirmation, requete-confirmation, attempts to duplicate results, etc. must be performed BEFORE they can conclude that those neutrinos were indeed moving at speeds higher than light.

If this observation turns out to be a true discovery, it may require a revision of relativity as it is known today. But most likely it will not overturn it completely. :-)

I am VERY rusty in my fundamental physics, so please forgive me if this opinion turns out to be nonsense X D

PS : if you are interested on reading the original paper where this came out, it's available HERE:

http://arxiv.org/ftp/arxiv/papers/1109/1109.4897.pdf

Aprendiendo de Otros

2011-09-16T19:11:00.000-07:00

Los puertorriqueños tienen que aprender de las luchas de otros.

Décadas atrás, cuando en los estados del Sur se les negaba irresponsablemente a los ciudadanos negros la igualdad de derechos, éstos no se dieron por vencidos. Ellos insistieron en su lucha pacífica, y lograron deslegitimizar el sistema segregacionista al punto de que se hizo social y políticamente insostenible para el gobierno mantenerlo. Gracias a su lucha consistente y firme, la segregación colapsó, y los negros lograron obtener la igualdad de derechos que la Constitución les garantiza.

El Estado Libre Asociado, ese embeleco injusto y criminal que mantiene a Puerto Rico sumido en el subdesarrollo y el tercermundismo colonial, no es otra cosa sino una forma moderna de Apartheid, de segregación étnica, que sobrevive mediante subterfugios y pretextos, para proteger los intereses económicos de unos pocos a expensas de los derechos y la prosperidad de la inmensa mayoría.

Es necesario deslegimizar el coloniaje en las esferas de poder politico, y en los medios de telecomunicación masiva de los 50 estados. Hay que insistir, fastidiar, jeringar, hasta que la existencia de ese sistema segregacionista, discriminador y criminal llamado “ELA” se convierta en un liability. Hay que deslegitimizar completamente el coloniaje, delatarlo como el grotesco engendro racista que es, hasta el punto en que nadie en el Congreso, ni en el poder Ejecutivo , ni en las multinacionales se atreva a apoyarlo nunca más.

Para eso es que se supone que en Puerto Rico existe un partido “estadista”. El PNP no debe esperar a que el status de Puerto Rico se convierta en un asunto de importancia para el Congreso; la responsabilidad de un partido estadista es HACER que el status de Puerto Rico se convierta en un asunto de importancia. La organización y ejecución de éste tipo de campaña de medios masiva para retratar al ELA como lo que realmente es debería ser trabajo de Luis Fortuño, Pedro Pierluisi, Kenneth McClintock, Thomas Rivera Schatz, Jennifer González, y el resto del liderato del PNP. El PNP debería pedir tiempo en cuanto programa de discusión política existe en las cadenas nacionales de television, marroneando el punto ad nauseaum ante cada pundit de la derecha y la izquierda.

Ganar un plebiscito no es la meta, es apenas el principio. Tal vez no se obtenga la estadidad aunque ésta gane un plebiscito de status con 49%, o aún con 52%. Pero una victoria plebiscitaria, con los números que sean, levantará el issue de una forma significativa en los medios nacionales. Entonces le tocará a todos esos que mencioné antes irse a chavar , jeringar y mantener el issue vivo hasta que se logre una resolución final.

Es por eso que había que realizar el plebiscito en 2009, y no esperar a tener 3 años de issues y peleas entremezclados con el issue del status.

Pero más vale tarde que nunca. El pueblo estadista debe presionar a su partido estadista para que realizen el plebiscito y para que NO DEJEN MORIR EL ISSUE después del resultado.

The Myth of Pedro Albizu Campos

2011-09-14T13:23:00.000-07:00

The Myth of Pedro Albizu Campos

by Raul Soto

November 9, 2000

[NOTE: Since a number of people have in the past expressed interest in using some posts for radio programs or other types of communications in the States, I'm sending this in English to save you all the trouble of translating it. ]

One of the most interesting things about today's 'independentismo' is its nationalistic streak, and their newly-found devotion to the figure of Pedro Albizu Campos. T-Shirts, posters, portraits, and quotes of Albizu are common in 'independentista' nazionalist rallies around the Island and in the US.

But how just much of what they say about Albizu is true, and how much is product of historical revisionism, of an attempt to manufacture a legend, a mythical hero, marthyr, prophet and leader, which can be used to rally together and unite the numerous pro-independence tribelets?

Here are some of the most common myths about Pedro Albizu Campos and some answers to them, from a conversation a statehooder friend of mine had with an Independentista professor from the UPR :

1. Albizu dedicated his life to be the lawyer of the workers and the poor

This is a lie. After 1937, Albizu spent most of his time perpetually in jail, not because he "dedicated his life to the poor", but because he was perpetually inciting those of weaker minds to violence.

2. Albizu was the President and Leader of one of the most influential political parties of his era

The Nationalist Party, contrary to this claim, was numerically tiny (just look at the 1932 election results, less than 4,000 votes). Of course, old Pete couldn't deal with the fact that *practically nobody* liked him. This, by the way, included INDEPENDENTISTAS themselves (think his color had to do something with that? Doesn't anybody find curious that all those lilly-white present-day "patriotas" who wouldn't be caught DEAD shaking the hand of a black man, give all these hellium-filled speeches about Albizu? I'll tell you why - because he's DEAD. If he were alive, Mari, Gallisá, Fufi Santori, Muriente, Farinacci, and yes, the little troika of Ruben, Fernando and Manuel wouldn't touch him with a ten foot pole). So dear old Pedro, after his crushing electoral defeat, decided to denounce the electoral process (talk about a sore loser).

I guess it all comes down to how one defines "influential". If by influental one means a small rabble of black-shirted (just like Mussolini's boys. Coincidence? Read on...) fanatics running amok and attempting to (and succeeding, as in the case of Riggs) murder anyone who disagrees with them (they even tried to off Santiago Iglesias, the labor leader, because he was pro-american), then I guess they might be 'influential'.

3. With his potential, his education, experience and proven intelligence, he could have been rich, successful, and maybe even challenge Luis Muñoz Marín for political power in the colony.

There's an old Aerosmith tune called "Dream On", and the title applies here. Albizu wouldn't have been elected dog catcher. Just ask any old geezer who lived through that era. Albizu was the kind of guy whose speeches are perhaps fun to listen (if you like screaming), but who scares the bejeezus out of people if the prospect of his gaining power became a reality.

Besides, he went to the polls only ONCE, and he got LESS than 4,000 votes. Some potential for political power...

4. Albizu decided to give his life, talents in the struggle for the freedom of Puerto Rico, when PR was threatened with the loss of its culture and "collective being" under the forced-americanization programs of the 20's and 30's

And instead, he was a sickening Hispanophile (funny, he wasn't into mentioning his African side) who even supported Franco, and before that, the Spanish Monarchy. Of course, all good fascists stick together.

Think about that, the grandson of people who were brought to the Island as SLAVES, under the lash and the most cruel conditions, and he supports the very regime that enslaved his family. Well, if statehooders are "pitiyankis", does that mean that Albizu was a "piticatalán" o "pitigallego"?

As for this "collective being" psychobabble: get real, we're all INDIVIDUALS. By the way, what happened to the Spaniards who populated the Island and then became Puerto Ricans, who took away their "collective being"? And why is it OK for that to have happened, but ANY kind of cultural influence from the US is not? And what about the Africans? You're not going to tell me that those folks were Catholic, ate rice and beans, and spoke Spanish in Ghana and Guinea, now are you? What happened to their "collective being"?

5. One can disagree with his rethoric and his methods, as the PIP did, and perhaps his personality, but no one can dismiss that he's a central figure in our history, because he directed a movement of people with the balls to risk their lives, families and property to fight for the freedom they thought was necessary

Hogwash. Albizu is a pimple in the history of Puerto Rico. He had NO popular support, his political thinking was profoundly FASCIST; he was also a conservative catholic who probably would have persecuted protestants, and he was NO FRIEND of labor, as you and the PIP would have us believe.

Remember what Albizu's solution to the cane workers' was during the strike of 1934-35? "Les daremos hombres de talla". As The Who put it: "Here's the new boss. Same as the old boss".

The quicker Albizu and his message of HATRED and DIVISION is relegated to the dustbin of history, the better off the Island will be. And, let's not forget, at his most violent, the PIP was the #2 party in Puerto Rico, poised to challenge the PPD for control of the Island. And just then Albizu and his yahoos decided to go for a coup d'etat. Ironic, ain't it? That the guy who spewed forth so much blather about independence is probably the guy responsible for hundreds of thousands of PRs turning AWAY from independence, and towards the USA? That's right, Albizu scared the hell out of people of that time. Incidentally, the Jayuya and Utuado fiasco is also where the independentistas got their "foaming at the mouth, bomb throwing, wild-eyed, raging lunatics" stereotype. If he had only let Concepción de Gracia and his guys do their stuff...

But no, as with all megalomaniacs, "I did it MY way"

6. We have to admire him for the same reasons that the world admires Washington, Bolívar, Sandino, Zapata, Mandela, Martin Luther Kind, José Martí, Maceo, San Martín and many others; because he decided to fight a clearly superior enemy, because he loved his people and wanted their freedom.

BS. It shows a remarkable lack of historical knowledge, or a serious ideological blindness, to say that. Unlike the men mentioned above, ALL of whom had MUCH MORE popular support than Albizu ever did, Albizu led a FASCIST movement (did you know what's the German word for Nationalist? NAZI). And you know what Fascism is all about, right? Well, we saw what it did in Europe during the 20's, 30's and 40's, right? And in Spain until the 70's. In fact, look at Milosevic, a good old nationalist if there ever was one. And this is to be admired???

And again, in 1948 the PIP got more than 22% of the vote. Why couldn't Albizu cooperate with them, his fellow independentistas? I'll tell you why, because his EGO got in the way. Funny, even TODAY, independentistas have more ego than camaraderie among themselves. Some things (and some people) never change.

Oh, and another thing: Fidel was in the Sierra Maestra with his troops. Washington was with his, crossing the Delaware. Bolivar put his own lands and his own money on the line to be with his troops. So did Mao during the "Long March". But WHERE was Albizu while his "troops" tried to take over Barrio Obrero, Jayuya and Utuado? Was he on the front, giving orders? Was he on a hand-to-hand battle against the oppressor or his colonial lackeys? NO! He was HIDING in an apartment in Old San Juan, and he came out naked, wrapped in a white towel, when the Police got him.

What a leader (not) !!!

7. He's worthy of an important place in the history of Puerto Rico and the Americas

I betcha if he were alive, YOU would be the first one to want him committed...

8. Statehooders say that Albizu was a terrorist. That's what the British said about Washington and his rebels, the Salvadorian oligarchy about the FMLN, Pinochet about Allende's people, Somoza and Batista about the guerrillas that confronted them, and so on. Each person should decide what his/her position in the political spectrum should be

The truth is that ALL those guys mentioned there had some measure of popular support, but Albizu? ONLY AFTER HE WAS SAFELY IN THE GRAVE. And even then it would be less than 3%.

Albizu is a freaking myth created by the pseudo-intellectual petit-burgeois of the ivory towers, so that they could have some hero to follow and to brainwash impressionable minds with some of that good ol' patriotic fervor.

But not to worry, PRs have more common sense than that.

9. If Albizu was so insignificant as statehooders desperately claim, then why even mention him? One doesn't waste a pixel to criticize a myth, unless of course one views him as a threat

Just because someone disparages Albizu doesn't mean that he's a threat. Besides, the guy's been safely dead for over 30 years; and, at last glance, other than the usual blather from the ivory tower independentista set, his movement (mind you, I'll be GENEROUS and include ALL the independentistas under the same tent, although how the Frente Socialista with its classic adherence to Marxist crud, and the Partido Nacionalista with its adherence to Fascist standards get together is beyond me) has NO POPULAR SUPPORT. So, some threat.

10. Every movement has its heroes, and one of the PR Independence Movement's heroes is Albizu, for his dedication and courage to put his life in the line for his beliefs and the independence of Puerto Rico

Did you know that one of the requirements to practice Law in Puerto Rico is to swear loyalty to the US Constitution? So there's your 'patriot', swearing loyalty to the supreme law of the supposed oppressor. Albizu did it; as casey Stengel said "You can look it up".

11. Say what you want, and spin your disdain for Albizu any way you like. The fact remains that Albizu, as a man, may have been as flawed as any man is. But as a symbol of independence, of sacrifice, of love of his country, he will never lose his place in our history and in our hearts,

I assume that you speak for yourself. To me, he is the symbol of fanaticism, of racist hatred, and of immature passion. A guy who could have contributed a lot, but instead he wasted his life away.

12. The myth has public streets named in his honor, books written about his life and struggles, monuments stand for his memory. These things stand in diametrical contradiction to your ravings, and place him in the realm of the Titans of our independence movement as José de Diego, Betances, etc.

So? That's precisely the point. He's a myth created by the pseudo-intellectual petit burgeois of the ivory towers; and the monuments, books, and everything else is done in order to manufacture a Puerto Rican Bolívar, or Washington.

De Diego? Wasn't he Central Aguirre's lawyer during the sugarcane worker's strike? See, that's the essential problem with the supposed "independentistas" (really, now, isn't the sad truth that most of you talk the talk, but when it's time to walk the walk you get the shivers and vote Popular?). On the one hand, a lot of this "patriotero" talk; but on the other hand, it's TOTAL adherence to the status quo. What did Jacobo Morales call it? Oh, yeah, "Patriotas de Cafetín"...

13. You are sadly mistaken when you state "Albizu is a fricking myth created by the pseudo-intellectual petit burgeois of the ivory towers"

Where's the proof behind your claim? The FACT is that Albizu only went to the polls ONCE, and got LESS THAN 4,000 VOTES. Is that what you call a leader? When he was in jail, the VAST MAJORITY of Puerto Ricans, including Independentistas, were totally in agreement. It is only NOW, that he is safely dead and harmless, that he is supposedly venerated. Why?

14. More accurately, he was a product of the military colonial establishment of the US and their policies to erase our existence as a distinct culture

Really? The first thing is that by 1901, there was a CIVILIAN government in PR. The very first in our history, since Albizu's beloved Spaniards had never seen it fit to permit PRs to be ruled by civilians. There was also a Legislature that enacted all of the local laws, another first for PR.

As far as "erasing our existence as a distinct culture", the fact is that just as the Spanish imposed their Castilian language on the Taínos and the Africans they brought here under the lash, the US attempted to teach English (let's not even get into the historical fact that the FIRST public school system in PR was also part of the benefits of US rule, the Spanish believed in keeping the majority of the population illiterate and ignorant). Funny, all the hullaballo about English in the schools and not a single peep about the cultural GENOCIDE the Spanish perpetrated against the Africans and Taínos.

Albizu was more of a product of an illegitimate birth by a white man (a Spaniard) who did NOT recognize him as his son until Albizu was an adult, and of the racism of his independentista peers. Of course, to admit that his OWN kind rejected him because he was black would be too big an admission, right? Better to reject "the invader" than to actually look at Puerto Rico's society for what it REALLY was, and to a large degree, continues to be.

15. Albizu was the manifestation of the Puerto Rican Nation immune system, in raising to the defense of its identity. Without colonial rule, there would have been no Albizu, no need of him

The problem with what you say is that you seem to believe that there is some kind of "collective thought process" going on. Perhaps the Borg are like that, but human beings, and certainly Puerto Ricans, are not. The fact is, of course, that we are ALL individuals, unique, each and every single one of us. I don't want to burst your bubble, but I betcha if you ask 100 people what a Puerto Rican is, or what is the "Puerto Rican nation", you're going to get 100 totally different answers.

Albizu was simply a man faced with tremendous racism, rejection by both the blanquito society in PR and the racist society up north (although, with all the racism, he DID manage to go to Darmouth and Harvard. That's one hell of a way to stamp someone out, isn't it? By letting them go to the most prestigious institutions you have? To this day, independentistas are the maximum beneficiaries of the system they so delight in condemning. I wonder what would happen if it really came down to crunch time?)

Faced with that, he goes into this fantasy world where under the Spanish (notice that his father was a Spaniard that never took care of him. One could easily conclude that Albizu's EXTREME Hispanophilia was simply the little boy in search for the father that never was) everything was all right and all Puerto Ricans were taken care of. A culturally homogeneous Puerto Rico, where everyone had the same values and so forth.

What folly! It was false then and it is false now. Which, I guess, is probably one of the prime reasons Albizu couldn't get much popular support then...

Triangulando

2011-09-14T11:56:00.000-07:00

TRIANGULANDO

http://www.elnuevodia.com/legislanobligatoriedaddereflectoresenlosvehiculosdemotor-1059855.html

Ésto es lo que hacen los LegisLadrones para tapar que no tienen ni perra idea de cómo mejorar las cosas en la Isla : añadir MÁS formas en que te puedan clavar con un boleto y tumbarte tu dinero.

El que te va a llevar enredao, te lleva enredao con o sin triangulito.

Eso sí, como bien dijo alguien ya, el importador de esos triangulitos va a vender de repente más de 1 MILLÓN de unidades, y se va a JARTAR de $$$.

¿Saben lo que SÍ DEBERÍA ser ley, pero no lo es en PR? Que exista un website como OpenSecrets.com donde el pueblo pueda ver QUIEN le dona dinero a cuál político, CUÁNTO y cuándo.

Así, por ejemplo, podríamos ver a cuáles políticos les dará $$$ el importador de los triangulitos :-)

Apartheid en el Caribe

2011-08-18T13:34:00.000-07:00

Apartheid en el Caribe

Ahora que el Gobernador Luis Fortuño ha anunciado la celebración de un plebiscito de status, es imperante educar a los puertorriqueños, particularmente a los estadistas, sobre lo que realmente es el ELA.

En las escuelas públicas nos metieron a todos en la cabeza los cuentos aquellos de que el ELA era un “status de avanzada”, “lo mejor de los dos mundos”, mezcla de Utopía y Disneylandia, la razón por la que no andamos en taparrabos comiendo piedras. Todavía hoy demasiada gente sigue creyéndoselo, aunque baste salir a la calle para ver que es mentira.

Pero si rebuscamos debajo de la retórica embrutecedora del Partido Popular, nos damos cuenta de que el principio fundamental tras el ELA es que como los puertorriqueños son “diferentes”, no pueden tener los mismos derechos y privilegios que los demás ciudadanos americanos. ¿Y de dónde salió una idea tan retrógrada? De la segregación.

La gente que se inventó el ELA durante la primera mitad del siglo 20 fueron los mismos racistas que validaron y enforzaron las leyes Jim Crow en el sur de EEUU, imponiéndole a los negros un status legal inferior, discriminatorio y racista – porque eran “diferentes”. El ELA salió de esa misma mentalidad - es un engendro racista, retrógrado, un tipo de apartheid y de segregación creado hace más de medio siglo para oficializar el discrimen contra los puertorriqueños. Por eso nuestros estudiantes, nuestros enfermos y nuestros ancianos reciben mucho menos dinero federal. El ELA significa MENOS becas, MENOS Seguro Social, MENOS Medicare. MENOS justicia.

Los EEUU comenzaron a dejar atrás esa etapa con el movimiento de derechos civiles en los 1960s, que culminó con la derogación de la segregación. Con la elección de un presidente de ascendencia africana, los EEUU han demostrado que la mayoría de la nación se zapateó de encima el demonio del racismo.

EXCEPTO en Puerto Rico.

Los negros lograron deslegitimizar la segregación. Hoy se considera algo tan inhumano y asqueante que apoyarla es políticamente insostenible, suicidio para cualquier politico. ¿Acaso el coloniaje que mantiene cuatro millones de puertorriqueños en un status de perpetua inferioridad política es menos inhumano y asqueante?

Ya es tiempo que el Comisionado Residente proclame a viva voz en el Congreso que el ELA es una verguenza inaceptable, una mancha racista sin lugar en una nación libre, democrática y progresista. Ya es tiempo de que el mundo vea al ELA como lo que es: una reliquia racista, un tipo de apartheid espantoso diseñado para segregar a los puertorriqueños en una reservación caribeña, con menos derechos y menos privilegios que los demás. El ELA colonial es una alternativa tan impensable en un plebiscito como la segregación.

Una vez se logre deslegitimizar al ELA, una vez lo desenmascaremos como el engendro racista que es, una vez congresistas a sueldo como Nydia Velazquez y Luis Gutiérrez dejen de a apoyarlo a cambio de dinero del PPD, ENTONCES Puerto Rico podrá finalmente decidir su futuro entre opciones reales: la estadidad, la independencia, y la libre asociación.

Rheumatoid Arthritis: Overview, Molecular Mechanisms and Biologics Treatments

2011-08-17T01:39:00.001-07:00

Rheumatoid Arthritis: Overview, Molecular Mechanisms and Biologics Treatments

Raul Soto-Velez^1, BSME

¹ MS Biotechnology and Bioinformatics program, California State University Channel Islands, Camarillo, California

Abstract

This paper presents an overview of rheumatoid arthritis, its demographics, and descriptions of the main molecular mechanism of disease and biochemical pathway. The main available treatments are discussed, with emphasis on biologicals. Finally, a new drug is proposed, and its mechanism of action, effect in the disease’s main molecular pathway, proposed delivery methods, formulation options, and cost estimates are described and discussed.

Keywords: rheumatoid arthritis · TNFα · interleukin · cytokines

Introduction

Rheumatoid arthritis (RA) is a chronic, systemic, progressive autoimmune disease [Choy, 2001][Dudler, 2011][Shin 2009][Hekmat, 2011], characterized by the symmetrical inflammation of the synovial lining of the small joints of the hands, wrists, feet, and knees [Rasch, et at. 2003] [Shiel, 2011]. It is the most common type of inflammatory arthritis [Firestein, 2003]. The disease ultimately leads to the destruction of the cartilage, erosion of the bone, and deformities in joints [Moreland 1999][Shin 2009]. At its most advanced stage, rheumatoid arthritis leads to loss of functionality of the joints [Dudler, 2011].

Various cell types are involved in the initiation and progression of rheumatoid arthritis, among them B cells [Bokarewa, 2007], T cells [Firestein, 2003], macrophages [Boilard 2010], mast cells [Shin, 2009], and platelets [Boilard 2011]. Various signaling molecules are also involved in the mechanisms of disease, including inflammatory and destructive mediators such as cytokines, prostaglandines, and metalloproteinases [Bresnihan, 1998].

Two cytokines in particular, tumor necrosis factor alpha (TNFα) and interleukin – 1 beta (IL-1β) have been found to be the main players in the biochemical pathways that cause inflammation and cell death in rheumatoid arthritis [Bresnihan, 1998]. Other cytokines involved in rheumatoid arthritis are interleukin-6, interleukin-10, interleukin-4 [Choy, 2001], and interleukin-17 [Chabaud, 1998][Kotake, 1999]. Other cytokines such as interleukin-23/17A are expressed in limited amounts in patients with advanced rheumatoid arthritis, but do not have a large role in the disease [Hillyer, 2009].

Demographics and Social Impact

Rheumatoid arthritis is the most common of all inflammatory arthritides [Lawrence, 2008]. It occurs in approximately 0.5 % – 1.0 % of the world’s population [Lundkvist, 2008], and in approximately 2% of people aged 60 or above [Rasch, 2003] in the United States.

Prevalence of rheumatoid arthritis appears to increase with age [Lundkvist, 2008]; in the United States, for people aged between sixty and sixty nine years, prevalence has been estimated to be between 1.59% - 1.89%; while for people aged sixty years or older, it has been estimated to be between 2.46% - 2.80% [Rasch, 2003].

Rheumatoid arthritis has significant social and personal costs [Choy, 2001]. Patient’s life expectancy is reduced by between three and eighteen years [Choy, 2001]. Presently there is no cure for rheumatoid arthritis [Choy, 2001] [Dudler 2011]. Within twenty years, 80% of rheumatoid arthritis patients are disabled and unable to work [Choy, 2001].

Genetic factors appear to have an important role in the susceptibility to rheumatoid arthritis, and a number of genes have been identified as related to the pathogenesis of the disease and as potential targets for treatments [Perricone, 2011]. In the United States, Mexican-Americans have a higher rate of rheumatoid arthritis that non-Hispanic whites, while African Americans have a lower rate [Rasch, 2003]. The prevalence of rheumatoid arthritis in women is approximately 150% higher than in men [Rasch, 2003].

The social and economic costs of rheumatoid arthritis have been estimated to be approximately 41.6 billion euros (US $59.94 billion) in the United States, and 45.30 billion euros (US $65.27 billion) in Europe [Lundkvist, 2008].

Diagnosis

A new classification criteria, which provides specific guidelines for the diagnosis of rheumatoid arthritis, was published in August 2010 [Kaneko, 2011].

A combination of various diagnostic methods is used to diagnose rheumatoid arthritis [Shiel, 2011]. Blood tests are typically done to perform immunological assays that detect the presence of antibodies associated with rheumatoid arthritis; such as rheumatoid factor (RF), antibodies to cyclic citrullinated peptides (anti-CCP) [Schellekens, et al, 2000], and antinuclear antibody (ANA) [Shiel, 2011]. Other blood tests commonly used in the diagnosis of rheumatoid arthritis are the elevated erythrocyte sedimentation rate (ESR) test; and testing for the presence of C-reactive protein, which correlates to inflammation in the body [Shiel, 2011].

Radiography (X-rays) is commonly used to follow the progress of the disease by monitoring the erosion of the joint bones and the inflammation of soft tissue in the joints [Shiel, 2011].

Magnetic resonance imaging (MRI) has also been investigated as a diagnostic tool for early detection rheumatoid arthritis [Suter, 2010]. Magnetic resonance imaging is able to detect erosion in the joint bones and inflammation in the synovium at an earlier stage than X-Rays [Suter, 2010].

Mechanism of Disease

Figure 1 shows a comparison of a healthy joint against a joint afflicted with rheumatoid arthritis.

The inflammatory process is normally regulated by mediators that initiate the inflammatory response and mediators that inhibit it [Choy 2001]. In rheumatoid arthritis patients these regulators are not balanced, which allows an increase in inflammation that leads to tissue damage and destruction [Choy 2001].

In a normal, healthy joint, a layer of cartilage tissue covers and protects the ends of the bones, surrounded by a synovial membrane which consists of a layer one or two cells thick [Choy, 2001] and which holds the synovial fluid that lubricates and nurtures cartilage tissue [Lee, 2007].

In a joint with early rheumatoid arthritis, the synovial membrane becomes inflammated and thickens due to hyperplasia and hypertrophy of the cells that line the synovium, and begins to invade the cartilage tissue [Choy, 2001]. The synovial membrane is infiltrated by T cells and B cells [Choy, 2001].

When rheumatoid arthritis reaches a more advanced (established) state, the inflammated synovial tissue becomes the pannus, inflammatory tissue that invades and destroys the bone and cartilage in the joint [Choy, 2001].

Figure 1: Pathogenesis of Rheumatoid Arthritis (Choy 2001)

It is not yet known what triggers the immune response that causes the body’s antibodies to attack the cartilage and the synovial membrane [Shiel, 2011]. It is known, however, that increased expression of inflammatory cytokines such as TNF α, IL-1, IL-6, and others has a key role in the inflammatory response and tissue destruction elements of the disease [Egan, 2003].

The mechanisms that control the secretion of cytokines are not completely known [Chaofeng, 2009]. Lymphocytes are attracted to the site where antibodies attack the joint tissues, where they differentiate into macrophages and release cytokines such as tumor necrosis factor α (TNF α), interleukin-1 (IL-1), and interleukin-6 (IL-6) [Shiel, 2011].

TNFα increases the expression of adhesion molecules in endothelial cells, which in turn recruits additional immune cells to the site of the attack, amplifying the immune response [Choy, 2001] [Shiel, 2011]. IL-1 and IL-6 act as signaling molecules, also recruiting more immune cells to the afflicted area [Choy, 2001]. IL-1 is an important mediator of the autoimmune response, bone resorption and cartilage damage in rheumatoid arthritis, although it is not a major mediator in inflammation or joint swelling [Schiff, 2000]. Exposure to IL-1 and TNFα stimulates the expression of IL-6, another inflammatory cytokine [Ishimi, 1990] [Palmqvist, 2002] [Palmqvist, 2008]. TNFα and IL-1β regulate gene expression in microphages and in fibroblast-like synoviocytes, stimulating the expression of cytokines such as IL-6, IL-8, while reducing the expression of IL-17 [Mi Choi, 2010]. The combined effect of all these factors increases the joint damage caused by the degradation of connective tissue [Choy, 2001].

Elevated levels of TNF α and IL-1β have also been found to induce osteoporosis in rheumatoid arthritis patients by up-regulating the apoptosis of osteoblasts [Tsuboi, 1999]. Elevated levels of cytokines such as TNF α and IL-1β have also been linked to Alzheimer’s disease [Tobinick 2008], recurrent ovarian cancer [Madhusudan, 2005], and autoimmune thyroid diseases [Wang, 2007].

In addition to cytokines and monocytes, platelets have also been shown to have a role in rheumatoid arthritis [Boilard 2010]. The regulated synthesis of interleukin 1β by activated platelets mediates inflammatory signaling [Lindemann, 2001]. Adhesion of platelets-neutrophil complexes in vivo contributes to acute inflammatory responses [Kornerup, 2010]. Platelet microparticles, which are submicrometer vesicles generated by activated platelets, have been found to induce the secretion of cytokines such as IL-1 by synovial fibroblasts [Boilard 2010]. Platelet-polymorphonuclear neutrophil (PMN) adhesion has been shown to contribute to inflammation [Pastakia, 1996]. The production of microparticles from the platelet membrane is activated via the collagen receptor GPVI [Boilard 2011]. In rheumatoid arthritis patients, high levels of microparticles in the synovial fluid stimulate the production of IL-1, thus increasing joint inflammation [Boilard 2011]. Research has shown that a raised platelet count is correlated to rheumatoid arthritis [Farr, 1983] and that this can be used to create functional assays that monitor disease activity [Gyorgy, 2011].

Platelets can also induce inflammatory responses in the synovial membrane of the joints in rheumatoid arthritis patients by a separate pathway that does not involve microparticles [Boilard, 2011]. Platelets interact with collagen and become activated by means of the platelet collagen receptor Glycoprotein IV [Smethurst, 2006]. Activated platelets express cyclooxygenase-1 (COX-1), which increases the paracrine production of prostacyclin in fibroblast-like cells called synoviocytes [Boilard, 2011].

The TNFα / NF-kB Biochemical Pathway

Tumor Necrosis Factor alpha (TNFα), a cytokine secreted by macrophages and monocytes, has been found to mediate the inflammatory response and the activation of apoptosis in cells in rheumatoid arthritis, among other diseases [Chen, 2002][ Baumgartner, 2000]. In rheumatoid arthritis patients, high levels of TNFα can be found in the synovial fluid, synovial tissue, and in the cartilage-pannus junction [Baumgartner, 2000]. IL-1 release triggered by TNFα has been linked experimentally to decreases in patient’s cognitive abilities [Terrando, 2010].

It is known that cytokines binding to transmembrane receptors causes an increase of tyrosine phosphorylation, which in turn triggers the activation of signal transduction pathways [Bracke, 1998]. TNFα interacts with two membrane-bound receptors, TNF-R1 and TNF-R2, with TNF-R1 being the one involved in the most important biochemical pathway for rheumatoid arthritis, the TNFα / NF-kB signal transduction pathway [Chen, 2002][Locksley, 2001].

When TNFα binds to TNF-R1, it activates a signal transduction pathway that leads to the activation of transcription factors NF-kB and c-Jun, which are involved in the transcription of genes related to cell death, immunological and inflammatory responses, and cancer, among others (Chen, 2002). Figure 2 illustrates the signal transduction pathway for TNFα / NF-kB.

When TNFα binds to the TNF-R1 membrane-bound receptor, the intra-cellular domain of the TNF-R1 receptor releases the SODD (silencer of death domain) inhibitory protein [Chen, 2002]. When this happens, the TNF receptor-associated death domain (TRADD) recognizes the change in the intra-cellular domain of TNF-R1 and recruits adaptor proteins such as receptor-interacting proteins (RIP), which is a protein kinase; TNF-R-associated factor 2 (TRAF2); and Fas-associated death domain (FADD)[Chen, 2002] [Locksley, 2001].

RIP, TRAF2 and FADD in turn recruit enzymes to the intracellular domain of TNF-R1 in order to initiate the signaling cascade [Chen, 2002]. FADD recruits caspase-8, TRAF2 recruits cIAP-1 and CIAP-2, and activates a cascade of kinases that results in the phosphorylation and activation of c-Jun [Chen, 2002].

NF-kB is normally found bound to inhibitor IkB proteins in the cytoplasm, which maintains it inactive [Chen, 2002]. The kinase cascade that phosphorylates and activates c-Jun also causes the phosphorylation and activation of the IKK (IkB kinase) complex, which mediates the phosphorylation of IkB proteins; this in turn causes IkB to disassociate from NF-kB [Chen, 2002]. Once NF-kB is separated from IkB, it becomes activated, and translocated into the nucleus of the cell, where it recruits other transcription factors and expresses genes related to apoptosis (cell death) and the inflammatory response [Chen, 2002].

Figure 2: TNFα / NF-kB signal transduction pathway (Chen, 2002)

NF-kB triggers the inflammatory response by promoting the transcription of genes that express inflammatory cytokines such as interleukin-1 (IL-1a and IL-β) [Dinarello, 1996]. IL-1 activates T-cells and enhances the proliferation of fibroblasts, which in turn causes the formation of the pannus and contributes to the destruction of bone, cartilage and joint tissues [Furst, 2004].

Other Relevant Pathways

Inhibiting the action of TNFα and IL-1 suppresses the symptoms of rheumatoid arthritis in many patients; however, in a large percentage of patients symptoms persist, indicating that there are alternate pathways involved in the mechanism of the disease [Walker, 2005]. In addition to the two platelet-related mechanisms mentioned previously, another pathway that has been proposed and investigated is the Jak-STAT signal transduction pathway [Walker, 2005].

Treatment of Rheumatoid Arthritis

The main purpose of pharmacological treatments for rheumatoid arthritis is to prevent joint damage, reduce the inflammatory response, and improve joint function [Hekmat, 2011].

There are three fundamental ways of inhibiting the biochemical pathways that trigger tissue inflammation and cell apoptosis: neutralizing the action of inflammatory cytokines (keep them from binding with their corresponding transmembrane receptors by binding the cytokines with a soluble receptor, a monoclonal antibody, or a natural antagonist), blocking the transmembrane receptors for inflammatory cytokines (use a receptor antagonist or a monoclonal antibody to bind to the receptor and blocking the cytokine from binding), and activating pathways that will express anti-inflammatory cytokines such as IL-4 or IL-10, which inhibit the expression of inflammatory cytokines [Chen, 2002].

On in-vitro studies performed on synovial cells from rheumatoid arthritis patients, inhibiting the action of TNFα had the effect of reducing the production of cytokines associated with inflammatory responses, such as IL-1, IL-6, and IL-8, among others [Chen, 2002]. This key role of TNFα makes it a prime target for drugs that inhibit its effect [Chen, 2002]. The TNF-R2 receptor fused with the human IgG1 Fc region has also been used to treat rheumatoid arthritis, but it is not as effective as other antibodies against cells with TNF on the cell surface [Nagashima 2011].

There are three main types of drugs used to treat rheumatoid arthritis: NSAIDs, DMARDs, and biologics [Shiel, 2011]. These are frequently used in combinations for best effect [Shiel, 2011]. In this paper, we will provide a general description of NSAIDs and DMARDs, and will focus on biologics and their mechanisms of action at the molecular level. This paper will further focus on the four biologic treatments most widely used against rheumatoid arthritis: Enbrel (Etanecerpt), Humira (Adalimumab), Kineret (Anakinra), and Remicade (Infliximab) [Cush, 2010].

NSAIDS

The first class of drugs used to treat rheumatoid arthritis are Non Specific Anti-Inflammation Drugs (NSAIDs) [Shiel , 2011]. NSAIDs are fast-acting drugs that treat the symptoms of rheumatoid arthritis such as pain, swelling, and inflammation [Shiel, 2011]. NSAIDs do not alter the course of the disease or slow down the progression of joint destruction [Shiel, 2011].

NSAIDs act as cyclooxygenase (Cox-1 and Cox-2) inhibitors [Silverstein, 2000]. These cyclooxygenase enzymes play a key role in the production of prostaglandines; by inhibiting their actions, NSAIDs reduce swelling and pain [Silverstein, 2000]. Cox-1 inhibition also causes gastrointestinal toxic effects, such as ulcers [Silverstein, 2000]. Celecoxib, which is a Cox-2- specific inhibitor, has been shown experimentally to cause lower gastrointestinal toxic effects than ibuprofen [Silverstein, 2000]. Table 1 lists the most commonly used NSAIDs.

NSAIDs
Generic name	Commercial Name
Acetylsalicylate	Aspirin
Naproxen	Naprosyn
Ibuprofen	Advil, Medipren, Motrin
Etodolac	Lodine
Cox-2 inhibitors, such as Celecoxib	Celebrex

Table 1 : NSAIDs used in the treatment of rheumatoid arthritis (Shiel, 2011)

DMARDS

The second class of drugs used to treat rheumatoid arthritis are Disease Modifying Anti Rheumatoid Drugs (DMARD) [Shiel, 2011]. DMARDs slow down the progression of the disease, but they act slower than NSAIDs; their effect becomes observable weeks or months after the patient starts to take them [Shiel, 2011]. Table 2 lists the most commonly used DMARDs.

A research study performed by Mottonen, et al [1999] compared combination therapies consisting of various DMARDs such as sulphasalazine, methotrexate, hydroxy-chloroquine, and prednisolone, against a single-drug therapy. Combination therapy showed significant improvements in swollen joint count over the single-drug treatment [Mottonen, 1999]. In some patients, however, DMARDs do not attain satisfactory responses due to toxicity [Moreland, 1999].

Another research study, performed by Cohen [2001] compared the effects of treating rheumatoid arthritis with leflunomide against the effects using methotrexate, in a two-year-long, randomized, controlled clinical trial. Both treatments slowed down the progression of the disease, with leflunomide showing better results than methotrexate [Cohen, 2001].

A more recent research study performed by DeStefano [2010] compared combination therapies of leflunomide plus an anti-TNFα biologic against methotrexate plus an anti- TNFα biologic. The study shows that both DMARDs can be used safely in combination with anti- TNFα biologics [DeStefano, 2010].

DMARDs
Generic name	Commercial Name
Hydroxychloroquine	Plaquenil
Sulfasalazine	Azulfidine
Leflunomide	Arava
Gold salts such as Gold thioglucose Gold thiomalate Oral gold, auranofin	Solganal Myochrysine Ridaura
D-penicillamine	Depen, Cuprimine
methotrexate	Trexall
azathioprine	Imuran
cyclophosphamide	Cytoxan
chlorambucil	Leukeran
cyclosporine	Sandimmune

Table 2 : DMARDs used in the treatment of rheumatoid arthritis (Shiel, 2011)

Biologic treatments for Rheumatoid Arthritis

A third class of drugs used to treat rheumatoid arthritis are Biologics. While DMARDs are non-specific anti-inflammation drugs that target the immune system in a general way [Shiel, 2011], most biologics target specific cell surface markers or specific signaling molecules to inhibit their action and prevent the triggering of biochemical pathways that lead to inflammation responses and apoptosis [Rasheed 2008]. Table 3 lists various biologic drugs used to treat rheumatoid arthritis.

The current treatment approach is to combine use of DMARDs and biologics at the early stages of the disease to achieve complete remission [Dudler, 2011]. Klareskog [2004] compared a combined treatment of rheumatoid arthritis patients using etanercept and methotrexate (DMARD) against treatment with each alone, using a double-blind randomized trial. The combined treatment reduced symptoms, improved patient’s functional disabilities, and slowed down the disease’s progression. [Klareskog, 2004].

Biologics
Generic name	Commercial Name
Etanercept	Enbrel
Infliximab	Remicade
Anakinra	Kineret
Adalimumab	Humira
Rituximab	Rituxan
Abatacept	Orencia
Golimumab	Simponi
Certolizumab pegol	Cimzia
Tocilizumab	Actemra

Table 3 : Biologics used in the treatment of rheumatoid arthritis (Cush, 2010)

A study performed by Graudal, et al [2010] in the Netherlands showed that biologics, glucocorticoids, DMARDs, and combined agents had similar effects on patients after one year of treatment; which led these researchers to recommend that biologics should be used only for patients that are not responsive to DMARDs treatments [Graudal, 2010].

Combination therapy using multiple biologic drugs has not demonstrated any synergistic effects; in a study that combined the use of Etanercept, a TNFα inhibitor, with Anakinra, an IL-1 inhibitor, patients did not gain any additional benefits, while the risk of serious infections increased significantly [Genovese, 2004].

As mentioned previously, this paper will focus on the four biologic treatments most widely used against rheumatoid arthritis: Enbrel (Etanecerpt), Humira (Adalimumab), Kineret (Anakinra), and Remicade (Infliximab) [Cush, 2010].

Etanercept (Enbrel)

Etanercept , which is sold under the commercial name Enbrel, is a recombinant dimeric fusion protein, which combines the human gene for the extracellular ligand-binding domain of two human soluble TNFα type-II receptors with the gene for the Fc (fragment crystallizable) component of human immunoglobulin G1 (IgG1) [Tobinick 2008] [Wikipedia: Etanercept, 2011]. It inhibits TNFα by binding to it, which prevents it from binding to transmembrane receptors [Cush, 2010]. It has a half life of 5 days [Cush, 2010]. Effects on most patients can be seen 2 - 4 weeks after the treatment begins [Cush, 2010]. Figure 3 shows how soluble receptors such as Enbrel bind to cytokines to inhibit their action.

The most common adverse effects observed in Enbrel patients are injection site reactions such as skin irritation, and upper respiratory infections such as cold, sinusitis, or bronchitis [Cush, 2010]. Less common adverse effects observed are bacterial infections, optic neuritis, multiple sclerosis, nerve disorders, and heart failure [Cush, 2010].

Figure 3: Inhibition of Cytokines by binding with monoclonal antibodies or soluble receptors (Choy, 2001).

Enbrel is administered by subcutaneous injection, once or twice per week [Cush, 2010]. FDA prescription guidelines do not require using methotrexate along with Enbrel [Cush, 2010]. The dose is 50 mg weekly, or 25 mg twice per week [Cush, 2010]. The estimated annual cost of treatment is $15,436 [Cush, 2010].

In clinical trials, Enbrel has been shown to reduce symptoms of rheumatoid arthritis, to slow down the progression of joint damage, and to improve the general quality of life in patients [Moreland, 1999][Haraoui 2007]. A clinical trial was performed by Johnsen, et al [2006] to determine the effects of a dosing regimen of 50 mg twice weekly, twice the current regime. No increase in effect or benefits to patients were observed at the higher dose, when compared to the current dose [Johnsen, 2006].

Etanercept has also been evaluated as a treatment for Alzheimer’s disease [Tobinick 2008] and recurrent ovarian cancer [Madhusudan, 2005]. Excessive amounts of TNFα, which has been found to regulate synaptic functions in neural networks, have been linked to Alzheimer’s disease [Tobinick 2006]. Alzheimer’s patients treated with Enbrel showed rapid cognitive improvements within minutes of receiving the drug [Tobinick 2008]. TNFα , as a major mediator of inflammation, is produced chronically in ovarian tumors, and the increase in cytokine production triggered by TNFα is believed to assist in tumor growth [Madhusudan, 2005]. The Madhusudan study found evidence of biological activity of etanercept against ovarian cancer, and recommended further research [Madhusudan, 2005].

Adalimumab (Humira)

Adalimumab , which is sold under the commercial name Humira, is a fully-human monoclonal antibody [Wikipedia: Adalimumab, 2011] that binds to TNFα and inhibits it from binding to transmembrane receptors. [Cush, 2010]. It has a half life of 12-14 days [Cush, 2010]. Effects on most patients can be seen 2 - 4 weeks after the treatment begins [Cush, 2010]. Figure 3 shows how monoclonal antibodies bind to cytokines to inhibit their action.

The most common adverse effects observed in Humira patients are similar to those observed in Enbrel patients: injection site reactions such as skin irritation, and upper respiratory infections such as cold, sinusitis, or bronchitis [Cush, 2010]. Less common adverse effects observed are bacterial infections, optic neuritis, multiple sclerosis, nerve disorders, and heart failure [Cush, 2010].

Humira is administered by subcutaneous injection, every other week [Cush, 2010]. FDA prescription guidelines suggest using methotrexate along with Humira [Cush, 2010]. The dose is 40 mg once every two weeks[Cush, 2010]. The estimated annual cost of treatment is $14,522 [Cush, 2010].

In clinical trials, Adalimumab has been shown to be safe and effective in the treatment of rheumatoid arthritis and other inflammatory conditions both in monotherapy [van de Putte, 2003], and in combination therapy with methotrexate [Breedveld, 2006][Weinblatt, 2003]. Combination therapy was found to be more effective than monotherapy [Breedveld, 2006].

Anakinra (Kineret)

Anakinra, which is sold under the commercial name Kineret, is a receptor antagonist [Wikipedia: Anakinra, 2011] [Furst, 2004] that inhibits the effect of Interleukin-1 (IL-1) by competitively inhibiting the binding of IL-1 to the IL-1 transmembrane receptors [Schiff, 2000][Cush, 2010]. It has a half life of 6 hours [Cush, 2010]. Effects on most patients can be seen 4 - 6 weeks after the treatment begins [Cush, 2010]. Figure 4 shows how receptor antagonists such as Anakinra bind to transmembrane receptors to inhibit the action of cytokines.

The most common adverse effects observed in Kineret patients are similar to those observed in Enbrel and Humira patients: injection site reactions such as skin irritation, and upper respiratory infections such as cold, sinusitis, or bronchitis [Cush, 2010]. Headaches are also a common adverse effect of Kineret, not observed in other biologics [Cush, 2010]. Less common adverse effects observed are pneumonia, skin or joint infections, and very low white blood cell counts [Cush, 2010].

Kineret is administered by subcutaneous injection, daily [Cush, 2010]. FDA prescription guidelines do not require using methotrexate along with Kineret [Cush, 2010]. The dose is 100 mg daily [Cush, 2010]. The estimated annual cost of treatment is $12,800 [Cush, 2010].

Figure 4: Blocking of transmembrane receptors by binding with monoclonal antibodies or receptor antagonists (Choy, 2001)

In clinical trials, Anakinra has been shown to be mildly to moderately effective in reducing symptoms of active rheumatoid arthritis in patients, both in monotherapy [Fleischmann, 2003] and combined with methotrexate [Furst, 2004].

Infliximab (Remicade)

Infliximab, which is sold under the commercial name Remicade, is a mouse-human chimeric antibody [Wikipedia: Remicade, 2011] that inhibits the action of TNFα by binding to it [Cush, 2010]. It has a half life of 9 days [Cush, 2010]. Effects on most patients can be seen 2 - 4 weeks after the treatment begins [Cush, 2010]. Figure 3 shows how monoclonal antibodies bind to cytokines to inhibit their action.

The most common adverse effects observed in Remicade patients are infusion reactions such as itching, rash, nausea, and headaches; and upper respiratory infections such as cold, bronchitis, and sinusitis [Cush, 2010]. Less common adverse effects observed are anaphylaxis; opportunistic bacterial infections such as pneumonia or joint infections; tuberculosis; fungal infections; nerve disorders such as optic neuritis and multiple sclerosis; and worsening of heart failure [Cush, 2010].

Unlike Enbrel, Kineret or Humira, which are self-administered by subcutaneous injection, Remicade is administered by intravenous infusion in the clinic or doctor's office, every 8 weeks [Cush, 2010]. FDA prescription guidelines require using methotrexate along with Remicade [Cush, 2010]. The initial dose is 3 - 5 mg/kg at weeks 0, 2, and 6; and if necessary this dose can be increased to 5 - 10 mg/kg [Cush, 2010]. Maintenance doses are required every 4 - 8 weeks [Cush, 2010]. The estimated annual cost of treatment is between $13,940 and $30,287 [Cush, 2010].

Clinical trials have compared monotherapy with Infliximab against monotherapy with methotrexate, and against a combined therapy of both Infliximab and methotrexate [StClair, 2004][Maini, 1998]. It was found that the combined therapy is more effective than monotherapy with either drug alone [StClair, 2004] [Maini, 1998]. However, other studies in Infliximab patients showed poor response, prompting the physicians to switch patients to other treatments [Mori 2011].

Investigational Drugs

According to ClinicalTrials.gov, a website maintained by the National Institutes of Health (NIH), there are eleven drugs for the treatment of rheumatoid arthritis currently undergoing clinical trials; as shown in Table 4.

Drug	Sponsor	Stage
CP-690,550	Pfizer	III
Biological: Certolizumab Pegol	UCB i	III
PPAR-Gamma Agonists	University of Michigan / NIH	III
Ocrelizumab	Roche	III
CRx-102	CombinatoRx	II
Apremilast	Baylor Research Institute	II
SCIO-469	Scios, Inc.	II
Tranilast	Imperial College London	I
ACZ885 Canakinumab	Novartis	I
SBI-087	Wyeth	I
Cura-100	Cura Biotech LLC	I

Table 4 : Rheumatoid drugs currently in clinical trials

Proposed Drug

Laliumab, which will be sold under the commercial name Jazireum®, is a fully human monoclonal antibody that treats autoimmune disease by blocking the active site of the Tumor Necrosis Factor Receptor-1 (TNF-R1) transmembrane protein. Figure 5 shows a computer rendition of the Lalitumab protein molecule model, obtained using X-Ray crystallography, WinCoot, and Swiss PDB Viewer.

Figure 5: Laliumab (Jazireum®), a fully human monoclonal antibody
(source: http://mimetibody.com/)

Mechanism of Action

Laliumab disrupts the interaction between TNFα and the TNF-R1 transmembrane receptor by blocking the active site of the receptor, and thus inhibiting TNFα from binding. By binding competitively with the TNF-R1 receptor (Figure 6), Laliumab prevents the formation of the TNFα-TNF R1 complex, and this in turn prevents the triggering of the pathway which produces cell necrosis and inflammation in rheumatoid arthritis and other autoimmune diseases.

Adverse Events

As with other anti-TNFα biologics, the main adverse events associated with Laliumab are injection site reactions such as irritated skin, and opportunistic infections in the respiratory tract, such as cold, sinusitis, and bronchitis.

Less common adverse events are also similar to those caused by other anti- TNFα biologics: opportunistic bacterial infections; nerve disorders such as seizures, multiple sclerosis, and eye nerve inflammation; psoriasis; allergic reactions; autoimmune reactions; and heart failure.

Formulation, Dose, and Cost Estimate

Laliumab is self-administered by subcutaneous injection. It is available in two dosage options: a 50 mg/mL autoinjector, and a 50 mg single-use prefilled syringe.

Laliumab has a half-life of approximately 12-14 days. Most patients will begin to feel effects within 2 – 4 weeks after the start of the treatment. FDA prescription guidelines suggest using Laliumab along with methotrexate for optimal effect. The estimated annual cost of treatment is $15,000.

Figure 6: Laliumab blocks the action of TNFaby binding to the TNF-R1 receptor active site

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15. Furst D. Anakinra: Recombinant Human Interleukin-1 Receptor Antagonist in the Treatment of Rheumatoid Arthritis. Clinical Therapeutics 2004; 26(12):1960-1975.

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20. Hillyer P, et al. Investigating the Role of the Interleukin-23/17A axis in rheumatoid arthritis. Rheumatology 2009; 48: 1581-1589.

21. Ishimi Y, et al. IL-6 is Produced by Osteoblasts and Induces Bone Resorption. J Immunol 1990; 145(10); 3297-3303.

22. Johnsen A, et al. Comparison of 2 Doses of Etanercept (50 vs 100 mg) in Active Rheumatoid Arthritis: A Randomized Double Blind Study. J Rheumatol 2006;33;659-664.

23. Kaneko Y, et al. Sensitivity and Specificity of 2010 rheumatoid arthritis classification criteria. Rheumatology. 2011.1093.

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25. Kornerup K, et al. Circulating Platelet-Neutrophil Complexes are Important for Subsequent Neutrophil Activation and Migration. J Appl Physiol 109: 758–767, 2010.

26. Kotake S, et al. IL-17 in Synovial Fluids from Patients with Rheumatoid Arthritis is a Potent Stimulator of Osteoclastogenesis. J. Clin. Invest. 103:1345–1352 (1999).

27. Lee D, et al. Cadherin-11 in Synovial Lining Formation and Pathology in Arthritis. Science. February 2007; 315:1006-1010.

28. Lindemann S, et al. Activated Platelets Mediate Inflammatory Signaling by Regulated Interleukin-1β Synthesis. Journal of Cell Biology. August 2001; 154(3):485–490.

29. Lundkvist J, et al. The Burden of Rheumatoid Arthritis and Access to Treatment: Health Burden and Costs. Eur J Health Econ. 2008; 8 (Suppl 2):S49–S60.

30. Madhusudan S, et al. Study of Etanercept, a Tumor Necrosis Factor-Alpha Inhibitor, in Recurrent Ovarian Cancer. J Clin Oncol 23(25):5950-5959.

31. Maini R, et al. Therapeutic Efficacy of Multiple Intravenous Infusions of Anti-Tumor Necrosis Factor a Monoclonal Antibody Combined with Low-Dose Weekly Methotrexate in Rheumatoid Arthritis. Arthritis & Rheumatism. 1998; 41(9); 1552-1563.

32. Mi Choi H, et al. Differential effect of IL-1β and TNF-α on the production of IL-6, IL-8 and PGE2 in Fibroblast-like synoviocytes and THP-1 macrophages. Rheumatol Int. 2010;30:1025–1033.

33. Moreland L, et al. Treatment of Rheumatoid Arthritis with a Recombinant Human Tumor Necrosis Factor Receptor (p75)-Fc Fusion Protein. The New England Journal of Medicine. 1997; 337(3): 141-147.

34. Moreland L, et al. Etanercept Therapy in Rheumatoid Arthritis. Ann Intern Med. 1999;130:478-486.

35. Mori S & Yukitaka U. Primary Lack of Efficacy of Infliximab Therapy for Rheumatoid Arthritis: Pharmacokinetic Characterization and Assessment of Switching to Tocilizumab. Mod Rheumatol. 2011. 10:1007.

36. Mottonen T, et al. Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. The Lancet. 1999; 353; 1568-1573.

37. Nagashima H, et al. TNF Receptor II Fusion Protein with Tandemly Repeated Fc Domains. J Biochem. 2011; 149 (3): 337-346.

38. Palmqvist P, et al. IL-6, Leukemia Inhibitory Factor, and Oncostatis M Stimulate Bone Resorption and Regulate the Expression of Receptor Activator of NF-kB Ligand, Osteoprotegerin, and Receptor Activator of NF-kB in Mouse Calvarie. J Immunol 2002; 169; 3353-3362.

39. Palmqvist P, et al. IL-1β and TNFα Regulate IL-6-type Cytokines in Gingival Fibroblasts. Journal of Dental Research 2008; 87; 558-563.

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41. Rasch E, et al. Prevalence of Rheumatoid Arthritis in Persons 60 Years of Age and Older in the United States. Arthritis & Rheumatism. 2003; 48(4); 917–926.

42. Schellekens G, et al. The Diagnostic Properties of Rheumatoid Arthritis Antibodies Recognizing a Cyclic Citrullinated Peptide. Arthritis & Rheumatism. January 2000; 43(1); 155–163.

43. Schiff M. Role of Interleukin 1 and Interleukin 1 Receptor Antagonist in the Mediation of Rheumatoid Arthritis. Ann Rheum Dis 2000;59(suppl I):i103–i108.

44. Shin K, et al. Mast Cells Contribute to Autoimmune Inflammatory Arthritis via their Tryptase / Heparin Complexes. J Immunol 2009;182;647-656.

45. Silverstein F, et al. Nonsteroidal Anti-Inflammatory Drugs for Osteoarthritis and Rheumatoid Arthritis: The CLASS Study, a Randomized Controlled Trial. JAMA September 2000; 284(10); 1247-1255.

46. Smethurst P. Structural Basis for the Platelet-Collagen Interaction. J Biol. Chem 2007; 282(2); 1296–1304.

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48. Suter L, et al. Role of Magnetic Resonance Imaging in the Diagnosis and Prognosis of Rheumatoid Arthritis. Arthritis Care & Research. May 2011; 63(5); 675-688.

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Review Articles

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3. Choy E, Panayi G, Cytokine Pathways and Joint Inflammation in Rheumatoid Arthritis. N Engl J Med. March 2001; 344.12:907-915

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13. Walker J and Smith M. The Jak-STAT pathway in rheumatoid arthritis. J Rheumatol 2005;32;1650-1653.

Websites

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http://en.wikipedia.org/wiki/Anakinra
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http://clinicaltrials.gov

Accessed: 05 May 2011.

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Recent discoveries on genetic factors related to Attention - Deficit / Hyperactivity Disorder (ADHD)

2011-08-17T01:02:00.000-07:00

Recent discoveries on genetic factors related to Attention - Deficit / Hyperactivity Disorder (ADHD)

Raul Soto-Velez

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a behavioral childhood condition with neurological and genetic basis [Purper-Ouaki et al, 2010]. Its behavioral and cognitive symptoms, such as lack of concentration, difficulties with self control, impulsiveness, and motor hyperactivity, often have a negative impact in the child’s social development and ability [Stergiakouli et al, 2010]. These symptoms often persist into adulthood [Purper-Ouaki et al, 2010].

Genetic factors are part of ADHD’s multifactorial, heterogeneous etiology [Purper-Ouaki et al, 2010]. Studies with monozygotic and dizygotic twins pairs, and adopted siblings have shown that ADHD is highly heritable (0.76) [Thakur et al, 2010; Stergiakouli et al, 2010].

This paper presents some of the most recent research findings related to some of the genetic factors affecting Attention-Deficit / Hyperactivity Disorder (ADHD) and its treatment.

Relationship between a SLC6A4 gene polymorphism and response to methylphenidate (MPH) in ADHD patients [Thakur et al, 2010]

The purpose of this study [Thakur et al, 2010] was to investigate the relationship, if any, between a polymorphism in the SLC6A4 gene and the patient’s behavioral responses to methylphenidate. SLC6A4 is the gene that encodes the serotonin transporter protein.

Methylphenidate (MPH) can reduce ADHD symptoms in children by as much as 70% [Kim et al, 2010]. Methylphenidate is believed to work by modulating dopamine and serotonin transmission in the patient’s brain [Thakur et al, 2010].

In the SLC6A4 gene’s promoter region, the polymorphism is composed of three alleles: s (short), l_A (long A) and l_G (long G) [Thakur et al, 2010]. Since alleles s and l_G were determined to be associated with a low transcription level of the gene, they were considered as equivalent [Thakur et al, 2010]. The study therefore used the following genotypes: s’s’ (composed of alleles ss, l_G l_G , and s l_G), s’l’ (composed of alleles l_A l_G , and s l_A), and l’l’ (composed of alleles l_A l_A).

Hypothesis

The triallelic polymorphism of the promoter region of SLC6A4, the serotonin transporter gene, has a significant effect on the patient’s response to methylphenidate (MPH). Those patients who are homozygous for the “long” allele (l’l’ genotype) respond better to methylphenidate than patients who are homozygous for the “short” allele (s’s’ genotype) [Thakur et al, 2010].

Experimental Design

ADHD patients were treated with 0.5 mg per kg per day of methylphenidate, or with placebo. Their behavior was evaluated at the start of treatment (baseline) and after each week of treatment using Conner’s Global Index (CGI) for parents and teachers. The patients were genotyped to determine their genotype groups for this gene, and their DNA was amplified using Polymerase Chain Reaction (PCR). The different alleles were then separated using agarose gel electrophoresis.

A mixed-mode ANOVA (Analysis of Variance) statistical analysis was used to determine any statistically significant interactions between genotype, treatment, and genotype/ treatment interactions [Thakur et al, 2010].

Results

The study found that the effect of methylphenidate treatment varies according to the patient’s SLC6A4 genotype. Patients with the l’l’ genotype showed a statistically significant improvement in behavior when using methylphenidate, and a minimal response to placebo; while those with the s’s’ genotype showed better responses to placebo than to methylphenidate. An intermediate level of response was observed in patients with the s’l’ genotype when compared to l’l’ and s’s’ patients.

Conclusion

The hypothesis, that the triallelic polymorphism of the SLC6A4 gene’s promoter region has a significant effect on the patient’s response to methylphenidate treatment, was not rejected. Methylphenidate had a greater effect in the behavior l’l’ genotype ADHD patients, and lower effect in s’l’ genotype ADHD patients. Methylphenidate did not have a significant effect in improving symptoms of s’s’ genotype ADHD patients.

Relationship between two SLC6A2 gene polymorphisms, and response to methylphenidate (MPH) in ADHD patients [Kim et al, 2010]

The purpose of this study [Kim et al, 2010] was to investigate the relationship, if any, of two specific polymorphisms of SLC6A2, the gene that encodes the norepinephrine transporter protein, with behavioral responses to methylphenidate in children and adolescents. The -3081 (A/T) polymorphism consists of a single nucleotide change, from A to T, in the SLC6A2 gene’s promoter region [Kim et al, 2010]. The G1287A polymorphism also consists of a single nucleotide change, at exon 9 of the gene [Kim et al, 2010].

Hypothesis

The -3081(A/T) and G1287A polymorphisms of the norepinephrine transporter gene SLC6A2 have a significant effect on the response to methylphenidate treatment in ADHD patients [Kim et al, 2010].

Experimental Design

The behavior of ADHD patients taking periodically-adjusted doses of methylphenidate was evaluated using the Clinical Global Impression Improvement (CGI-I) scale. Patients were also evaluated using the ADHD Rating Scale IV (ARS). Patients were evaluated by psychiatrists prior to medication, medicated with methylphenidate during eight weeks, and evaluated by psychiatrists again to determine the effectiveness, if any, of the treatment [Kim et al, 2010].

Genomic DNA samples were taken from the patients in order to determine their genotypes; DNA was amplified using Polymerase Chain Reaction (PCR). An estimation of allele frequencies was obtained for the genotypes of all patients. A Hardy-Weinberg equilibrium for genotype and allele frequencies was performed using a goodness-of-fit c² test. The correlation between the changes in ARS scores after treatment with methylphenidate, and the subjects’ SLC6A2 genotype, was evaluated using a one-way ANOVA statistical analysis, and a t-test hypothesis test [Kim et al, 2010].

Results

For the -3081 polymorphism, the study found that methylphenidate treatment had a significant effect on ADHD symptoms on subjects homozygous or heterozygous for the T allele (T/T or A/T genotypes). These subjects showed a measurable improvement in their ADHD symptoms after treatment with methylphenidate.

The study did not detect any association between methylphenidate treatment for ADHD symptoms and the G1287A polymorphism genotypes.

Conclusions

The hypothesis that -3081(A/T) polymorphisms of the norepinephrine transporter gene SLC6A2 is involved in the subjects’ response to methylphenidate treatment was not rejected. Experimental results showed evidence that methylphenidate treatment had a significant effect on patients homozygous or heterozygous for the T allele.

The hypothesis that G1287A polymorphisms of the norepinephrine transporter gene SLC6A2 have a significant effect on the subjects’response to methylphenidate was rejected. No such effect was observed.

References

1. Kim et al.: Possible association of norepinephrine transporter -3081(A/T) polymorphism with methylphenidate response in attention deficit hyperactivity disorder. Behavioral and Brain Functions 2010; 6:57.

2. Purper-Ouaki et al.: Neurobiology of attention deficit/hyperactivity disorder. Med Sci (Paris). 2010 May; 26(5): 487-496.

Stergiakouli et al.: Fitting the pieces together: current research on the genetic basis of attention-deficit/hyperactivity disorder (ADHD). Neuropsychiatric Disease and Treatment 2010; 6 551-560.

4. Thakur et al.: The 5-HTTLPR polymorphism of the serotonin transporter gene and short term behavioral response to methylphenidate in children with ADHD. BMC Psychiatry 2010; 10: 50.

El Fanatismo Político Puertorriqueño y la Religión

2011-06-21T13:23:00.000-07:00

En Puerto Rico, Juan del Pueblo defiende la colonia porque en PR la afiliación política funciona IGUALITO que una religión. En la colonia se cree por FE, según el Santo Evangelio del Beato Muñoz.

La inmensa mayoría de la gente en PR es "popular" o "penepé" o "independentista" porque su familia lo es, porque desde chiquito se les enseña a aceptar sin cuestionar lo que diga tal o cual partido, y a demonizar sin razonar lo que digan los contrarios. Las personas de otras ideologías son herejes, sus líderes son blasfemos, sus postulados son sacrilegios, y ni se les puede escuchar siquiera porque "te confunden".

Al que osa apartarse de la religión política familiar para votar por candidaturas, no afiliado, o por otro partido que no sea el de "la familia" lo insultan, lo maltratan, sus propios familiares le dan de codo y de traidor pa abajo le dicen de todo. "Ay , nena, tu abuela tiene que estarse revolcando en la tumba, ella que corría los montes detrás de Muñoz Marín". En muchos casos hasta les dejan de hablar.

ESA es la dinámica política real de un pueblo que en pleno s.21 sigue siendo en su mayoría primitivo y fanático en lo que a politica concierne.

El Perro del Político

2011-04-27T12:57:00.000-07:00

(gracias a Ángel Álamo por postear éste tremendo chiste... )

Reunidos en una casa de campo un domingo, jugando dominó....

1- Un ingeniero ordenó a su perro:
...¡ Caliper, muestra tus habilidades!

El perro agarró un martillo, unas tablas y se armó él solo una perrera.
Todos admitieron que era increíble.

2-Un contable dijo que su perro podía hacer algo mejor:
¡ Cash Flow , muestra tus habilidades!

El perro fué a la cocina, volvió con 24 galletas y las dividió en 8 pilas de 3 galletitas cada una.
Todos admitieron que era genial..

3- El químico dijo que su perro podía hacer algo aún mejor:
¡ Óxido , muestra tus habilidades!

Óxido caminó hasta la nevera, tomó un litro de leche, peló un plátano, usó la licuadora y se hizo un batido.
Todos aceptaron que era impresionante.

4- El informático sabía que podía ganarles a todos:
¡ Megabyte , hazlo!

Megabyte atravesó el cuarto, encendió la computadora, controló si tenía virus, mejoró el sistema operativo, mandó un e-mail e instaló un juego excelente. Todos sabían que esto era muy difícil de superar.

Miraron de reojo al político, que estaba de pié observandolo todo, y le preguntaron:
Y su perro, ¿qué puede hacer...?

5- El político llamó a su perro y le dijo:
¡ Senador, muestra tus habilidades!

Senador se levantó de un salto,
se comió las galletas,
se tomó el batido,
se cagó en la alfombra,
borró todos los archivos de la computadora ,
atacó a los otros cuatro perros,
ocupó la perrera con un título de propiedad falso
alegó inmunidad política....
¡¡¡ y le echó la culpa a la pasada administración !!!

Human Gene Patents: Privatization of our Species?

2011-04-21T11:54:00.000-07:00

Human Gene Patents:

Privatization of our Species?

by Raul Soto-Velez

Human Genes : who should own them?

The practice of patenting genes has always been surrounded by controversy. The debate is framed by fundamental question such as: Are genes really patentable matter? Why should anyone “own” a gene? What are the scientific and economic consequences of patenting genes? What are the potential consequences of discontinuing this practice?

In a landmark 2010 decision, Association for Molecular Pathology, et al. v. U.S. Patent and Trademark Office, et al , Judge Robert Sweet of the United States District Court in Southern New York invalidated several patents owned by Myriad Genetics related to breast and ovarian cancer. In addition to casting doubt over the legality of existing patents that cover thousands of human genes, this decision has revived the debate over the desirability and legality of the practice of patenting genes, particularly human genes; the impact of this practice in public health, the advancement of science and research; and the financial importance of gene patents to the companies that hold them.

Analysis

A very brief history of human gene patents

The USPTO has been granting patents for DNA sequences since 1980 (Foubister, 2000). On 1991, Dr. Craig Venter, from the National Institutes of Health (NIH) applied applied to patent 337 complementary human DNA sequences (Bluestone, 1991). Since then, over 20% of human DNA sequences have been patented (Jensen and Murray, 2005). All 20,000 to 25,000 human genes are now sequenced and in the public domain, after being mapped by the Human Genome Project (Landau, 2009). This means that the remaining genes are no longer considered as new or novel patentable matter.

Competing interests: Reasons for patenting human genes

Supporters of gene patents –mostly patent attorneys and owners of biotechnology companies– predict that eliminating gene patents would have a negative effect on the quality and quantity of scientific research and innovation. They assert that the exclusive rights over intellectual property granted by patents helps them attract investors. Without the monopoly provided by patents, they argue, investors would be less likely to risk the large amounts of capital necessary to bring drugs or diagnostic tests to market. They also point out that patents promote disclosure and reduce secrecy, allowing all researchers access to the inventions (Schwartz, 2010) (Haun, 2010).

However, a study commissioned by the U.S. Department of Health and Human Services (Evans, 2010) disproves this assertion. The study found that for genes which were not covered by patents, such as cystic fibrosis and Huntington’s disease, multiple private and public laboratories were competing to develop products, a competition based on quality, innovation, and providing better services. In contrast, genes covered by patents were only studied by the institution holding the monopoly. For these genes the study found a totally different picture: no competition, and overall lower levels of quality and innovation.

Are human gene patents against scientific progress?

Article I, Section 8, Clause 8 of the United States Constitution establishes the purpose of patents as “to promote the progress of science and useful arts”. In the light of this definition, it is legitimate to question in which way, if any, do gene patents promote the progress of science.

Gene patents actually make it harder and more expensive for scientists and researchers to study genes and develop cures. The cost and complexity of determining which patents apply to one’s research, of licensing and paying royalties to holders of multiple overlapping patents (“patent thickets”), and the risk of bumping against someone else’s patented IP actually discourage researchers and companies that want to commercialize drugs, vaccines, or treatments related to the patented genes. This has the deleterious effect of inhibiting innovation (Van Overwalle, 2010) (Vince, 2002).

Gene patents make diagnostic tests for genetically-related health conditions less available to patients (due to exclusive licensing deals with a few laboratories), and more expensive (companies like Myriad charge a high license fee to the laboratories, plus a fee of $3,200 per each use, for their breast and ovarian cancer diagnostic tests). Both the reduced availability and the high cost make it harder for patients to get a second opinion (Foubister, 2000) (Salzberg, 2010). The American Medical Association has expressed concerns that patents on genes related to diseases may actually reduce the amount of diagnostic tests that are developed for genetic-related conditions (Foubister, 2000). In a survey by the University of Pennsylvania, 20% of the research laboratories surveyed stated that they declined to develop tests for a specific genetic condition because the gene for that condition was patented (Foubister, 2000).

In a challenge to gene patent owners, and assuming that the price for sequencing a person’s entire genome will drop significantly in the near future, scientists have developed do-it-yourself computational screens that allow an individual to screen his or her own genome for the presence of specific gene alleles, and have made the software available for free (Salzbert and Pertea, 2010).

Legal aspects: Legality of Gene Patents

Gene patents fail a number of important requirements for patentable matter.

· Chakrabarty: It is questionable whether existing gene patents meet the fundamental requirement for patentable subject matter established by the US Supreme Court in Diamond v Chakrabarty: “anything under the sun that is made by man”.

Naturally-occurring genes are not made by man, they are the product of millions of years of evolutionary processes such as natural selection. To get around this, Myriad’s patent claims refer not to the native DNA sequences in genes, but to DNA molecules isolated outside of the body. According to Myriad, this amounts to a “transformation”, meeting one of the tests for patentable matter under the machine-or-transformation test (transforming a particular article into a different state or thing) established by the US Court of Appeals for the Federal Circuit in In Re Bilski.

In small-molecule drugs, where changing a single atom can change the properties and biological function of a molecule, Myriad’s transformation rationale would likely be valid, and the product of the transformation would likely be patentable. But DNA is different. The inherent value of the DNA molecule is in the information it codifies, and this information does not change when the DNA is isolated. If this isolated DNA had really been “transformed” into a different state or thing, it would be useless as a diagnostic tool. Isolated DNA is useful precisely because it has exactly the same information as the native genes in the patient. At best, the identification and isolation of a gene and its function should be regarded as a discovery, not a patentable invention.

This scientific fact was recognized by Judge Sweet, when he affirmed that “the entire premise behind Myriad’s genetic testing is that the claimed isolated DNA retains, in all relevant respects, the identical nucleotide sequence found in native DNA” (Langreth, 2010). Furthermore, he asserted that isolated DNA “is not markedly different from native DNA as it exists in nature” (Van Overwalle, 2010), and considered Myriad’s transformation argument to be “a lawyer’s trick that circumvents the prohibition of the direct patenting of the DNA in our bodies, but which in practice reaches the same result” (Schwartz, 2010).

The United States Department of Justice agrees with this view. In an amicus curiae brief the Justice Department stated, among other things, that “the chemical structure of native human genes is a product of nature, and it is no less a product of nature when that structure is ‘isolated’ from its natural environment than are cotton fibers that have been separated from cotton seeds” (Salzberg, 2010).

In Re Bilski: The discovery of the relationship between certain mutations in the BRCA genes and breast and ovarian cancer is an abstract idea, and abstract mental processes fail the In Re Bilski test for patentable subject matters. These mutations occur in nature, and therefore are not patentable. In his decision, Judge Sweet declared that Myriad’s claim was an abstract mental process for comparing gene sequences (Hall et al, 2011), and therefore not patentable.

Utility: Another questionable aspect of gene patents is the practice of patenting gene fragments for which the full sequence and function is often not known (Haun, 2010) (Mayer, 2002). One of the requirements for a patent is to demostrate the utility of the invention. If the function of the claimed invention is unknown or poorly understood, the utility requirement cannot be satisfied, and the patents should be invalidated.

Legal aspects: potential outcomes of changing the law

Eliminating gene patents will not affect most patents related to biotechnology drugs or diagnostic tests. Genetically engineered protein molecules and organisms that do not exist in nature, which are the basis of most biotechnology drugs, are still patentable. Diagnostic tests that are based on non-obvious, novel methods are still patentable. Eliminating gene patents will force biotechnology companies to compete on the basis of creativity, innovation, and service, rather than depending on a monopolistic practices that shield them from competition.

Conclusions

Patenting genes and other basic discoveries in genetics has had great impact in public health and medical research – and not for the better.

The legality of gene patents is questionable, as they fail several fundamental patentable-matter criteria. The fundamental claim that supports gene patents –that isolated DNA is “transformed” and therefore “different” from native DNA in the body— has been rejected by a U.S. Federal Court and by the U.S. Department of Justice. Claims from patent lawyers and biotechnology company owners –parties that have a strong economic interest in maintaining the current gene patent paradigm– that without gene patents there will be less genetic research are contradicted by studies that show that the opposite is true.

Gene patents work against the express purpose of the U.S. patent system: to promote the progress of science and useful arts. They are used by companies to erect barriers that negatively impact research, discovery, and innovation. They hurt innovation by establishing monopolies that reduce or stifle competition; raise the cost of diagnostic tests and restrict their availability; and make it harder and more expensive for scientists to study genes and develop diagnostics, treatments, and cures.

Human genes are not anyone’s invention. No one should own them.

References:

1. Association for Molecular Pathology, et al., v United States Patent and Trademark Office, et al., No. 09-cv-4515, 94 USPQ2d 1683 (S.D.N.Y. March 29, 2010).

2. Bluestone, Mimi. 1991 NIH Patent Covers Most Genes Ever. Nature Biotechnology. December 1991: Vol. 9, Issue 12, 1312. [DOI: 10.1038/nbt1291-1310b]. http://dx.doi.org/10.1038/nbt1291-1310b (accessed: 27 March 2011)

3. Evans, James. 2010 Genes, Patents, Common Sense and the Law. GeneWatch, Council for Responsible Genetics, Vol.23, Issue 5. (28 Nov 2010). http://www.councilforresponsiblegenetics.org/GeneWatch/GeneWatchPage.aspx?pageId=293. (accessed: 09 March 2011).

4. Foubister, Vida. 2000 Gene Patents Raise Concerns for Researchers, Clinicians. American Medical News: American Medical Association (AMA). (21 Feb 2000). http://www.ama-assn.org/amednews/2000/02/21/prsb0221.htm. (accessed: 09 March 2011).

5. Haun, Holly. 2010. Genetics and Patenting. US Department of Energy, Oak Ridge National Laboratory Office of Science, Office of Biological and Environmental Research, Human Genome Program. (07 July 2010. http:/www.ornl.gov/sci/techresources/Human_Genome%20/elsi/patents.shtml. (accessed: 25 March 2011).

6. Jensen, Kyle and Murray, Fiona. 2005 Intellectual Property Landscape of the Human Genome. Science. 14 October 2005: 310 (5746), 239-240. [DOI:10.1126/science.1120014]. http://www.sciencemag.org/content/310/5746/239.summary (accessed: 26 March 2011)

7. Landau, Elizabeth. 2009 How Human Genes Become Patented. CNN. (13 May 2009). http://www.cnn.com/2009/HEALTH/05/13/genes.patent.myriad/index.html#cnn. (accessed: 09 March 2011).

8. Langreth, Robert. 2010 Finally, Common Sense Prevails On Gene Patents. Forbes. (30 March 2010). http://blogs.forbes.com/sciencebiz/2010/03/30/finally-common-sense-prevails-on-gene-patents. (accessed: 09 March 2011).

9. Mayer, Sue. 2002 Are Gene Patents in the Public Interest?. Bio-IT World. (12 Nov 2002). http://www.bio-itworld.com/archive/111202/insights_public.html. (accessed: 09 March 2011).

10. Salzberg, Steven. 2010 The Feds Come Out Against Gene Patents. It’s About Time. Forbes. (31 Oct 2010). http://blogs.forbes.com/sciencebiz/2010/10/31/the-%20feds-come-out-against-gene-patents-its-about-time/. (accessed: 09 March 2011).

11. Salzberg, Steven and Pertea, Mihaela. 2010 Do-it-Yourself Genetic Testing. Genome Biology.7 October 2010: 11 (404). [DOI:10.1186/gb-2010-11-10-404]. http://genomebiology.com/2010/11/10/404 (accessed: 28 March 2011).

12. Schwartz, John. 2010 Judge Invalidates Human Gene Patent. The New York Times. (29 March 2010). B1. http://www.nytimes.com/2010/03/30/business/30gene.html?_r=1&pag. (accessed: 09 March 2011).

13. United States Department of Justice, Brief for the United States as Amicus Curiae in Support of Neither Party, Association for Molecular Pathology, et al., v United States Patent and Trademark Office, et al., No. 2010-1406, in case no. 09-cv-4515.

http://graphics8.nytimes.com/packages/pdf/business/genepatents-USamicusbrief.pdf

(Accessed 27 March 2011)

14. Van Overwalle, Geertrui. 2010 Turning Patent Swords into Shares. Science. 17 December 2010: 330 (6011), 1630-1631. [DOI:10.1126/science.1189592]. http://www.sciencemag.org/content/330/6011/1630.summary (accessed: 26 March 2011)

15. Vince, Gaia. 2002 Gene Patents "Inhibit Innovation". New Scientist. (23 July 2002). http://www.newscientist.com/article/dn2580-gene-patents-inhibit-innovation.html. (accessed: 09 March 2011).

BBC: Autistic brains "organised differently" say scientists

2011-04-05T14:52:00.000-07:00

"People with autism use their brains differently from other people, which may explain why some have extraordinary abilities to remember and draw objects in detail, according to new research."

Autistic brains "organised differently" say scientists
http://www.bbc.co.uk/news/health-12937009

Quantum physics explanation for smell gains traction

2011-03-24T16:01:00.001-07:00

"The theory that our sense of smell has its basis in quantum physics events is gaining traction, say researchers."

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Quantum computing device hints at powerful future

2011-03-22T16:40:00.001-07:00

"It uses the strange "quantum states" of matter to perform calculations in a way that, if scaled up, could vastly outperform conventional computers..."

Quantum computing device hints at powerful future

http://www.bbc.co.uk/news/science-environment-12811199

22 March 2011
Last updated at 01:47 ET

2011-03-11T09:06:00.000-08:00

"Americans deserve better than the European model that Barack Obama is trying to implement."

- Daniel Hannan

http://online.wsj.com/article/SB10001424052748703559604576176620582972608.html

A Letter to America

MARCH 11, 2011

By DANIEL HANNAN

The following essay is adapted from the Encounter Books Broadside, "Why America Must Not Follow Europe," No. 19 in a series.

On a U.S. talk-radio show recently, I was asked what I thought about the notion that Barack Obama had been born in Kenya. "Pah!" I replied (or words to that effect). "Your president was plainly born in Brussels."

American conservatives have struggled to press President Obama's policies into a meaningful narrative. Is he a socialist? No, at least not in the sense of wanting the state to own key industries. Is he a straightforward New Deal big spender, in the model of FDR and LBJ? Not exactly.

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Barbara Kelley

Americans understandably seek to define their president in American terms. But looking across from my side of the Atlantic, there is a much simpler explanation. President Obama wants to Europeanize the U.S. All right, he wouldn't put it in those terms, partly because the electorate wouldn't wear it and partly because he sees himself as less Eurocentric than any of his 43 predecessors.

My guess is that if anything, Obama would verbalize his ideology using the same vocabulary that Eurocrats do. He would say he wants a fairer America, a more tolerant America, a less arrogant America, a more engaged America. When you prize away the cliché, what these phrases amount to are higher taxes, less patriotism, a bigger role for state bureaucracies and a transfer of sovereignty to global institutions.

He is not pursuing a set of random initiatives lashed arbitrarily together, but a program of comprehensive Europeanization: European health care, European welfare, European carbon taxes, European day care, European college education, even a European foreign policy, based on engagement with supranational technocracies, nuclear disarmament and a reluctance to deploy forces overseas.

No previous president has offered such uncritical support for European integration. On his very first trip to Europe as president, Obama declared, "In my view, there is no Old Europe or New Europe. There is a united Europe." Having silkily dispensed with the old Rumsfeldian idea that the U.S. should deal with EU states as individual nations, he went on to dismiss the euroskeptic majorities in most European countries: "I believe in a strong Europe, and a strong European Union, and my administration is committed to doing everything we can to support you."

It's hardly surprising that Obama should be such an enthusiast for a European superstate: He is building his own version at home. I don't doubt the sincerity of those Americans who want to copy the European model. A few may be snobs who wear their euro-enthusiasm as a badge of sophistication. But most genuinely believe that making their country less American and more like the rest of the world would make it more comfortable and peaceable.

All right, growth would be slower, but the quality of life might improve. All right, taxes would be higher, but workers need no longer fear sickness or unemployment. All right, the U.S. would no longer be the world's superpower, but perhaps that would make it more popular. Is a European future truly so terrible?

Yes. Take it from me, my friends. I have been an elected member of the European Parliament for 11 years. I have seen firsthand what the European political model means. I inhabit your future—or at least the future toward which your current rulers seem intent on taking you. Before you follow us, let me tell you about it.

The critical difference between the American and European unions has to do with the location of power. The U.S. was founded on what we might loosely call the Jeffersonian ideal: the notion that decisions should be taken as closely as possible to the people they affect. The EU, by contrast, was based on precisely the opposite ideal. Article One of its foundational treaty commits its nations to establish "an ever-closer union."

From that distinction, much follows. The U.S. has evolved a series of unique institutions designed to limit the power of the state: recall mechanisms, ballot initiatives, balanced budget rules, open primaries, localism, states' rights, term limits, the direct election of public officials, from the sheriff to the school board. The EU, by contrast, has placed supreme power in the hands of 27 unelected Commissioners, who have been made deliberately invulnerable to public opinion.

The will of the people is generally seen by Eurocrats as an obstacle to overcome, not a reason to change direction. When France, the Netherlands and Ireland voted against the European Constitution, the referendum results were swatted aside and the document adopted regardless. For, in Brussels, the ruling doctrine—that the nation-state must be transcended—is seen as more important than freedom, democracy or the rule of law.

This doctrine has had several malign consequences. For example, it has made the assimilation of immigrants far more difficult. Whereas the U.S. is based around the idea that anyone who buys into American values can become American, the EU clings to the notion that national identities are anachronistic and dangerous. Unsurprisingly, some newcomers, finding their adopted countries scorned, have turned to other, less apologetic identities. Hint to my American friends: If you go around the world apologizing for everything, you make it harder for immigrants to want to belong.

The single worst aspect of Europeanization, however, is its impact on the economy. Many Americans, and many Europeans, have a collective memory of how Europe managed to combine economic growth with social justice. Didn't Western Europe do tremendously well after World War II? Wasn't its success associated with something called "Rhineland capitalism" or "the social market"?

Like most folk memories, the idea of a European economic miracle has some basis in fact. Between 1945 and 1974, Western Europe did indeed outperform the U.S. And in retrospect, we can see why. Europe happened to enjoy perfect conditions for rapid growth. Infrastructure had been destroyed during the war, but an educated, industrious and disciplined work force remained. On top of which, Europe received a massive external stimulus. Thirteen billion dollars were disbursed through the Marshall Plan between 1948 and 1952, on top of the $12 billion already given by the U.S. in aid since the end of the war.

In the circumstances, it would have been extraordinary had Europe not prospered. Human nature being what it is, however, few European leaders attributed their success to the fact that they were recovering from an artificial low, still less to external assistance.

They convinced themselves, rather, that they were responsible for their countries' growth rates. Their genius, they thought, lay in having hit upon a European "third way" between the excesses of American capitalism and the totalitarianism of Soviet communism.

They believed in markets, but regulated markets. Instead of the industrial strife that they had experienced before the war, they would establish a tripartite system in which employers, labor unions and government officials worked together. Instead of seesawing between Left and Right, they would have consensual coalition governments in which both Christian Democrats and Social Democrats accepted the broad framework of a mixed market. Instead of competition between states, they would pursue political and economic integration.

We can now see where that road leads: to burgeoning bureaucracy, more spending, higher taxes, slower growth and rising unemployment. But an entire political class has grown up believing not just in the economic superiority of euro-corporatism but in its moral superiority. After all, if the American system were better—if people and businesses could thrive without government supervision—there would be less need for politicians. As Upton Sinclair once observed, "It is difficult to get a man to understand something when his job depends on not understanding it."

Nonetheless, the economic data are pitilessly clear. For the past 40 years, Europeans have fallen further and further behind Americans in their standard of living. In 1974, Western Europe, defined as the 15 members of the EU prior to the admission of the former communist countries in 2004, accounted for 36% of world GDP. Today that figure is 26%. In 2020 it will be 15%. In the same period, the U.S. share of world GDP has remained, and is forecast to remain, fairly steady at around 26%.

At the same time, Europe has become accustomed to a high level of structural unemployment. Indeed, if we exclude the United Kingdom, the EU failed to produce a single net private-sector job between 1980 and 1992. Only now, as the U.S. applies a European-style economic strategy based on fiscal stimulus, nationalization, bailouts, quantitative easing and the regulation of private-sector remuneration, has the rate of unemployment in the U.S. leaped to European levels.

Why is a European politician urging America to avoid Europeanization? Well, I'm not European; I'm British. My country is linked to the U.S., and to the wider Anglosphere, by ties of history and geography, commerce and law, blood and speech.

As a Briton, I see the American republic as a repository of our traditional freedoms. The doctrines rooted in the common law, in the Magna Carta, and in the Bill of Rights found their fullest and most sublime expression in the old courthouse of Philadelphia. Britain, as a result of its unhappy membership in the European Union, has now surrendered a large part of its birthright. But our freedoms live on in America.

Which brings me to my country's present tragedy. The fears that the American patriot leaders had about a Hanoverian tyranny were, in retrospect, exaggerated. The United Kingdom did not develop into an absolutist state. Power continued to pass from the Crown to the House of Commons.

Until now. Nearly two and a half centuries after the Declaration of Independence, the grievances it adumbrated are belatedly coming true—but in Britain, rather than in North America. Colossal sums are being commandeered by the government in order to fund bailouts and nationalizations without any proper parliamentary authorization. Legislation happens increasingly through what are called standing orders, a device that allows ministers to make laws without parliamentary consent—often for the purpose of implementing EU standards. Elections have been drained of purpose, and turnout is falling.

How aptly the British people might today apply the ringing phrases of the Declaration of Independence against their own rulers, who have "combined with others to subject us to a jurisdiction foreign to our constitution, and unacknowledged by our laws."

Throughout my career in politics, I have campaigned to apply Jeffersonian democracy to British political conditions, to recover those British freedoms that have flourished more happily in America than in their native soil, to repatriate our revolution. So you can imagine how I feel when I see the U.S. making the same mistakes that Britain has made: expanding its government, regulating private commerce, centralizing its jurisdiction, breaking the link between taxation and representation, abandoning its sovereignty.

You deserve better, cousins. And we expect better.

Mr. Hannan is a member of the European Parliament.

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