text:
|Publication number
|Publication type
|Application number
|Publication date
|Mar 27, 1990
|Filing date
|Apr 11, 1988
|Priority date
|Apr 11, 1988
|Fee status
|Also published as
|Publication number
|Glen W. Rantala, Donald R. Janke
|Original Assignee
|Square D Company
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (8), Referenced by (49), Classifications (6), Legal Events (9)
|External Links: USPTO, USPTO Assignment, Espacenet
This application is related to applications filed concurrently herewith, entitled "Ladder Sequence Controller", Ser. No. 180,093; "Peer-To-Peer Register Exchange Controller for PLCs", Ser. No. 179,674; "High-Speed Press Control System", Ser. No. 179,743; and, "Bus interface Board System", Ser. No. 179,756. The contents of these applications are incorporated herein by reference.
This invention relates generally to a programmable logic controller for controlling machine tools and particularly relates to a programmable logic controller having a control processor, and an associated scan processor with its own program counter.
The use of programmable logic controllers or PLCs to control machine tools such as punch presses, screw machines and automatic welders is well-known. The PLCs contain microprocessors operating under a set of sequential instructions to sense the condition of the machine tool, and to provide outputs for controlling the closing and opening of valves and switches to operate the machine tool.
Previously, some of these PLCs have used a control processor and scan processor arrangement to increase the processing of status and control information. In one such PLC, the control processor assigned certain instructions to the scan processor, and when the scan processor finished, the control processor assigned another routine to the scan processor. For that reason, the scan processor never needed a separate readable program counter because it only performed inline routines and never needed to save the contents of the program counter to do a subroutine.
It would be desirable to operate this PLC with subroutines fetched directly from a user compiled memory so as to expedite the operation of the PLC and to identify the different error conditions occurring in the scan processor so that the control processor can determine if the error was momentary or continuous and act accordingly.
The invention furnishes the ability for both the control processor and the scan processor to read the contents of a program counter. The ability of the scan processor to read the program counter facilitates the scan processor to execute subroutines on its own without direction from the control processor.
The invention also provided control logic identifying a parity error in the compiled user memory, a parity error in an image memory or an incorrect command from the control processor to the scan processor.
This assures that the data is accurate before it is coupled as an input into the scan processor.
FIG. 1 is a block diagram of a programmable logic controller of the invention controlling a machine tool; and,
FIG. 2 is a block diagram of the circuit connection of the program counter, and including the control logic that identifies the different operating conditions.
FIG. 1 shows a block diagram of a processor system 11 in accordance with the invention. System 11 includes an executive memory 17 intermediate user memory 14, compiled user memory 15, a communications interface 18, a bus interface 20 and a keyswitch 21. The foregoing component blocks will be described herein below. The system 11 also includes scan processor 22 and a math coprocessor 27. The scan processor 22 scans and executes a ladder logic program stored in the compiled user memory ram 15. The math co-processor 27 performs the math functions required in response to control from the control processor 12.
Control processor 12, which is of suitable known design, coordinates all processor system 11 operations. This includes performing all communication via a communications interface port and a system bus. Control processor 12 also compiles the ladder program in the compiled user memory and also handles all interrupts and error conditions from the scan processor, system bus, and the remainder of the programmable controller system. In this mode, the scan processor 22 performs computation of output states and register values based upon the current state of inputs and registers; the operations and the sequence in which they are performed is controlled by the program in the compiled user memory. The control processor accesses state and register values accessed from the image memory.
The intermediate user memory 14 and the compiled user memory 15 comprises two distinct portions of memory for maximum efficiency in scanning and program manipulation. The intermediate user memory 14 is a separate RAM and contains a compiled version of the code which is optimized to serve as executable instructions for the scan processor.
In operation, the program from the intermediate user memory 14 is compiled and then downloaded to the compiled user memory 15. Compiled user memory 15 is implemented with static CMOS devices which are battery backed and parity protected.
The compiled user memory provides 64-bit compiled user program storage for up to 32K words. Each word is comprised of scan processor instructions and control codes, and two 16-bit operands for data or program control.
The compiled user memory is randomly accessible by the control processor for purposes of loading and editing user programs. The scan processor accesses the compiled user memory directly as an executive memory of successive instructions. Access by the scan processor is limited to read only operations on the two 16-bit operands when they are coded as immediate data. Branches or subroutines require alteration of the program counter per operand contained in the instruction or scan processor computation.
Importantly, the scan processor controls its own program counter, which points to the compiled user memory. This capability permits the user to utilize subroutines rather than repeated sections of in-line code in his program, for timers and coaunters, etc. By using the same subroutine over and over again for such functions as timers, the amount of required memory to hold this code is greatly reduced.
FIG. 2 is a block diagram indicating communications to the program counter of the scan processor 22 and the control logic identifying various operating commands. Importantly, as indicated, the program counter 40 communicates directly with the compiled user memory 15 and the ALU 42. The various command registers in compiled user memory 15 are labeled in FIG. 2 and effect control of the program counter 40 through logic control 41. The branch operand registers of memory 15 couple directly to the program counter 40.
The executive program that is being executed by the scan processor may be represented as follows:
______________________________________EXECUTIVE PROGRAM(Compiled and downloaded tocompiled user memory)Address Instruction # Instruction______________________________________0000 1 Instr. 2 Instr. 3 GOSUB A 4 Instr. 5 GOSUB B 6 GOSUB B 7 GOSUB A 8 Instr. 9 GOSUB ANNNN 10 GO TO #1______________________________________
Instructions 1 through 10 are executed in a continuous loop. Instead of including the entire programming instructions for both subroutine A and B, each time they are required, this code is written only once, and then accessed by the alterable program counter.
______________________________________SUBROUTINE A SUBROUTINE B______________________________________Instr. 1 Instr. 1Instr. 2 Instr. 2Instr. 3 Instr. 3etc. etc.Return Return______________________________________
The sequence for this operation would be as follows: The program counter (which contains the address of the next instruction to be executed) is incremented as the sequential instructions of the executive loop are executed. When a subroutine is encountered, the value of the next in-line sequential address for the program counter is stored away in a temporary register called a stack. The address in the program counter is then changed to the address of the subroutine. The program counter is then incremented sequentially to execute the instructions in the subroutine. When the subroutine "Return" instruction is encountered, the last address location that was written to the stack is now written into the program counter. This then points the program counter to the instruction in the executive loop that followed the last executive instruction. That last executive instruction was the instruction that directed the program counter to the last executed subroutine. The program counter thus continues executive instructions immediately following the last "go to subroutine" instruction.
The ability to control the program counter also permits the use of timed or event driven interrupts, which may be generated by intelligent I/O. This is because the interrupt will be handled in the same manner as the subroutines, in that the interrupt code is written as a subroutine, with a "return" terminator. The main difference between the subroutines described above, and the interrupt, is that the interrupt routine will be called by a hardware interrupt being generated, rather than an instruction which directs the program counter to the first instructions of the subroutine.
______________________________________ INTERRUPT______________________________________ Instr. 1 Instr. 2 Instr. 3 etc. Halt Instruction______________________________________
The scan processor executes the user program upon command from the control processor. The operation of the scan processor is stopped by a halt command received from the control processor, the execution of a halt instruction, or by parity error detected in either the compiled user memory or image memory.
This scan processor performs computation of output states and register values based upon the current state of inputs and registers. The operations and the sequence in which they are performed is controlled by the program contained in the compiled user memory. The I/O states and register values are accessed from the image memory.
The processor system 11 makes use of an image memory to hold the state of all I/O and registers. The contents of the image memory are transferred to the external I/O, and the present I/O state transferred to the image memory, at the end of every scan. Internal registers will not be transferred on the bus.
The time necessary to do an I/O update is a function of the number of I/O registers assigned to the system and the degree of register fragmentation. Register fragmentation occurs when there are inputs and outputs in the same register. The I/O can be allocated in groups of four, registers may contain up to four different I/O groups. During the I/O update, any forcing operations in effect will take place.
The ladder program is solved after the image memory 16 is set up. The program is normally scanned in ascending rung order beginning with rung number 1.
The image memory 16 consists of a battery-backed RAM that provides 16-bit data and status fields for user registers and control registers. The image memory 16 contains both the internal and external I/O and registers. Between scans, the control processor 12 transmits the current values in image memory 16 to the appropriate external devices. It also updates the image memory 16 according to the external I/O and registers in preparation for the next scan. Parity protection is provided for all bytes of the memory.
The image memory 16 table is fully accessible by the svcanning processor 22 and control processor 12.
The control processor is furnished with circuits to interface it to a math co-processor 27. This match co-processor 27 will perform math functions under the control of the control processor 12 and will free the control processor from this time-consuming task.
Since the control processor does not scan the ladder program, but has control of the math co-processor 27, the scanning processor 22 must interrupt the control processor 12 for floating point operations. A separate dedicated math co-processor 22 can perform the math operations more efficiently.
The key-operated selector switch 21 allows the control processor 12 to be locked into any one of four operating modes: RUN, RUN PROGRAM, DISABLE or HALT. In the RUN mode, the control processor 12 scans normally but cannot program, while in the RUN PROGRAM mode, the control processor 12 scans normally and the programmer can alter the ladder program. In the HALT mode, the control processor 12 is not operating on the program; and in the DISABLED OUTPUT mode, the control processor 12 operates on the ladder diagram program, but all external outputs are held in an off state.
The hardware of the scan processor 22 has the ability to distinguish between error conditions which occur when the scan processor is scanning.
More specifically, the scan processor reports a specific error code to the control processor to distinguish three categories or types of errors. For example, parity errors can be distinguished in the compiled user memory 15 and in the image memory 16. Also, collision errors, that is indications that the scan processor is receiving illegal commands from the control processor when the scan processor is running, can be distinguished.
One simplified example of the operation of the system 11 of FIG. 1 is as follows:
Assume that the system 11 is used in a bottling plant to control the operation of placing any empty carton in the proper loading location after the last carton as been filled with bottles, so that the empty carton can now be filled with bottles.
The empty carton is filled in response to a weight input signal. In response to a weight signal, an output will be provided to cause a component of the machine to push the full carton away from the loading machine and a second component of the machine to push to empty carton into the loading position to receive the bottles. The key switch 21 has been set to the RUN mode.
Upon a clear condition or power up, the user program is loaded into the CMOS RAM area of the intermediate user memory 14. At this time, the control processor 12 transfers this compiled program into the compiled user memory 15.
Assume a full carton is in the sensed position. This information will be received by the control processor 12 through the bus interface 20 and transferred to the image memory 16. All inputs and outputs contained in the image memory 16 are parity checked. A bit will then be set in image memory 16 by processor 12 to indicate the carton full state.
As the scan processor 22 executes the executive program in the compiled user memory 19, and compares input information from the image memory 16 in relation to the instructions in the executive program, it establishes that the carton full state has occurred. The scan processor 22 now knows that the carton is full, and that an event has occurred which requires an output to do two things, move the carton out of the way and move an empty carton into a loading position.
The scan processor 22 now sets the corresponding output bit in the image memory 16. The control processor 12 now reads the output bit in the image memory 16 and sends a signal to the output device through bus interface 20. The output device simultaneously moves the full carton off of the loading position and pushes the empty carton into the loading position.
The sensor input device now detects that there is an empty carton in the loading position (low weight of carton). This information is transmitted through the bus and bus interface 20 to the control processor 12. The control processor 12 then clears the corresponding input bit in the image memory 16. This is only one partial operation of one machine, however the data through the scan processor is evident.
Some control functions are math intensified such as input scaling. In a high-speed production situation, the required math calculation could take longer than the necessary scan period of the scan processor 27. In these cases, it is desirable to off-load math calculations to parallel math processor 27 to increase scan rate and not slow the scan rate down by the time taken to do the math calculations. In other words, the math calculations are provided by the math co-processor 27 such as not to reduce the scan rate of the system 11.
While the invention has been particularly shown and described with reference to a preferred embodiment thereof, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the spirit and scope of the invention.
|Cited Patent
|Filing date
|Publication date
|Nov 23, 1970
|Sep 5, 1972
|Nippon Electric Co
|Micro-program control system
|Jun 6, 1977
|Oct 3, 1978
|Allen-Bradley Company
|Program protection module for programmable controller
|Jun 1, 1978
|Aug 21, 1979
|Allen-Bradley Company
|Digital control system with Boolean processor
|Apr 5, 1978
|Apr 29, 1980
|Allen-Bradley Company
|Program loader for programmable controller
|Aug 24, 1978
|Jul 29, 1980
|Texas Instruments Incorporated
|Automatic end-of-scan control system for a programmable process controller with expandable memory
|Dec 6, 1984
|Feb 24, 1987
|Northern Telecom Limited
|Signal multiplexing circuit
|Aug 2, 1984
|Dec 29, 1987
|Quatse Jesse T
|Boolean processor for a progammable controller
|Nov 9, 1982
|May 10, 1984
|Siemens Ag
|Vorrichtung zur mikrobefehls-bereitstellung fuer mindestens zwei unabhaengig arbeitende funktionseinheiten in einem integrierten, mikroprogrammierten elektronischen baustein und verfahren zu ihrem betrieb
|Citing Patent
|Filing date
|Publication date
|Oct 30, 1990
|Jul 6, 1993
|Allen-Bradley Company, Inc.
|Programmable controller processor with an intelligent functional module interface
|Dec 26, 1991
|Oct 5, 1993
|Square D Company
|Network interface board having memory mapped mailbox registers including alarm registers for storing prioritized alarm messages from programmable logic controllers
|Mar 27, 1995
|Jan 14, 1997
|Siemens Energy & Automation, Inc.
|High speed programmable logic controller
|Sep 28, 1994
|Jan 13, 1998
|Tetra Laval Holdings & Finance, S.A.
|Control system for a packaging machine
|Jun 7, 1995
|Mar 10, 1998
|Tetra Laval Holdings & Finance S.A.
|Control system having error correcting apparatus
|Oct 15, 1996
|Oct 19, 1999
|Tetra Laval Holdings & Finance, Sa
|Control system for a packaging machine
|Oct 6, 1998
|May 15, 2001
|Schneider Automation Inc.
|System for a modular terminal input/output interface for communicating messaging application layer over encoded ethernet to transport layer
|Sep 10, 1997
|Aug 28, 2001
|Schneider Automation Inc.
|Web interface to a programmable controller
|Dec 30, 1998
|Dec 4, 2001
|Schneider Automation, Inc.
|Input/output (I/O) scanner for a control system with peer determination
|Oct 6, 1998
|Aug 13, 2002
|Schneider Automation, Inc.
|MODBUS plus ethernet bridge
|Mar 12, 2001
|Oct 15, 2002
|Schneider Automation, Inc.
|Messaging application layer over ethernet to transport layer (TCP) communications method and apparatus for a modular terminal input/output system
|Jun 15, 2000
|May 4, 2004
|Schneider Automation Inc.
|Web interface to an input/output device
|Dec 30, 1998
|Jan 18, 2005
|Schneider Automation Inc.
|Embedded file system for a programmable logic controller
|Dec 30, 1998
|Feb 8, 2005
|Schneider Automation Inc.
|Interface to a programmable logic controller
|Nov 7, 2000
|Apr 4, 2006
|Schneider Automation Inc.
|Method and apparatus for an active standby control system on a network
|Apr 2, 2002
|Apr 11, 2006
|Schneider Automation Inc.
|Method and apparatus for ethernet prioritized device clock synchronization
|Jul 7, 2000
|Apr 18, 2006
|Schneider Automation Inc.
|Method and apparatus for an active standby control system on a network
|Aug 9, 2000
|Apr 25, 2006
|Schneider Automation Inc.
|System for programming a factory automation device using a web browser
|Mar 13, 2000
|Jun 6, 2006
|Schneider Automation Inc.
|System for programming a programmable logic controller using a web browser
|Jun 20, 2003
|Jun 13, 2006
|Schneider Automation Inc.
|Interface to a programmable logic controller
|Nov 8, 1999
|Dec 5, 2006
|Schneider Automation Inc.
|Method and system for monitoring a controller and displaying data from the controller in a format provided by the controller
|Apr 10, 2002
|Jan 9, 2007
|Schneider Automation Inc.
|Communication system for a control system over Ethernet and IP networks
|Jul 7, 2000
|Feb 20, 2007
|Schneider Automation Inc.
|Method and system for transmitting and activating an application requesting human intervention in an automation network
|Mar 2, 2002
|Apr 14, 2009
|Schneider Automation Inc.
|Input/output (I/O) scanner for a control system with peer determination
|Nov 26, 2001
|Sep 15, 2009
|Schneider Automation Inc.
|Messaging application layer over ethernet to transport layer (TCP) communications method and apparatus for a modular terminal input/output system
|Dec 30, 2003
|Jul 31, 2012
|Baxter International, Inc.
|System and method for verifying medical device operational parameters
|Nov 27, 2002
|Oct 16, 2012
|Square D Company
|System and method for interfacing with a controller
|Oct 9, 2003
|Feb 19, 2013
|International Business Machines Corporation
|Method and system for autonomic execution path selection in an application
|Jan 11, 2011
|Dec 24, 2013
|International Business Machines Corporation
|Qualifying collection of performance monitoring events by types of interrupt when interrupt occurs
|Jan 29, 2008
|Apr 1, 2014
|International Business Machines Corporation
|Counting instruction execution and data accesses
|Dec 30, 2003
|Jul 8, 2014
|Baxter International Inc.
|System and method for notification and escalation of medical data
|Jan 11, 2012
|Jul 15, 2014
|International Business Machines Corporation
|Autonomic hardware assist for patching code
|Dec 15, 2000
|Jul 11, 2002
|Baker Richard A.
|Web interface to a device and an electrical network control system
|Apr 2, 2002
|Nov 14, 2002
|Schneider Electric
|Method for managing bandwidth on an ethernet network
|Apr 2, 2002
|Nov 14, 2002
|Schneider Electric
|Method and apparatus for ethernet prioritized device clock synchronization
|Apr 10, 2002
|Dec 19, 2002
|Francois Jammes
|Communication system for a control system over ethernet and IP networks
|Mar 2, 2002
|Feb 13, 2003
|Ron Naismith
|Input/output (I/O) scanner for a control system with peer determination
|Nov 27, 2002
|Jul 24, 2003
|Papadopoulos A. Dean
|System and method for interfacing with a controller
|Apr 30, 2002
|Jul 31, 2003
|Tuan Bui
|Medical treatment verification system and method
|May 31, 2002
|Oct 30, 2003
|Wilkes Gordon J.
|Automated messaging center system and method for use with a healthcare system
|May 31, 2002
|Dec 4, 2003
|Richardson Bill R.
|Biometric security for access to a storage device for a healthcare facility
|Dec 30, 2003
|Sep 2, 2004
|Simpson Thomas L. C.
|System and method for notification and escalation of medical data
|Jun 20, 2003
|Oct 21, 2004
|Klindt Charles J.
|Interface to a programmable logic controller
|Apr 17, 2003
|Oct 21, 2004
|Schneider Automation Inc.
|System and method for transmitting data
|Oct 9, 2003
|Apr 14, 2005
|International Business Machines Corporation
|Method and system for autonomic execution path selection in an application
|Aug 10, 2012
|Aug 15, 2013
|Siemens Aktiengesellschaft
|Embedded Multi-Processor Parallel Processing System and Operating Method for Same
|Dec 24, 2010
|Jul 4, 2012
|Programmable logic controller and data processing method thereof
|Dec 24, 2010
|Jul 4, 2012
|Programmable logic controller and control method thereof
|Dec 24, 2010
|Mar 11, 2015
|Programmable logic controller and control method thereof
|U.S. Classification
|International Classification
|Cooperative Classification
|European Classification
|Apr 10, 1989
Owner name: SQUARE D COMPANY, A MI CORP., MICHIGAN
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:GATES, DIRK I.;REEL/FRAME:005046/0773
Effective date: 19880517
Owner name: SQUARE D COMPANY, A MI CORP., MICHIGAN
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:RANATAL, GLEN W.;JANKE, DONALD R.;REEL/FRAME:005046/0771
Effective date: 19880426
Owner name: SQUARE D COMPANY, A MI CORP., MICHIGAN
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:WATT, KIM J.;REEL/FRAME:005046/0772
Effective date: 19880422
|Aug 23, 1993
|Fee payment
Year of fee payment: 4
|Dec 5, 1994
Owner name: MODICON, INC., MASSACHUSETTS
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:SQUARE D COMPANY;REEL/FRAME:007235/0131
Effective date: 19941014
|Mar 27, 1995
Owner name: AEG SCHNEIDER AUTOMATION, INC.
Free format text: CHANGE OF NAME;ASSIGNOR:MODICON, INC.;REEL/FRAME:007397/0801
Effective date: 19941014
|Dec 22, 1997
Owner name: SCHNEIDER AUTOMATION INC., MASSACHUSETTS
Free format text: CHANGE OF NAME;ASSIGNOR:AEG SCHNEIDER AUTOMATION, INC.;REEL/FRAME:008855/0799
Effective date: 19960801
|Feb 13, 1998
|Maintenance fee reminder mailed
|Mar 20, 1998
|Surcharge for late payment
|Mar 20, 1998
|Fee payment
Year of fee payment: 8
|Aug 30, 2001
|Fee payment
Year of fee payment: 12


text:
The Sepon Copper project is a patented copper leaching process comprised of crushing, acid grinding, acid flotation, pressure oxidation and a solvent extraction electrowinning circuit designed to produce 60 000 t/y of cathode copper, which has subsequently been increased by Ausenco to 80 000 t/y.
The project scope included all plant services including reagents, oxygen plant, cooling towers and infrastructure such as power supply, water supply, accommodation to house 4 000 personnel, roads, bridges, waste services and tailings storage.
Ausenco's scope was for the full EPCM of the project which included process plant and associated infrastructure.

subset: commoncrawl


text:
I'm dark, crude, sarcastic and twisted which is perfectly complimented by my yogi/buddhist spirituality. But I'm compassionate and optimistic all the same. I did volunteer nursing in the deep jungles of Honduras, and still found comic relief with dead baby jokes.
I love being spontaneous, like taking a 3 hour road trip to nowhere in particular for lunch. Or an impromptu trip to Costa Rica? Who's coming with me? Seriously, I always want to be somewhere outdoors, and anytime I have a few days off, I'm out the door.
Movies: The Color Purple, Eternal Sunshine, American Beauty, Vicky Christina Barcelona, Goonies, Turtles Can Fly, Spaceballs, PeeWee Herman, The Princess Bride, Raising Arizona, Lost Highway. I'm always game for anything independent, foreign or documentary.
Music: Hmmmm. Tori Amos, John Denver, Alice Cooper, LA Guns, Slightly Stoopid, Green Day, Snoop Dogg, No Doubt, Amy Winehouse, Peter Paul and Mary, Tom Jones, Metallica, Guns N' Roses, Tupac, Simon and Garfunkel, Sublime, Megadeth.
Food: I love Italian--pasta and pasta :), Thai, Mediterranean, Mexican, Indian, Sushi. I love shitty diner food, vegan rocks sometimes, breakfast is always yummy.
The Great Outdoors


text:
I was looking around at the sub communities and figured why not. I thought it would cure some boredom cases out there. Sorry if any of these are repeats from previous rounds.Pick a girl and a boy for each.1. Biggest Mastermind-2. Most Creative-3. Best Adviser-4. Most Responsible-5. Biggest Manipulator-6. Best All Around Attitude-7. Biggest Rebel-8. Shyest(if there even is any)-9. Most Gullible-10. Biggest Influence-
WINNERS OF ROUND THREE!1. Most Wisest- Sherry Stringfield and Johnny Depp2. Most Graceful- Cate Blanchett, Sean Astin, and Orlando Bloom3. Best Singer- Billy Boyd and Britney Spears4. Most Trustworthy- Holly Marie Combs, Orlando Bloom, Billy Boyd, and George Clonney6. Most Cuddly- Alexandra Astin and Billy Boyd7. Best Entertainer- Dominic Monaghan and Hannah Wood8. Most Evil- Keira Knightley and Orlando Bloom9. Most Angelic- Alexandra Astin and Billy Boyd10. Best TV show character- Evangeline Lilly and Dominic Monaghan11. Most Amusing- Dominic Monaghan and Hannah Wood12. Best Leader- Matthew Fox and Cate BlanchettCONGRATS!( Awards for the Winners!Collapse )
Round 3Because, at the moment I have nothing better to do...Pick a boy AND a girl for each category, maybe even a little explanation of why you chose that particular person.Please, if some of you are easily offended, Don't take any of these the wrong way. It's just for fun!:-D1. Most Wisest-2. Most Graceful-3. Best Singer-4. Most Trustworthy-6. Most Cuddly-7. Best Entertainer-8. Most Evil-9. Most Angelic-10. Best TV show character-11. Most Amusing-12. Best Leader-Have Fun Kiddies!!
For the winners!( Read more...Collapse )
Here are the rules: Copy and paste this entry form and fill it out with your nominations. In each catergory you will nominate a boy and a girl. You can not nominate yourself. Have fun!!!1. Cutest Couple (for this one, just name 1 couple)2. Biggest Flirt3. Most Likely To End Up In Jail (remember, we are just joking around on this one, please don't take it seriously!)4. Most Artistic5. Funniest Member


text:
Report summaryTotal and PetroChina signed a contract for the development and commercialisation of the South Sulige field in March 2006. Total submitted the Overall Development Plan (ODP) in November 2008, following a 30-month evaluation period. However, the company had to revise its plans due to the government's concerns over high budgeted costs. In 2010, the operatorship was transferred to PetroChina and the project was integrated into the state company's existing facilities.
What's included?
This report includes 2 file(s)
- South Sulige PDF - 690.54 KB 15 Pages, 15 Tables, 8 Figures
- South Sulige XLS - 611.00 KB


text:
If you've turned on your television in New Jersey at any point in the last year, you've more than likely seen the commercial.
Continue Reading »»
Please note: All comments will be reviewed and may take up to 24 hours to appear on the site.
© 2017 BridgeTower Media. All information on this site is copyrighted by BridgeTower Media.
All images are the sole property of BridgeTower Media and no rights are granted for any use without the express written consent of BridgeTower Media.


text:
Isoprostanes are produced during peroxidation of membrane lipids by free radicals and reactive oxygen species. Initially, they were recognized as being valuable markers of oxidative stress, and in the past 10 years, dozens of disease states and experimental conditions with diverse etiologies have been shown to be associated with marked increases in urinary, plasma, and tissue levels of isoprostanes. However, they are not just mere markers; they evoke important biological responses on virtually every cell type found within the lung, and these responses exhibit compound-, tissue-, and species-related variations. In fact, the isoprostanes may mediate many of the features of the disease states for which they are used as indicators. In this review, I describe the chemistry, metabolism, and pharmacology of isoprostanes, with a particular emphasis on pulmonary cell types, and the possible roles of isoprostanes in pulmonary pathophysiology.
- oxidative stress
- arachidonic acid
- lipid peroxidation
- inflammation
- smooth muscle
- endothelium
- platelet
just over a decade ago, Morrow et al. (106) first described the nonenzymatic production of a series of prostaglandin-like compounds during peroxidation of membrane phospholipids by free radicals and reactive oxygen species. Since that seminal discovery, many studies have pointed out the usefulness of these compounds, particularly 8-iso-PGF2α, as markers of oxidative stress under many different clinical and experimental conditions (reviewed in Refs. 59,112, 144). Concurrently, others began to show that they also evoke important biological responses, first in vascular smooth muscle and platelets and then in many other cell types (see cellular actions). From these two avenues of investigation, a large and rapidly growing literature has developed, beginning in 1992 with the first three papers by Morrow and colleagues (102, 103, 106) to use the term "isoprostane" in referring to these compounds and growing exponentially ever since (see Fig. 1). In response to this outpouring of data, there have been a number of reviews of the existing literature (112, 144); however, these have emphasized particularly the chemistry of the isoprostanes (e.g., their structure, genesis, nomenclature, and detection), with relatively less discussion about their biological actions. I (59) have previously reviewed some of the biological effects of isoprostanes on smooth muscle. However, since the writing of that review, the literature has doubled again (Fig. 1), and it is now known that isoprostanes have effects on virtually every cell type found in the lungs; moreover, there have been some important new advances in our understanding of the signaling pathways by which isoprostanes act. In this review, I collate these data and bring them to bear particularly on pulmonary physiology and pathophysiology.
For detailed descriptions of isoprostane chemistry (e.g., their generation and nomenclature), the reader is directed to those earlier reviews written by Morrow and Roberts (112) and Rokach et al. (144). Briefly, though, oxygen-centered radicals such as peroxide and superoxide can react with the unsaturated bonds of arachidonic acid, leading to the formation of as many as four different bicycloendoperoxide intermediates differing in whether the peroxide group has been added to C-6/C-8, to C-9/C-11, or to C-12/C-14 (Fig. 2). Reduction of the intermediates leads to four different classes of isoprostane regioisomers, all composed of a cyclopentane ring with two alkyl chainscis to one another (Fig. 2). The prostanoids, on the other hand, have the two side chains trans to one another (Fig.3).
In addition to its well-described role in the production of prostanoids, cyclooxygenase (COX) can also contribute to isoprostane production in vascular smooth muscle (68,69), endothelium (167), platelets (74, 127,132-134), monocytes (125, 129, 131), macrophages (149, 160), and mesangial cells (74). However, it is not entirely clear whether the isoprostanes are direct products of COX or arise secondarily to an "overflow" of COX-derived reactive oxygen species. Some recent data (167) suggest the latter may be the case; 8-iso-PGF2α production in endothelial cells was shown to be COX dependent (in that it could be inhibited by indomethacin or aspirin) and also sensitive to catalase but not to superoxide dismutase, suggesting that hydrogen peroxide (H2O2) originating from COX was responsible.
Reactive nitrogen species may also participate in the production of isoprostanes. For example, nitric oxide (NO; on its own a weak oxidizing agent) reacts with superoxide to produce peroxynitrite (ONOO−), a highly reactive and cytotoxic molecule (136). Exposure of myelin suspensions (162), low-density lipoproteins (101), or human plasma (101) to peroxynitrite leads to lipid peroxidation and generation of isoprostanes; this effect is not mimicked by NO or superoxide alone (162). BN-80933 (a new neuroprotective compound combining potent antioxidant and selective neuronal NO synthase inhibitory actions) significantly reduced 8-iso-PGF2α levels in a rat model of cerebral ischemia-reperfusion injury (87); however, a follow-up study indicated that this effect of BN-80933 might be due more to its antioxidant properties than to its ability to inhibit NO synthesis (30). N-nitro-l-arginine methyl ester (a NO synthase inhibitor) greatly inhibited cytokine-induced production of 8-iso-PGF2αfrom pulmonary artery smooth muscle (69); this effect did not involve modulation of COX activity by NO because cytokine-induced release of PGE2 from these cells was unaffected.
Polyunsaturated fatty acids other than arachidonic acid are also vulnerable to reactive oxygen species and produce isoprostanes. For example, in addition to the four classes of F2-isoprostanes that can arise from arachidonic acid (eicosatetraenoic acid), peroxidation of eicosapentaenoic acid is predicted to lead to the generation of six classes of F3-isoprostanes (117,144), α-linolenic and γ-linolenic acids to two classes of E1- and F1-isoprostanes, respectively (13, 123), and docosahexaenoic acid to eight classes of D4-isoprostanes and eight classes of E4-isoprostanes (140) (Fig. 2). Each of these classes comprise up to eight racemic isomers, leading to an astounding number of isoprostane molecules!
Although dozens (hundreds?) of different isoprostane molecules can be produced by such free radical-mediated peroxidation, the group of isoprostane molecules most commonly referred to in the literature are those in which peroxidation occurs at C-9/C-11 of arachidonic acid, producing the family of 8-isoprostanes. Moreover, the particular member of this family that is by far the most prominent in the literature is 8-iso-PGF2α (Fig. 3). However, there is now evidence that D- and E-ring isoprostane species can also be produced in vivo and can accumulate to levels only slightly less than those of 8-iso-PGF2α (i.e., 1–2 orders of magnitude higher than circulating levels of prostaglandins) (82,105, 107, 108, 112, 113, 140). Also, like their PGD2and PGE2 cousins, dehydration of D- and E-ring isoprostanes in vitro and in vivo has produced A2- or J2-isoprostanes (17, 18). The widely differing pharmacological actions of some of these isoprostanes are only just beginning to be understood (see cellular actions).
The bicyclic endoperoxide intermediates that give rise to the isoprostanes can also rearrange to form other highly reactive molecules such as the isolevuglandins (12, 145) and isothromboxanes (104, 144), and isoleukotrienes have also been identified (48), but these are not discussed in this review.
For many reasons, isoprostanes are very well suited as biochemical markers of oxidative stress. First, they can be measured accurately down to picomolar levels (9, 152, 166) with analytic techniques such as HPLC (8), gas chromatography-mass spectrometry (1, 45, 108, 111, 133, 143, 144, 152), or radioimmunoassay (15, 166). The former two techniques are supremely able to discriminate between the different types of isoprostanes but require extensive preparation of the material (e.g., phospholipid extraction, alkaline hydrolysis) and expensive instrumentation (111). Radioimmunoassays are somewhat easier to perform and are widely commercially available; however, many of these are not able (or have not yet been shown to be able) to distinguish between the prostanoids and the isoprostanes, let alone between the different types of isoprostanes. One group (15) has described a radioimmunoassay that uses a monoclonal antibody directed against 8-iso-PGF2α conjugated to BSA; this assay exhibits a detection limit of 23 pmol/l, with very low cross-reactivity ratios of ∼10:1 for 8-iso-PGF2β, 100:1 for PGF2α, 8-iso-PGF3α, and 8-iso-15-keto-13,14-dihydro-PGF2α, and 10,000:1 for 8-iso-15-keto-PGF2α and 15-keto-13,14-dihydro-PGF2α. It is even possible to use isoprostanes to assess oxidative stress or damage in specific target organs of interest (e.g., via biopsy); for example, in carbon tetrachloride-induced hepatoxicity, isoprostanes were markedly elevated in the liver, lung, and kidney but not in the brain or heart (103).
Second, they are stable in isolated samples of body fluids; their presence was first detected in fresh and stored samples of plasma and urine (3, 106) and then more recently in cerebrospinal (46), pericardial (86), and bronchoalveolar (43, 98) fluids. A particularly exciting recent development has been the demonstration that they can be detected in breath condensates (15, 100), providing an exceedingly noninvasive route for their measurement.
Third, and most importantly, their measured values do not exhibit diurnal variations (53, 166) but do vary markedly in clinical and experimental conditions characterized by oxidative stress, and these values closely parallel disease severity.
In this way, a long list of respiratory-related pathologies has come to be associated with isoprostanes. 8-iso-PGF2αis generated in substantial amounts in otherwise "normal" individuals exposed to cigarette smoke (19, 28, 105, 127,141), allergen (32, 99), ozone (50), or hyperoxia (160, 161) and during ventilated ischemia (11) and is markedly elevated in patients with a wide variety of lung diseases such as asthma (32, 35,97), chronic obstructive pulmonary disease (128), interstitial lung disease (98), cystic fibrosis (23,100), acute lung injury including acute respiratory distress syndrome (15), and severe respiratory failure in infants (43).
Similarly, a number of cardiovascular conditions feature marked elevations in isoprostane levels, including renal (158), cerebral (87), and myocardial (29, 94, 142) ischemia-reperfusion injury; unstable angina (21); heart failure (86); coronary heart disease (90); acute ischemic stroke (163); hypercholesterolemia (26); atherosclerosis (131,135); and preeclampsia (5, 156). Isoprostane levels are increased in pulmonary hypertension (20) and during exposure to agents that are associated with hypertension, such as subpressor doses of angiotensin II (47, 116, 139), inflammatory mediators (68, 69), and growth factors (116).
Finally, 8-iso-PGF2α has been found to be a useful marker of oxidative damage and lipid peroxidation in disease states as diverse as Alzheimer's disease (96), multiple sclerosis (46), diabetes mellitus (27, 45), systemic lupus erythematosus (58), and several hepatic pathologies (10, 103, 110, 130) as well as in experimental settings ranging from humans in space flight (157) to sled dogs during endurance exercise training (55)!
Although the synthesis of prostanoids by COX first requires that arachidonic acid be liberated from the plasma membrane by phospholipases (22, 115), this is not necessarily true for the production of isoprostanes by free radicals; there is now good reason to believe that the latter can act on free fatty acids as well as on those still esterified to membrane phospholipids (102).
For example, isoprostanes have been identified within phospholipids extracted from surgical specimens of lung (11), atherosclerotic vasculature (119, 131, 135), lymphatics (118), brain (140), and preeclamptic decidua basalis (156). Levels of free and esterified isoprostanes in plasma from smokers remain significantly elevated above baseline for weeks after cessation of smoking, even though other markers of smoking such as urinary nicotine and cotinine become undetectable (105,141). In carbon tetrachloride-induced hepatotoxicity (103), isoprostanes begin to accumulate almost immediately in phospholipids extracted from the liver (and to some extent in the lungs and kidney) and shortly thereafter in the circulation; the latter reach a peak at 4 h (77-fold) and remain markedly elevated above baseline at 24 (21-fold) and 48 (10-fold) h, indicating prolonged oxidative stress and/or on-going release of esterified isoprostanes. The presence of the isoprostanes within the membrane is expected to have profound effects on membrane fluidity as discussed inmediators of pulmonary pathophysiology? Membrane properties.
Isoprostanes esterified in the membrane may then be released at some later time by phospholipases (144) because they are suitable substrates for bee venom phospholipase A2(102, 108), and phospholipase A2 inhibitors (mepacrine) partially reduce growth factor-induced isoprostane release in cultured cells (116).
Once isoprostanes are generated and released into the circulation, they appear to be quickly metabolized and eliminated. In one study done in the rabbit (8), it was shown that a bolus injection of 8-iso-PGF2α was rapidly distributed in the circulation, with a half-life of distribution of ∼1 min, and then was rapidly eliminated, with a half-life of ∼4 min. Using HPLC, they went on to show that 8-iso-PGF2α was degraded to several β-oxidized metabolites, culminating in formation of α-tetranor-15-keto-13,14-dihydro-8-iso-PGF2α. It was hypothesized that the metabolism of this isoprostane followed a sequential pathway similar to that ascertained for prostaglandins, involving 1) oxidation of C-15 by 15-hydroxyprostaglandin dehydrogenase and 2) reduction of the C-13,14 double bond by Δ13-reductase followed by 3) β-oxidation to α-tetranor-15-keto-13,14-dihydro-8-iso-PGF2α. The parent 8-iso-PGF2α and its metabolites began to accumulate in the urine within 20 min; 80% of the original radioactive label was present in the urine by 4 h. These findings parallel closely those made in an earlier study (143) using a single human volunteer and a rhesus monkey; 75% of the original radioactivity was found in the urine 4.5 h after infusion of the parent compound, with the primary metabolite being 2,3-dinor-5,6-dihydro-PGF2α. A more recent study done by another group (19) showed that the metabolites also include 2,3-dinor-PGF2α in humans and 2,3,4,5-tetranor-5,6-dihydro-PGF2α in rats.
Other more chemically reactive isoeicosanoids such as the A2-isoprostanes (18) and isolevuglandins (12) covalently adduct to proteins and are therefore protected from rapid clearance via the kidney.
Although there is an abundant literature pertaining to isoprostanes as markers of oxidative stress, we are only just now beginning to appreciate the wide variety of actions that the isoprostanes exert on the function of many different cell types. Thus isoprostanes should be considered not just "markers" but perhaps also as "mediators" of disease (see mediators of pulmonary pathophysiology?). However, the current literature describing the effects of isoprostanes is woefully inadequate at this time.
First, almost all the studies to date have focused on 8-iso-PGF2α despite the growing awareness that hundreds of isoprostane species can potentially exist, and evidence for the in vivo generation of some of these is now in hand (seeproducts of lipid peroxidation). Thus this fixation on 8-iso-PGF2α is distracting and detrimental; consider the results if the bulk of our understanding of prostanoid pharmacology came from studies of prostacyclin alone [or thromboxane (Tx) A2 alone or some other single eicosanoid] and the effects of the other prostanoids were extrapolated from them. Comparisons of the effects of 8-iso-PGF2α and 8-iso-PGE2 in a given tissue often reveal important differences; 8-iso-PGE2 evokes an electrophysiological response in epithelial cells (33), relaxation in canine airway smooth muscle (62), biochemical responses in calcifying vascular cells (124), and altered sensory neuronal function (34), whereas 8-iso-PGF2α is ineffective in all these respects. Only a handful of studies (62, 63, 79, 121, 146) have been done with isoprostanes other than 8-iso-PGF2α and 8-iso-PGE2; these, too, describe important differences between the isoprostanes. For example, in platelets pretreated with SQ-29548 to eliminate confounding effects via TxA2 (TP) receptors, eight different isoprostanes were tested and only 8-iso-PGE2 markedly increased cAMP accumulation (83). These marked differences in pharmacology between nearly identical chemical species attest to a highly discriminative mechanism, such as the involvement of specific membrane receptors, rather than to nonspecific effects, such as altered membrane fluidity (see Classic prostanoid receptors or unique isoprostane receptors? and Membrane properties).
Second, most of the existing pharmacological data were obtained in rodents, primarily the rat. Relatively few studies have been done with human tissues (25, 62, 71, 118, 121, 154), and there is strong evidence for species-related differences in the responses to isoprostanes: 1) in contrast to the airways in other species, those in the rabbit (54) and dog (62) do not constrict in response to 8-iso-PGE2 or 8-iso-PGF2α; 2) rat pulmonary arteries exhibit a relaxant response to 8-iso-PGF2α (67), in contrast to the vasoconstriction seen in other species; and 3) 8-iso-PGE2 constricts porcine and bovine but not ovine coronary arteries (76).
Third, the majority of the literature pertains to the effects of isoprostane on vascular smooth muscle and platelets; their effects on other cell types are only just now beginning to be understood.
Clearly, then, there is currently a very limited understanding of the physiological effects of these autacoids!
Classic prostanoid receptors or unique isoprostane receptors?
PGs were the first group of arachidonic acid metabolites to be identified and characterized in detail. There is now an extensive literature for these compounds that is not reviewed here; for this, the reader is referred elsewhere (22, 115). Briefly, however, there are five major prostanoid receptor types, termed D-prostanoid (DP), E-prostanoid (EP), F-prostanoid (FP), I-prostanoid (IP), and TP receptors that are each approximately an order of magnitude more selective for either PGD2, PGE2, PGF2α, PGI2, or TxA2, respectively (22, 115). The EP receptors can be further subclassified into four subtypes and the TP receptors into two subtypes (22, 115).
The selectivity of these receptors arises from interactions with the ketone or hydroxyl groups on the central cyclopentane ring as well as on the hydrocarbon chains. Although a different orientation (cis versus trans) of otherwise identical hydrocarbon chains on the cyclopentane ring might, on the surface, appear to be only a minor difference, it leads to either a roughly flat planar, densely packed molecule (the isoprostanes) or a wedge-shaped, arrowheaded molecule (prostanoids) (Fig. 3). Clearly, this would profoundly affect the way in which these molecules interact with membrane receptors. Thus it should not be assumed that 8-iso-PGF2α necessarily acts on FP receptors and/or that 8-iso-PGE2 acts on one of the EP receptors. In fact, many different groups have found the excitatory effects of both isoprostanes to be sensitive to a wide variety of agents that are structurally distinct but which all exhibit TP receptor-blocking activity, including ICI-192605 (62, 63, 67,71), SQ-29548 (4, 33, 38, 66, 70, 76-78, 88, 95, 147,164), L-657925 (164), L-670596 (33, 81,164), GR-32191 (33, 121), BAY U 3405 (120), LCB-2853 (91), BMS-180291 (95,174), and BM-13505 (76). Thus the bulk of the data would strongly suggest that TP receptors are involved.
However, mounting evidence suggests that there might be a novel isoprostane-selective receptor. To better understand the signaling mechanisms underlying the TP receptor-mediated responses that Banerjee et al. (4) and Takahashi et al. (158) had observed in vascular smooth muscle, Morrow, Roberts, and colleagues went on to examine the effects of 8-iso-PGF2αon platelets, which also express TP receptors. To their surprise, Longmire et al. (85), Morrow et al. (109), and Yin et al. (170) found that it is only a weak agonist for TP receptors and, in fact, acts primarily as an antagonist of the TP receptors on the platelet. After considering other possible explanations, they cautiously proposed the existence of a novel isoprostane receptor that happens to also show sensitivity to TP receptor antagonists. Concurrent studies by Fukunaga and colleagues (37, 38) using aortic smooth muscle showed that 8-iso-PGF2α displaces the binding of TP receptor-acting ligands with much less potency (2–3 orders of magnitude less) than the homoligands themselves but stimulated inositol 1,4,5-trisphosphate [Ins(1,4,5)P 3] production and [3H]thymidine incorporation with a higher potency than the TP agonists, leading them to also conclude that its effects were therefore probably transduced through a distinct receptor with close homology to the TP receptor. Later, they (40) described binding data and pharmacological responses to U-46619 in vascular smooth muscle that were not mimicked by 8-iso-PGF2α and provided evidence for low-affinity and high-affinity binding sites for 8-iso-PGF2α, which they interpreted to represent the TP receptor and a unique isoprostane receptor, respectively. High- and low-affinity binding sites for 8-iso-PGF2α have also been identified in endothelial cells (39, 171). A recent study (57) of brain microvessel smooth muscle cells described U-46619 responses that were not mimicked by 8-iso-PGF2α even though both acted on TP receptors in astroglia and endothelial cells from the same preparation. These accumulating data support the proposal that isoprostanes interact with a novel isoprostane-selective receptor on vascular smooth muscle while also acting nonselectively as an antagonist on TP receptors on the vascular smooth muscle and platelets. However, this view is not held by all (147, 174).
12-iso-PGF2α (but not 8-iso-PGF2α) is a powerful agonist for FP receptors (79), and there is evidence that some isoprostane responses may involve EP receptors (33, 147).
Vascular smooth muscle.
The biological actions of 8-iso-PGF2α were first investigated in the renal vasculature in which they elicit profound vasoconstriction (106). Since then, 8-iso-PGF2α and 8-iso-PGE2 have been found to have excitatory effects on virtually every vascular smooth muscle in which they have been tested, as might be predicted by the widespread distribution of TP receptors on the vasculature including the aorta (77, 164,174) and carotid (95), coronary (76, 78, 94,153), cerebral (56), pial (56), pulmonary (4, 66, 70, 164), renal (38, 106,158), portal (88), umbilical (121), and retinal (81, 91) arteries.
Recently, Janssen et al. (63) examined the responses to seven different isoprostanes, two of the E-ring series (8-iso-PGE1 and 8-iso-PGE2) and several different F-ring compounds (8-iso-PGF1α, 8-iso-PGF1β, 8-iso-PGF2α, 8-iso-PGF2β, and 8-iso-PGF3α), in small-diameter pulmonary arteries and veins; this was done with ∼10th-order (diameter of 0.5–3.0 mm) human vasculature and 4th- to 6th-order (diameter 2–6 mm) canine vasculature. 8-iso-PGE2 was by far the most potent and effective of these isoprostanes in human pulmonary arteries and was roughly equivalent to 8-iso-PGF2α in human and canine pulmonary veins, evoking responses two to three times larger than those to potassium chloride. The other isoprostanes were either weakly effective (8-iso-PGE1, 8-iso-PGF1α, and 8-iso-PGF2β) or noneffective (8-iso-PGF1β and 8-iso-PGF3α), attesting to the high degree of specificity of the mechanism transducing these responses. The canine pulmonary artery was essentially unresponsive to any of the isoprostanes. Consistent with the literature, these contractions were sensitive to the TP receptor antagonist ICI-192605; they were also sensitive to the EP receptor antagonist (AH-6809), but we believe this represents a nonspecific effect of AH-6809 on TP receptors because these tissues do not exhibit any excitatory response to the EP-selective agonist PGE2 (63).
Three major signaling pathways have been found to be involved in mediating isoprostane contractions in vascular smooth muscle. On one hand, some studies of rat vasculature describe 8-iso-PGF2α-triggered activation of phospholipase C and elevation of cytosolic levels of Ins(1,4,5)P 3 (37, 38) as well as of 8-iso-PGF2α-evoked contractions, which are sensitive to the protein kinase C inhibitor calphostin C and to blockers of voltage-dependent Ca2+ channels (164). Others, however, show that the isoprostane does not alter intracellular Ca2+ concentration ([Ca2+]i) (40, 57, 63) but instead greatly enhances mitogen-activated protein (MAP) kinase activity when applied at nanomolar concentrations in rat aorta (40) and in porcine carotid artery (95). Unfortunately, the assays used to show this effect (phosphorylation of a peptide substrate) could not definitively identify the MAP kinase nor its downstream target(s).
My laboratory (63) also investigated the mechanisms underlying isoprostane-mediated excitation-contraction coupling in pulmonary vasculature using patch-clamp electrophysiological, fura 2 fluorometric, and standard muscle bath-based pharmacological techniques and also found that the isoprostanes caused little or no change in [Ca2+]i in single cells (although other agonists such as caffeine or phenylephrine did) nor were the isoprostane contractions affected by blocking the voltage-dependent Ca2+ channels (with nifedipine) or depleting the internal Ca2+ store (with cyclopiazonic acid). These findings led us to pursue the possibility that the contractions involve a change in the Ca2+ sensitivity of the contractile apparatus (rather than mobilization of Ca2+ per se). In smooth muscle, this phenomenon seems to generally involve activation of Rho and Rho kinase, which go on to phosphorylate and thereby suppress myosin light chain phosphatase (155); other pathways under investigation include protein kinase C, extracellular signal-regulated kinase (ERK) 1/ERK2, and p21-activated kinase (PAK) (24, 36,155). We found (63) that the isoprostane contractions were insensitive to two different blockers of protein kinase C with different mechanisms of action (chelerythrine and calphostin C, which interact with protein kinase C at its regulatory and catalytic sites, respectively). They were also insensitive to inhibitors of ERK1/ERK2 (PD-98059) or p38-activated kinase (SB-203580) but were essentially abolished by two structurally different blockers of Rho kinase (Y-27632 and HA-1077). Thus isoprostanes act in the pulmonary vasculature via Rho and Rho kinase, which presumably suppress myosin light chain phosphatase activity, resulting in a net accumulation of phosphorylated myosin light chains (Fig.4). Moreover, the responses are blocked by the tyrosine kinase inhibitor genistein (but not by its less active analog daidzen), suggesting that tyrosine kinases also play a key role, possibly in triggering the sequence of events outlined above; my laboratory is currently investigating the possible targets that are tyrosine phosphorylated during stimulation with isoprostanes.
Finally, in contrast to the two direct mechanisms summarized above, data from porcine retinal (81) and periventricular brain (57) microvessels suggest that isoprostanes may activate vascular smooth muscle indirectly via the endothelium: 1) 8-iso-PGF2α elevates [Ca2+]i in the retinal vascular endothelium but not within the smooth muscle per se and stimulates release of endothelin (81) and/or TxA2 (57),2) vasoconstriction is blocked by inhibitors of the synthesis of those autacoids (i.e., the endothelin-converting enzyme inhibitor phosphoramidon or the TxA2 synthase inhibitor CGS-12970, respectively) or by inhibitors of their receptors [i.e., the endothelin (ET) A receptor blocker BQ-123 or the TP receptor blocker L-670596, respectively], and 3) blockade of receptor-operated Ca2+ influx inhibited both the change in [Ca2+]i in the endothelium and contraction in the smooth muscle.
There are no published data yet on the effects of isoprostane on ion conductances in any smooth muscle tissue. However, in ongoing studies with patch-clamp electrophysiological techniques, my laboratory has found that 8-iso-PGE2 suppresses K+currents in airway and pulmonary arterial smooth muscle cells (D. Zhang, unpublished observations).
Airway smooth muscle.
Several groups have described TP antagonist-sensitive excitatory responses to 8-iso-PGE2 and 8-iso-PGF2α in airway smooth muscle of the rat (70), guinea pig (71), human (62,71), and pig (Janssen, unpublished observations). Interestingly, rabbit (54) and canine (62) trachealis do not exhibit a contractile response, whereas canine bronchi show only moderate contractions (62), consistent with the distribution of TP receptors in the airways of different species (22, 115). Once again, Janssen et al. (62) found that 8-iso-PGE2 was generally 10–100 times more potent than 8-iso-PGF2α, the isoprostane most commonly studied elsewhere. Furthermore, they were amazed at the specificity of these responses. For example, two isoprostanes that are nearly identical in structure to 8-iso-PGF2α, 8-iso-PGF2β (differs solely in the orientation of a single hydroxyl group on the cyclopentane ring) and 8-iso-PGF3α (differs only in possessing one extra double bond; Fig. 3), lacked any spasmogenic activity; in fact, 8-iso-PGF3α evoked dose-dependent relaxations (Fig. 5). In ongoing studies of the mechanisms underlying these bronchoconstrictor responses in human airway smooth muscle, my laboratory has identified many aspects in common with the signaling pathway underlying vasoconstriction; that is, the responses are sensitive to the TP receptor antagonist ICI-192605, the tyrosine kinase inhibitor genistein, and the Rho kinase inhibitor Y-27632 (Janssen, unpublished observations).
The E-ring isoprostanes 8-iso-PGE1 and 8-iso-PGE2 are powerful bronchodilators in canine airway smooth muscle, mimicking the effects of PGE2itself (62). The latter finding suggests that these responses are mediated through EP receptors. Experiments are ongoing, aimed at elucidating the signaling pathways involved (Janssen, unpublished observations).
8-iso-PGE2 and 8-iso-PGF2α stimulate shape change and aggregation in platelets (75, 83, 85, 109, 134) and reduce the antiadhesive effects of NO (93). In fact, several groups hypothesized that elevated levels of isoprostanes contribute to the increased activation of platelets (as indicated by plasma levels of TxA2 metabolites) seen in hypercholesterolemia (26), acute ischemic stroke (163), diabetes mellitus (27), and preeclampsia (156). Interestingly, 8-iso-PGF3αinterferes with ADP-induced platelet aggregation (83).
As outlined above, these effects are exerted through TP receptors that couple to the G proteins Gq and G11 and cause generation of Ins(1,4,5)P 3 and elevation of [Ca2+]i (72, 73, 134). 8-iso-PGE1 also stimulates adenylate cyclase activity (83), whereas several other isoprostanes including 8-iso-PGE2 and 8-iso-PGF2α do not (83).
There have been no studies yet on the effect of isoprostanes on airway epithelium. However, in gastrointestinal epithelium (33), 8-iso-PGE2 and/or 8-iso-PGF2α alter membrane ion channel activity (as indicated by increased short-circuit current), apparently via EP receptors (because their effects are not blocked by TP receptor antagonists but are reduced by desensitization of EP receptors).
Diverse responses to isoprostanes have been described in cultured endothelial cells. In the endothelium of microvessels, 8-iso-PGF2α stimulates DNA synthesis and proliferation, ET-1 mRNA and protein expression, TxA2synthesis, Ins(1,4,5)P 3 formation, and elevation of [Ca2+]i (39, 57, 81), the latter effect being, in part, sensitive to a blocker of receptor-operated Ca2+ influx (SKF-96365) but not to one of voltage-dependent Ca2+ influx (nifedipine). Another study (172) with human umbilical vein endothelial cells showed that 8-iso-PGE2 and/or 8-iso-PGF2α did not increase expression of intercellular adhesion molecule-1 or E-selectin but did induce some change in the endothelial cells, which, in turn, was sufficient to enhance neutrophil adhesion (see Inflammatory cells). At the whole animal level, isoprostanes increase plasma exudation in guinea pig airways (assessed via Evans blue dye extravasation) (108) and edema formation in rabbit lung (4).
Inflammatory cells.
8-iso-PGE2 and 8-iso-PGF2α were both found to enhance human polymorphonuclear granulocyte activity and adhesion to endothelial cells but did so via some indirect mechanism because neither isoprostane increased expression of CD11b or P-selectin nor were the levels of interleukin (IL)-6 or IL-8 altered, but CD11b expression was increased when naive neutrophils were exposed to isoprostane-pretreated endothelial cells or to supernatants from pretreated endothelial cells (172). Interestingly, this indirect activation was not inhibited by antagonists of TP or ET receptors (SQ-29548 and bosentan, respectively).
Neuronal cells.
8-iso-PGF2α augments sensory neuronal function in that it increases the release of transmitters from isolated sensory neurons, enhances the firing of C-nociceptors in situ and of cultured sensory neurons in vitro, and significantly reduces the threshold levels of mechanical and thermal stimuli required to trigger hind paw withdrawal (34). E-ring isoprostanes inhibit norepinephrine release in rat hypothalamus (31). Finally, 8-iso-PGF2α triggers Ca2+ influx in astrocytes via N-type (i.e., ω-conotoxin-sensitive) Ca2+ channels (57).
Nonpulmonary cell types.
Isoprostanes also constrict myometrium (25), muscularis mucosa of the canine proximal colon (33), gastric fundus, (147), ileum (147), and lymphatic vessels (118, 154), stimulate alkaline phosphatase activity and differentiation in calcifying vascular cells but inhibit these in preosteoblasts (124), and induce hypertrophy in cardiac ventricular myocytes. The latter effect is accompanied by inositol phosphate formation and is dependent on activation of c-Jun amino-terminal kinase (JNK1), c-Jun, phosphatidylinositol 3-kinase, and p70 S6 kinase (80).
Summary and physiological relevance.
It is clear, then, that isoprostanes are not just markers but that they can exert a wide range of biological effects, particularly on pulmonary cell types, depending on the species, tissue, and isomer being tested. Collectively, these findings emphasize the need for further investigations in this area and the danger in generalizing from studies done with 8-iso-PGF2α in rodent tissues.
One might question whether isoprostanes can accumulate to levels sufficient to trigger functional responses such as those listed above. Numerous independent measurements of isoprostane levels yield values in the nanomolar range in total plasma or urine of normal or healthy individuals (26, 27, 35, 106, 127, 163), and these levels are markedly elevated (as much as 200-fold; 112) during oxidative stress (see markers of oxidative stress). Although these systemic concentrations might be subthreshold for some of the responses listed above, they are sufficient to markedly augment the responses evoked by other agonists (i.e., to induce nonspecific hyperresponsiveness; see Airway hyperresponsiveness) and to stimulate MAP kinase activity (40, 95). Also, this measured value pertains to total plasma or urine after the isoprostanes have been diluted throughout the systemic circulation and metabolized by the kidney and liver; it is entirely reasonable that isoprostane levels are substantially higher at the site of oxidative stress (e.g., within the lung per se or in the immediate vicinity of the cells releasing the reactive oxygen species).
The recent awareness that isoprostanes are produced in abundance during oxidative stress and that they possess a diverse repertoire of biological actions may provide a whole new perspective on our understanding of pulmonary pathophysiology.
Membrane properties.
Much attention has been focused recently on the effects of free radicals in the lungs (7, 61, 89, 137); it may be that these are, in part, the result of actions exerted by isoprostanes on the membrane. For example, arachidonic acid is a long hydrocarbon chain that contributes to some extent to the fluidity and hydrophobic nature of the membrane; conversion of this molecule into a hairpinlike structure by forming a cyclopentane ring at its center as well as by introducing several hydroxyl groups on that cyclopentane ring while it is still esterified within the membrane would markedly alter membrane fluidity, integrity, and hydrophobicity (102, 112), all of which are common features of lipid peroxidation.
Mechanical responses to free radicals.
Similarly, the mechanical responses evoked by reactive oxygen species may, in fact, be mediated by isoprostanes produced by those free radicals. Canine airway smooth muscle exhibits a relaxant response to H2O2 (41, 61), whereas human airways show a bronchoconstrictor response (Fig.6) (137). The substantial body of literature summarized above predicts that such exposure to H2O2 would lead to generation of a variety of isoprostanes, although the precise composition of this mixture of isoprostanes (the relative proportions of different isoprostane species) might vary from tissue to tissue. Although it might therefore seem hard to predict the response of the tissues to such complex mixtures, it is worth pointing out that in the dog, most isoprostanes evoke substantial relaxations, but none exhibit any appreciable excitatory activity (62), so the net effect that one might predict from a mixture of isoprostanes is bronchodilation, which is, in fact, the observed response to H2O2 (Fig. 6) (41, 61). In human airway smooth muscle, on the other hand, several isoprostanes are powerful constricting agents, and only one (8-iso-PGF3α) is moderately inhibitory at very high concentrations (62), which would account for the observed bronchoconstrictor response to H2O2(Fig. 6) (137). Likewise in pulmonary vascular smooth muscle, both H2O2 and isoprostanes evoke contractions with similar pharmacological sensitivities (14, 60,62, 65).
Airway hyperresponsiveness.
Isoprostanes may contribute to nonspecific airway hyperresponsiveness because subthreshold concentrations of 8-iso-PGE2 and 8-iso-PGF2α have been shown in vascular smooth muscle (146) and platelets (134) to amplify the responses to norepinephrine, angiotensin II, and the Tx mimetic U-46619. Recently, it has been shown that lipopolysaccharide-induced murine airway hyperresponsiveness is COX independent and yet sensitive to a blocker of TP receptors or to the free radical scavengerN-acetylcysteine (51, 52); these observations are all consistent with the generation and pharmacological actions of isoprostanes.
Lung transplantation.
Cerebral, myocardial, and renal ischemia-reperfusion injury are all associated with generation of isoprostanes (see markers of oxidative stress), a substantial proportion of which may remain esterified within membrane phospholipids and be released over a prolonged period of time (see storage, release, and metabolism). These facts may be highly pertinent to lung transplantation; the donor lungs may, in fact, represent a major source of isoprostanes for days or weeks after the operation, affecting many parameters of lung function. Related to this, restoration of bronchial blood flow is recognized to be vital to the success of lung transplantation (126), and this may be adversely affected by the ongoing release of isoprostanes from the oxidatively stressed lungs.
Acute lung injury and pulmonary hypertension.
Acute lung injury and pulmonary hypertension are associated with increased metabolism of arachidonic acid (6, 44, 64, 92, 122,138, 165, 173) and are sensitive to inhibitors of TP receptors (16, 42, 114, 122, 151, 159, 165, 173), Tx synthase (16, 64, 114), COX (16, 64, 122, 151), and phospholipase A2 (84). Thus some speculate that TxA2 plays a central role in mediating these pathological changes, although others conclude differently (44). However, recent data (2, 44, 150, 168,169) link superoxide and peroxide to these changes, which raises another possibility: isoprostanes generated by COX or nonenzymatically by free radicals and acting through TP receptors may mediate these changes. 8-iso-PGF2α is released from several sources under conditions associated with acute lung injury and hypertension: from deendothelialized pulmonary artery smooth muscle on stimulation with growth factors (platelet-derived growth factor, transforming growth factor-β), proinflammatory cytokines (tumor necrosis factor-α, interferon-γ, and IL-1β), or superoxide (68, 69, 116); from pulmonary arterial endothelium stimulated with H2O2 (49); and from renal mesangial cells stimulated with IL-1 (74). 8-iso-PGF2α generated in this way would potentially disrupt endothelial barrier function (49) and trigger pulmonary and systemic vasoconstriction (see Vascular smooth muscle).
There is growing interest in isoprostanes as putatively important mediators in lung pathophysiology. First, they are produced in abundance by reactive oxygen species released from inflammatory cells in the airways or in a COX-dependent fashion by virtually every cell type present in the lungs (smooth muscle, epithelium, endothelium, platelets, and inflammatory cells; see products of lipid peroxidation). Second, they exert important biological actions on airway and pulmonary vascular smooth muscles, epithelium or endothelium, sensory nerves, and lymphatics (see cellular actions); these actions can account, in part, for the nonspecific smooth muscle hyperresponsiveness, bronchoconstriction, hypertension, edema, and hypertrophy that characterize many lung-related diseases. Third, the unique nature of the generation and pharmacology of isoprostanes can account for the sometimes paradoxical effects of steroids, free radical scavengers, COX inhibitors, and TP receptor blockers in experimental and clinical settings.
The isoprostane field is still in its infancy, and many important questions remain unanswered. Clearly, one important avenue of investigation pertains to the therapeutics designed to prevent the actions of isoprostanes in the lung.
On one hand, it should be possible to interfere with their production by using free radical scavengers. Numerous studies have documented an inverse relationship between the levels of isoprostanes and free radical scavengers such as vitamins A (23), C (130,141), and E (21, 23, 26, 27, 130, 135, 148); β-carotene (23, 130); selenium (35); superoxide dismutase and catalase (11), or a superoxide dismutase mimetic (4-hydroxy-2,2,6,6-tetramethyl piperidynoxyl) (149). In some cases, oral supplementation with these scavengers was accompanied by amelioration, proportional to the reduction in isoprostane levels, of the pathophysiology being studied (11, 26,130, 149). COX inhibitors and steroids, both used with success in the treatment of many pulmonary disorders, have also been shown to suppress isoprostane production by inflammatory cells stimulated with proinflammatory cytokines and growth factors (125, 129, 131, 149,160).
Rather than interfering with isoprostane production, an alternative approach would be to interfere with isoprostane signaling at the receptor level; TP receptor blockers have already been shown to be useful in this respect (see Classic prostanoid receptors or unique isoprostane receptors?). Further work is needed to clarify whether a novel isoprostane-specific receptor is, in fact, involved, and if so, what agents can be used to block those selectively. It is worth noting that although isoprostanes mediate such a variety of effects within the lungs, many of the currently available therapies for pulmonary diseases, including leukotriene antagonists, antihistamines, anticholinergics, α-adrenergic blockers, and β-agonists, are ineffective against the isoprostanes. Alternatively, a better understanding of the second messenger signaling pathways underlying isoprostane responses might also allow for the development of novel treatments for pulmonary diseases characterized, in part, by oxidative stress.
More investigation is needed to further elucidate the cellular actions of isoprostanes in the lungs. There have been no studies of their effects on airway epithelium or innervation and virtually none pertaining to their effects on different inflammatory cell types and the endothelium. Although some of their effects on smooth muscle have been described, little or nothing is known about their effects on gene expression, cytoskeletal rearrangement, hypertrophy, or apoptosis in smooth muscle. Also, their interactions with other spasmogens (resulting in nonspecific hyperresponsiveness) needs to be studied in more detail. The biological effects of many isoprostanes and their metabolites have not yet been examined, even though there is now evidence that isoprostanes with nearly identical structures can have very different pharmacological effects (see cellular actions). The signaling pathways involved are still poorly understood, and almost nothing has been published about their effects on kinases, ion channels, and Ca2+ handling.
Assuming that the exponential growth in the number of publications pertaining to isoprostanes continues (Fig. 1), the next few years are certain to hold answers to many of these questions.
Funding support for the studies of isoprostane effects on smooth muscle have been provided by the Canadian Institutes of Health Research and the Ontario Thoracic Society.
Address for reprint requests and other correspondence: L. J. Janssen, Dept. of Medicine, McMaster Univ., 50 Charlton Ave. East, Hamilton, ON L8N 4A6, Canada (E-mail: janssenl{at}mcmaster.ca).
- Copyright © 2001 the American Physiological Society


text:
|Property type
140sqm (1,600 sq ft), big kitchen, 2 bathrooms, Jacuzzi
3 conditioners, 3 TVsets, home theater, WiFi, fire-place
3rd floor, n/e, 5 sleeping places, renovated building and entrance
terrace, green courtyard with limited access, own parking lot
nearest metro stations: Kreshchatik, Teatral'naya, Maidan
Additional fees to be charged upon arrival
Cleaning Fee: 11$
Refundable Security Deposit: 110$
Reservation Detail:
After you successfully submit your reservation request, you will receive an e-mail response from the home owner or property manager, within the next 24 hours. At this point, the full details of your confirmed reservation including the address of the property and the contact details of your local host will be shared with you through e-mail.
We hope you have a pleasant stay!
*Plus compulsory or optional charges based on actual occupancy or consumption. The payment has to be made in the currency offered by the property manager, before use of conversion tool. Payments in other currencies have to be negotiated beforehand with the property manager. The currency conversion tool is provided for your convenience only and is non-binding.


text:
So to start: I'm 20 years old and going to university. I think I have always been a littebit shy and introverted, and I have never had real friends. I was bullied at school for about 3 or 4 years. I have never had any contact with girls, because I was no player and because I felt inferior after I have been bullied.
Now I'm a student at a university, I'm happy with the subject I'm studying and I think that there will be good job opportunities for me. But I haven't had any good contact at university, which doesn't bother me at all, because I'm used to be alone a lot. Thankfully having friends is not very important for me, because I also need space and time for myself, but I lack a very important ability, which is having a small talk or making contact with random people. What is even more important to me is that I don't know how to talk to girls, no matter if it's just friendship, casual sex or a relationship.
Basically I don't want any expressions of sympathy or anything, what I eventually want are tips how to change this. I guess that I look quite average, not like a player and I'm not fat either. But how can I have more luck with girls? I have in the recent past gone out with some girls, we just drank a coffee or something, but what I noticed is that I don't have the ability to make jokes or the sense of humor, which is, from what I heared, very important for girls. And it's nice to drink a coffee with them, but I think every guy wants more that just drinking a coffee.
Are there many differences between guys who are "boyfriend material" and "player" material? What do I have to change? How can I have a sense of humor?
Most Helpful Guy
You're an introvert, nothing wrong with that. I'm an ambivert, so Im blessed with both perspectives.
Talking to people is a skill that you need to practice just like anything else. Also, don't let anyone try to tell you that it is only a natural ability or anything stupid like that. I assure you that's not true. It's a science that can be learned, practiced, and mastered.
It's all just a game. People in general are extremely selfish by nature. Half the battle is literally just letting people talk about themselves, which they love to do. Just ask questions and pretend like you're interested haha... easy.
When it comes to women, it's all about confidence... that's what it boils down to. If you aren't naturally confident, then you can learn how to fake it to the point that it starts to work for you, and then you DO become naturally confident.
Read some books about seduction and then get out there and start practicing... there's no way around that. Don't be afraid of rejection... who cares what she thinks about you. Just be yourself and have fun. You'll start to notice that conversations have a flow, patterns, and certain "energies. It's up to both people to keep that conversation alive, and you'll get a better feel for this with practice.
Your own mind and fear is the only thing holding you back man. Step outside your comfort zone and just take a leap and go for it. The worst that can happen is she says no. Then fine... on to the next one. Sometimes you'll have to deal with bitches who will laugh or whatever, but that's all part of the experience. Don't let it get to you... you can't. That shit doesn't bother confident guys, and that's who you need to be to start having success. I've personally been rejected by literally hundreds of girls, but ya know what? I've also slept with around 60 girls, and I've had 4 long term relationships. I used to be shy, nervous, etc. around girls and i never got laid. Now i don't give a flying fuck... I'll walk up to a group of girls and half the time i don't even know what the hell I'm saying... just on autopilot. And it pays off because now girls come to me instead. Most of it really is just a numbers game... the more you approach, the higher your chance of success.
So read up on it and learn a few techniques, but ultimately you're just gonna have to man-up and get out there and do it. Good luck man10|10|0
Hey man, thank you very much for your comment, it means a lot to me. There is one question: what means confidence? first you have to know what confidence means. And I think your answer is more directed to people who want to hook up. Then you have to be "an asshole" as how I read it and heared it. How can I fake confidence?


text:
Shockrina Model
Tara GlynnHair Stylist Female Augusta, Georgia, US
Mayhem # 403061
About Me
I trained at Vidal Sassoon in Los Angeles, California. Did apprentership in Beverly Hills. And since then now work in Augusta full time. I am now an Educator for Paul Mitchell and teach cutting, coloring, and business building. I have some experience in editorial work. I am looking to do more editorial work and models for shoots of my own.
Have you worked with Tara Glynn? Add Credits for Tara Glynn! >>
Credit Notes
Paul Mitchell Charity Event, Augusta, GA December 2005
Martha Stewart Wedding, Summer 2000
Long Beach California Show with Vidal Sassoon, 2000
Shockrina Model
RSPhotogra... Photographer
Body Farm Makeup Artist
Toria Nichole Model
Gina aka Jean Model
martika Model
Loading Content


text:
Cockaleekie Bake
Recipe by Tea Jenny
This is a nice warming meal on it's own. I wanted to use leeks that were in season and a good price. and of course leeks have a nice delicate taste. I used mostly the white part of the leek and saved the dark green for soup so nothing went to waste. If you choose you can make the sauce with half milk and half stock.
Top Review by strawberrybird
My husband and guests loved this, but I thought the chicken came out a little dry. This may not be due to the recipe so much as the quality of the meat, but I wanted to mention it. The flavor was lovely and I enjoyed a new way of including leeks in my meals.
See Discussion:1 Review
Ingredients Nutrition
- 4 chicken breasts
- 2 large leeks
- 1 tablespoon olive oil or 1 tablespoon butter
- 40 g butter
- 25 g all-purpose flour
- 425 ml of cold milk
- salt and pepper
- breadcrumbs, roughly crumbed
- grated cheese
Directions See How It's Made
- Wash and chop leeks into one inch pieces and saute in oil or butter untill soft and coated.
- Then remove from pan and put in a 25cm x 20cm x 10cm oven proof dish.
- Cut up chicken into smallish pieces and brown in the same pan.
- Scatter the chicken evenly on top of the leeks.
- Set this to one side and make the sauce.
- Place butter, flour, milk, salt and pepper in a pot on the stove top and heat on a medium heat.
- Whisk untill the sauce starts to bubble and thicken and change to a wooden spoon to give it a good stir then whisk again thoroughly.
- Turn the heat down and cook the sauce for about 5 minutes.
- If you start with everything cold it won't go lumpy.
- You can if you like add cheese to this or just leave it plain.
- Pour sauce on top of chicken.
- Mix bread crumbs and cheese and sprinkle on the top.
- Place in a preheated oven at 175 or 350 for 45 minutes.


text:
There is a rumor going around that Hillary Clinton hopped on the 'Lolita Express' with her husband many many times. These rumors have turned into accusations that the Hillary Clinton email scandal could reveal damning evidence that she is a pedophile. If you haven't heard of the 'Lolita Express' it is a private jet owned by convicted pedophile Jeffrey Epstein.
There are whispers that the only reason people board Epstein's jet is to partake in the young children he supposedly provides on it. So far, the only evidence of the Clinton's pedophilia are the flight logs showing them flying on Epstein's plane to his "pedo island" dozens of times.
Hillary Clinton definitely has a past of disregarding the victimization of children. Early on in her career as a lawyer she was recorded bragging about getting a pedophile off the hook from child rape. She also laughed because she thought she was so smart to win that case. In the interview she inferred that she thought her client was guilty of the crime as she mentioned having him take a polygraph test of which he passed so she said that from that point on she never put trust in polygraph tests.
But NOW a series of YouTube videos have been released that present even more information that could wipe out the Clinton's and their associates. The presenter is Steve Pieczenik who is a psychiatrist, former United States Department of State official, author, and publisher. In these videos, he presents possible information that would link them to the same crimes as their pedophile friends.
In a video posted on November 1, Pieczenik spells out the extent of the corruption in the US government, "The Clinton's have been involved in co-opting our White House, our Judiciary, our CIA, our Federal Bureau of Investigations, our Attorney General Loretta Lynch and our Director of the FBI James Comey for some time now."
"What they've done is make sure that they were part and parcel of a group of people who were interrelated through political cronyism," Pieczenik continues. "However, in order to stop this coup, we in the intelligence community and others involved have informally gotten together and with their permission, I am beginning to announce that we have initiated a counter-coup through Julian Assange and Wikileaks."
Pieczenik then describes what has led to the massive release of Podesta emails through Wikileaks,even more important he confirmed an anonymous post on 4chan accusing Hillary Clinton of pedophilia as being authentic. Watch the VIDEO's here and decide for yourself.


text:
Postgame Notes
Postgame Notes
Jan. 30, 2013
Recap | Final Stats | Quotes | Photo Gallery
No. 18/21 Kansas State (16-4, 4-2) 83, Texas (9-11, 1-6) 57
Bramlage Coliseum – Manhattan, Kan.
Miscellaneous Notes
• Kansas State is now 296-97 (.754) all-time at Bramlage Coliseum… The Wildcats are 12-1 at home this year, including 11-1 at Bramlage Coliseum.
• The Wildcats are now 14-10 against Texas, and have won 5 of the last 7… K-State is 8-3 at home in the series… The 26-point victory is one point shy of the largest victory ever over Texas, with K-State winning 87-60 in the first meeting in 1971.
• The starting lineup for tonight's contest consisted sophomore guard Angel Rodriguez, junior guard Will Spradling, senior guard Rodney McGruder, senior forward Jordan Henriquez and junior forward Shane Southwell… K-State is now 1-0 when using this lineup.
• Attendance on Wednesday was announced as 12,109… K-State averaged 12,783 last season to rank 25th in the nation in attendance… Wildcat fans are averaging 12,567 so far this season.
Team Notes
• K-State held Texas to just 19 points in the first half… It marked the fifth time this season the Wildcats have kept an opponent to 20 or less in the opening stanza.
• The Wildcats had an assist-to-turnover ratio of 3.50… K-State entered the game leading the Big 12 in the category at 1.3… K-State also leads the conference in turnover margin at +2.3… The Wildcats forced Texas into 18 turnovers and committed just 6 for a +12 margin.
• Those 18 turnovers resulted in 33 points off turnovers for K-State, one point shy of a season-high… Texas only converted for 8 points off turnovers.
• With a number of starters in foul trouble, K-State had 45 points from the bench… That mark tied the season-high against North Dakota.
Individual Notes
• Thomas Gipson scored a season-high 17 points off the bench on 7-of-10 shooting and a perfect 3-of-3 at the free-throw line.
• Omari Lawrence had a career night off the bench… He scored a career-high 12 points shooting 5-of-10 and pulled down 6 rebounds… He provided a spark in the first half with 10 points.
• Jordan Henriquez started today's game, it was his first start since the Michigan game… He scored 7 points and had 4 rebounds.
• Angel Rodriguez just missed a double-double scoring 11 points and dishing out 8 assists… The starting point guard helped his assist-to-turnover ratio with only 1 turnover.


text:
Sherlock Pipe Wig Woo Over Dichro Window PaneTalent Glassworks
Out of Stock
Preorder Available! This product is on the way and will be in stock soon. Pre-ordering will let you receive yours as fast as possible because preorders ship first!
Product Description
Talent Glass - Wig Woo Window Over Dichro Spoon Pipe
The combination of multiple glass designs gives this glass spoon pipe an edge of uniqueness that shows Talent Glass mission to create superior glassware.
The bowl end features an awesome round wig wag design that gives the glass piece a trippy expression. The black layer around the wig wag pattern is nicely complemented by the black carb hole which is located next to the bowl. The glassblowers then add a shimmering dichro design that wraps itself around the spoon pipe.
Made from borosilicate glass, this handheld smoking pipe comes in the ever so popular spoon shaped design. Marvellously decorated this portable spoon pipe has great functionality and will be a prized possession for any glass pipe enthusiast.
Technical Specifications
brand Talent Glassworks material Glass


text:
How Can I help My Mom to deal with end of life concerns?
My Dad has passed on and Mom has no one her age to share her fears and concerns about death and her care. She is 82 and has yet to discuss anything.Also she has lost 2 sons and she still grieves for them.
Expert Answers
Because I am not a counselor, I can only give you a suggestion based on my experience as a funeral director. It's hard for anyone to lose a spouse, but to have also lost two sons, is especially difficult. It's nice that you sense that and acknowledge it.
Many funeral homes have someone on staff who follows up with a spouse after the funeral services to answer any questions and to also see how she's doing. If no one has done that, call the funeral home and ask if they can recommend a local counselor who might do that. You might also call her minister or clergyman, express your concerns, and ask if he/she would visit your mother or have someone from the church stop by. If you're not comfortable with that, you might also consider calling her doctor and asking if he/she would speak with your mother or maybe suggest someone who would.
Ministers, doctors, and funeral directors usually have contacts with counselors, grief support groups, and other professionals that they can recommend. Your mother's fortunate to have you looking out for her.
Stay Connected With Caring.com
Get news & tips via e-mail


text:
Sorry, the book that you are looking for is not available right now.
We did a search for other books with a similar title, however there were no matches. You can try selecting from a similar category, click on the author's name, or use the search box above to find your book.
The student books provide opportunities for students to discover, explore and connect to new mathematical concepts.
Series: Oxford Big Ideas Mathematics
Audience: Primary / High School
For Grades: 6
Format: Paperback
Language: English
Published: 27th November 2012
Country of Publication: AU
Weight (kg): 0.566


text:
David Vine of GlobalExpense offers his advice on how the MP expenses system should be overhauled.
While many of us have a few choice words of wisdom wed like to share with Sir Christopher Kelly, who is leading the Committee on Standards in Public Life review of the MP expenses system, the managing director of one expenses management company has released four top tips which he feels would radically improve the system.
Invest in digs
Vine suggests: Instead of paying rent to landlords or interest on MPs remortgage repayments, wouldnt it be better if the government bought homes for MPs to use during their stay in office? The Prime Minister will hand over the keys to 10 Downing Street when he hands th...
Please Login or Register to read the full article
The full article is available to registered AccountingWEB.co.uk members only. To read the rest of this article you'll need to login or register. Registration is FREE and allows you to view all content, ask questions, comment and much more.


text:
We have tried everything on these posts, including a new installation and every click is followed by the "LOADING...." screen. Sometimes CPU is pegged by Spiceworks *32.exe. Other times we are getting server busy error messages.
Basically at this point, it has become unusable. Is anyone else seeing the same thing?
This topic was created during version 4.7.
The latest version is 7.5.00101.
3 Replies
May 12, 2010 at 2:05 UTC
Definitely check your email settings and production.log in program files\spiceworks\log. If the email fetch is timing out it slows down the app/help desk. Also see how often you are checking for new messages.
May 12, 2010 at 2:18 UTC
We were checking mail every 60 seconds, but changed it to 300 seconds after reading some of the other postings.
I checked the logs and I do see entries like this:
[2010-05-12 09:22:25] Processing TicketsController#check_email (for 127.0.0.1 at 2010-05-12 09:22:25)
mailman: checking for new tickets
ExchangeMailer:Exception from Curl: #<Curl::Err::HostResolutionError: Couldn't resolve host name>
ExchangeMailer:Exception from Curl: #<Curl::Err::HostResolutionError: Couldn't resolve host name>
mailman: processing 1 mails
mailman: processing incoming Ticket e-mail...
mailman: ... parsing complete
An attempt was made to find/create an end user with the Configured Help Desk email address.
I guess my question is then, what is going on that it is timing out and not resolving the host name? Especially since the problem is sporadic.
thanks again for the reply!
May 22, 2010 at 8:56 UTC
Verify that any plugins you have installed are fully updated. Try disabling all and reinstate them to find one that's slowing your install down.
Also take a look at this how-to about other tips on improving Spiceworks performance. http://community.spiceworks.com/how_to/show/282
This discussion has been inactive for over a year.
You may get a better answer to your question by starting a new discussion.


text:
The BAS40-04L from ON Semiconductor is a RF Schottky Diode with Peak Reverse Voltage 40 V, Forward Voltage 0.38 V, Current Surge Peak 0.2 A, Current 0.12 A, Capacitance 17 to 0.24 pF. More details for BAS40-04L can be seen below.
You can now find similar products from multiple companies on everything RF.


text:
I for one really miss getting beastmen seals and kindred seals and doing BCNM battles with my good friends and praying for the phat loot drops to sell for making money.
I just dont get that feel from Levequests, and ther eis no real feeling of acomplishment you dont have to do much to earn the right to do a Levequest. Not counting the 400 FC NM Leves. Bt even those only have set rewards, again not the same feeling as a BCNM or KSNM.
What do you guys think?


text:
Oklahoma city cop charged with sexual assault of black women while on duty
Daniel Ken Holtzclaw, a police officer and former Eastern Michigan University football player, was arrested Thursday on suspicion of sexual assault of at least seven women between February and June 2014. All of the victims are black women . . .


text:
Over 3.5 million people worldwide have used the Entireweb Free Search Engine Submission service to submit their sites to search engines such as Google, Yahoo, Bing and more.
Within a few seconds, you can start using the leading search engine submission tool online.
Save time by submitting your site to all the top search engines and let people know you exist.
More than 3.5 million people have used Entireweb to submit their websites - now it's your turn.
This service is 100% free of charge and you can use it as often as you want!
Keep track of your submission process with your monthly notification emails.
Automatic Resubmissions
Increases the possibility of staying listed in the search engines.


text:
Style: 25803131 Color Code:
Pieced together patterned quilt jacket with hood. Buttons up the front. Two front slit pockets. Inside is fully lined with patterned fabric. A beautiful, statement-making piece!
**Special Note: The color of the lining in the studio shots (blue) is correct, not the color of the lining in the catalog shot (red).