text:
National Human Genome Research Institute
Letter of Intent Receipt Date: August 1, 1998 *
Application Receipt Date: December 10, 1998 *
January 9, 1998 NIH Guide: RFA HG-98-002
Research Network for Large-Scale Sequencing of the Human
June 19, 1998 NIH Guide: Update to RFA HG-98-002
Change in Submission Date and Scope
September 30, 1998 NIH Guide: Update to RFA HG-98-002
Change in Scope
The purpose of this RFA is to seek applications to participate in a research network, the goal of which is to make a major contribution to the completion of the first human genome sequence by 2005. This research network will be comprised of sequence production centers, specialized sequencing projects and a quality control center.
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, Research Network for Large-Scale Sequencing of the Human Genome, is related to several priority areas including cancer, heart disease and stroke, diabetes and chronic disability conditions, and maternal and infant health. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800).
Applications may be submitted by domestic non-profit and for-profit organizations, private and public, such as universities, colleges, companies, hospitals, laboratories, units of state or local governments, and eligible agencies of the Federal government. Applications from minority individuals and women are encouraged. Applications from foreign institutions will not be accepted; however subcontracts to foreign institutions will be considered. A principal investigator submitting an application for the sequencing production centers must have demonstrated experience in directing projects that have produced at least 7.5 Mb of high quality finished DNA sequence.
The administrative and funding mechanism to be used to support this program will be the Cooperative Agreement (U01), an "assistance" mechanism, which is distinguished from a regular research grant in that substantial scientific and/or programmatic involvement by National Human Genome Research Institute (NHGRI) staff with the awardee is anticipated. The cooperative agreement is used when participation by the National Institutes of Health (NIH) staff is warranted to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role; NIH staff will not assume direction, prime responsibility, or a dominant role in the activity. Details of the responsibilities, relationships, and governance of the studies funded under cooperative agreement(s) are discussed later in this document under the section "Terms and Conditions of Award". Each component of the Research Network will be awarded as a separate U01.
The Research Network will be composed of three separate, but complementary, activities:
The objectives of the three types of projects are described below. The project period that may be requested for each type of project is as follows:
Similarly, the sizes of the different types of awards will vary. The earliest anticipated award date is July 1, 1999. It is the intention of NHGRI that the Research Network will continue through Fiscal Year 2005, if needed to complete the human DNA sequence. NHGRI expects to solicit additional specialized sequencing projects during the term of the Research Network if funds are available and if continued activity of this type is warranted. NHGRI is committed to ongoing assessment of the quality of the DNA sequence produced in this project and therefore it is anticipated that there will be a future solicitation to continue a quality control center beyond the three-year term of the center that will be funded under this RFA.
The estimated funds available for the first year of support for awards under this RFA will be $60 million per year (total costs) for three to five sequence production projects and at least $10 million per year (total costs) for up to four specialized sequencing projects and one quality control center.
The usual PHS policies governing grants administration and management will apply. This level of support is dependent on the receipt of a sufficient number of applications of high scientific merit. Beyond the first year, the funding level of each of the centers will be based on an annual evaluation. For the sequencing production centers, the evaluation criteria will be whether progress toward completion of the sequence of the human genome is sufficient and is state-of-the-art, relative to that of the other sequence production centers, as determined by the Advisory Committee (see below), NHGRI staff and the National Advisory Council for Human Genome Research (NACHGR). For the specialized sequencing projects and the quality control center the criteria will be whether the project is meeting its goals and fulfilling the long- and short-term needs of the research network, as determined by the Advisory Committee, NHGRI staff and the NACHGR. The funding level for the research network will also be dependent upon the availability of funds.
NHGRI is currently engaged, along with several other federal, private, and international organizations, in a fifteen-year research program called the Human Genome Project (HGP). The goals of the HGP are to characterize the genomes of human and selected model organisms through complete mapping and sequencing, to develop technologies for genomic analysis, to examine the ethical, legal, and social implications of human genetics research, and to train scientists who will be able to utilize the tools and resources developed through the HGP to pursue biological studies that will improve human health.
The HGP started in 1990 and significant progress toward completing these goals has been made in the past seven years; several goals have already been achieved. The genetic mapping goals for both the human and the mouse have been met. The human and mouse physical mapping goals are nearly complete. There has also been good progress toward meeting the sequencing goals. The DNA sequence of both the E. coli and S. cerevisiae genomes has been determined (as have those of several other microorganisms), the sequence of the C. elegans genome is expected to be finished by 1998, and the complete DNA sequence of D. melanogaster is expected to be finished early in the next century.
Producing the first reference human DNA sequence by 2005 is now the HGP's primary goal. In the early years of the HGP, the focus of the research program was on mapping and technology development because it was recognized that good maps and better technology were needed if the entire human DNA sequence was to be completed within the projected budget and time period. Three years ago, it was concluded that map construction and technology development had progressed sufficiently to warrant initiation of a pilot-scale sequencing program to develop and test approaches to full-scale production sequencing of human DNA. NHGRI funded six pilot projects for this purpose in 1996. Under the pilot project program, several different strategies have been implemented, a number of new technologies have been developed or implemented, and new informatics tools have been implemented to handle the data. In the course of developing their sequence capabilities, the pilot projects have deposited more than 30 Mb of high-quality mammalian genomic DNA sequence in GenBank.
The HGP goals also call for side-by-side sequencing of regions of the mouse genome syntenic with regions of the human genome because these sequences will help to inform the discussion of the use of the mouse sequence in understanding the human sequence. The NHGRI-funded pilot projects have produced a few megabases of sequence from syntenic regions of the mouse genome.
In planning a program that will complete the sequence of the human genome by 2005, the most important component is adequate sequence production capacity. Additional infrastructural/organizational issues that need to be addressed in scaling up the current sequencing program effort have been identified during the pilot project program. It will be critical to ensure that the sequence production groups remain efficient and continue to evolve and become more efficient throughout the term of the program, and a number of additional supportive activities will be required to sustain and increase the productivity of the sequence production efforts over the long term. These include separate research efforts to: 1) evaluate new technology at a production level, 2) address problem regions in DNA (e.g., gaps, closure), 3) provide opportunities for new groups with promising approaches to attain production levels, and 4) evaluate the quality of the DNA sequence produced. It will also be important to facilitate continued and expanded communication and frequent exchange of information among the individual projects and NHGRI staff, as this has been found to provide significant benefits to the overall sequencing effort during the pilot project period.
Through this RFA, the NHGRI proposes to follow up the pilot project program with a Research Network that will make a substantial contribution to the international effort to sequence the human genome. Specifically, the Research Network's goal will be to complete 1.8 billion base pairs (60 percent) of human DNA sequence by 2005 (it is anticipated that the U.S. Department of Energy (DOE) and international partners in the HGP will complete the remaining 1.2 billion base pairs (40 percent) of the human genome sequence). This will require that the NHGRI program produces an annual average of almost 300 Mb of finished sequence, between 1999 and 2005. The coordination of the NHGRI effort by the Research Network is intended to enhance the productivity of the group as a whole, and thus increase the likelihood that the human sequence will be completed on time and within budget.
Completing the human sequence by 2005 will require the commitment of a substantial portion of NHGRI's resources. It is important to note, however, that NHGRI will continue to support the development of novel genomic technologies, including sequencing technology, outside of the Research Network, through its traditional grant program.
As stated above, the goal of the Research Network will be to complete 1.8 billion base pairs (60%) of the first human DNA sequence by 2005. This RFA calls for three types of components to make up the Research Network that will accomplish this goal:
Sequence Production Centers: These projects will be the central DNA sequence production units of the network. Acceptable objectives for applications include production of at least 20 Mb of finished human sequence in the first year, at least 40 to 50 Mb in the second year and at least 50 to 100 Mb in each year thereafter, at a cost of no more than $0.40 (total costs) per base pair in the first year and at an average of $0.25 or less per base pair over the life of the Research Network. Applicants for sequence production centers must follow the guidance given in the section below, entitled "Application Guidance for Production Sequencing". Proposals must also address the NHGRI policies for large-scale sequencing outlined below.
Specialized Sequencing Projects: The primary objective of this component of the Research Network is to increase the likelihood that the human DNA sequence will be completed by providing flexibility, capabilities or services that the sequence production centers cannot. Augmenting and complementing the sequence production centers, specialized sequencing projects can contribute to the overall HGP sequencing effort in any of a variety of ways. The following are examples of activities that would be appropriate for specialized sequencing projects:
This list is not intended to be inclusive and other ideas for specialized sequencing projects are welcome. All applications for specialized sequencing projects must present a plan, including a time line, that describes how and when the proposed effort will make a substantial contribution to the completion of the human DNA sequence. If a specialized project proposes to include a moderate-sized sequencing capacity in order to carry out its purpose, evidence of past experience in sequencing should be provided using the progress report format. The unit cost of sequencing in such a project should not exceed twice the average unit cost of sequencing in the production sequencing projects in the previous year. Applicants proposing to sequence at a moderate scale must also address issues listed below under "Application Guidance for Sequence Production Centers."
Quality Control Center: Applications are sought to support one cooperative agreement to evaluate, on an ongoing basis, the quality of the DNA sequence being produced by the sequence production and specialized sequencing centers. This is a new activity in the large-scale sequencing program. During the pilot project period, two sequence quality assessment exercises were completed; a description of the methods used is available. While the methods proposed for the quality control center need not be the same as those used in the previous exercises, applications that propose to carry out quality assessment must provide evidence for the robustness of the method(s) proposed or plans for assessing the validity of the proposed method(s) and of the sampling methods (e.g., how much material will be sampled). The first assessment of the quality of finished sequence must be completed no later than six months after funding of the quality control center, and the applicant should propose a plan for continued semi-annual assessments of data from the production centers and specialized sequencing centers, where needed. It is expected that sequence quality assessment methods will evolve over the period of the grant; therefore the applicant should provide a plan to ensure that the methods being used will be maintained at the state-of-the-art. The quality control center must also include an outreach capability to provide advice to, and assist, the sequence production centers with their in-house quality control programs. The quality control center should also include funds to cover the cost of the Steering and Advisory Committees' activities.
A principal investigator may apply for more than one of the types of centers described above. However, no P.I. will be awarded a production center and a quality control center and it is unlikely that any other combination of two awards will be made to one P.I. although two awards may be made to one institution.
During the past two years, as the pilot projects began to produce significant quantities of human DNA sequence, a number of issues arose that required the development of new policies by NHGRI. These policies will apply during the term of the Research Network. Thus, where appropriate, applicants must present plans to adhere to the policies.
Intellectual Property: In NHGRI's opinion, in the absence of additional biological information, human genomic DNA sequence information should be freely available for use by the entire research community and, therefore, should not be patented but released into the public domain. NHGRI will monitor its grantees' activities with respect to patenting human genomic sequence. (see NHGRI Policy Regarding Intellectual Property of Human Genomic Sequence).
Data Release: Finished mapping sequence and data: The U.S. HGP has adoped a policy of encouraging rapid release of mapping and sequence data into public databases. Guidelines developed by NHGRI and DOE advisors recommend that data be made publicly available within six months of the time they are verified.
Unfinished Sequence Data: Participants in the international human DNA sequencing effort have recommended that early stage human sequence data should be rapidly released. In response, NHGRI determined that its grantees should release all sequence assemblies of 2,000 base pair units or larger within 24 hours of assembly (see NHGRI Policy on Release of Human Genomic Sequence Data). Applicants should fully describe their plans for the release of mapping data and finished and unfinished sequence data.
Human Subjects Protection: Donors whose DNA will be sequenced in the project must give appropriate informed consent, and their confidentiality and anonymity must be ensured to the extent possible (recognizing that, because each individual's DNA sequence is unique, anonymity cannot ultimately be guaranteed). These issues have been addressed in a Guidance for the Use of DNA in Large-Scale Sequencing that was jointly issued by the NHGRI and the DOE human genome program in August, 1996. It is expected sufficient libraries will be available by the anticipated award date of grants funded under this RFA (July 1, 1999); if these libraries are available, human genomic DNA sequence generated under this RFA MUST be determined from resources made according to the NHGRI-DOE Guidance.
Sequence Quality: Quality standards are an important component of this program. After considerable discussion, the NHGRI adopted the goals that the sequence should be 99.99% accurate and there should be no gaps, either within or between clones (see NHGRI Standard for Quality of Human Genomic Sequence). Two sequence quality assessment exercises have been completed and have demonstrated that (1) it is possible to measure sequence quality at a low cost, and (2) that it is possible to produce sequence that meets the standard for accuracy. It is recognized, however, that it may not be possible to sequence all regions of the human genome to this standard. The policy recognizes this by providing that, in such regions, the sequence must be annotated to indicate what efforts were actually made to obtain high quality data. In the case of gaps, the annotation must include the size of the gap and the orientation of sequence fragments.
Applicants must consider and address the following in preparing applications for sequence production projects called for in this RFA:
Progress Report: In order to achieve the ambitious first-year goal outlined above, applicants must already have a proven record for high-throughput DNA sequencing (At least 7.5 Mb of finished sequence. As the standards for sequence quality are evolving rapidly, for purposes of this RFA, the applicable standard of quality will be posted on the NHGRI Web site as of 7/1/98; see Sequence Quality section below.). NHGRI has developed a progress report submission format that will allow applicants to submit large amounts of mapping and sequencing information electronically and that can be easily examined by the NHGRI staff and reviewers. Evidence of the applicant's past sequencing accomplishments must be provided electronically using this form. The remaining components of the NIH application are not to be submitted through this electronic format and should be sent to NIH in the printed form called for in the NIH application kit. A printed copy of the textual material contained in the electronic progress report (excluding Part B, the graphical and tabular material) should also be included with the application.
Sequence Production Plan: The applicant must present a plan and propose milestones for achieving the proposed level of scale up. This plan must cover all phases of sequence production, starting with construction of a sequence-ready map, through deposition of the finished sequence in GenBank. Issues that should be discussed include: (1) the choice of regions to be sequenced, including any special considerations that may arise specifically because of that choice, (2) the construction of sequence-ready maps, (3) sample preparation, (4) the sequencing process, (5) assembly of the finished sequence from the raw sequence traces and (6) automated annotation. It will be important to discuss bottlenecks or other problems that may be anticipated as the project increases in scale and how they will be addressed.
Sequence Cost: The calculated cost of sequencing (both prior and projected sequencing costs) must take into account all of the expenses associated with sequence production, beginning with construction of a sequence-ready map, through deposition of the finished sequence in GenBank (the costs of the sequence-ready maps must be included whether or not the maps are being produced in-house or at a different site). The total cost of sequencing must also include any production-related technology development (see below) that has been or will be supported by the project. However, the applicant may also provide a break-down of costs so that the reviewers can evaluate the contribution of different cost elements, such as production-related technology development, to the reported total cost.
Sequence Quality: Applicants must agree to submit their data for quality assessment during both the pre-award period (in order to allow the peer reviewers to evaluate this important factor) and during the course of the project period. For sequence data already finished by the application submission date, the assessment will be conducted using the methods employed in the previous NHGRI quality assessment exercises, in which all NHGRI grantees funded for large-scale sequencing cooperated in assessment of each other's data. This evaluation will be conducted after the application is submitted, but prior to the review meeting. The finished sequence to be evaluated will be chosen by NHGRI staff from the list of finished clones submitted by the P.I. in the progress report. During the course of the project period, the assessment will be done by the quality control center.
Internal Quality Control Program: Each sequence production center must also implement an internal quality control program. Applicants must propose an internal quality control program that evaluates sequence accuracy, fidelity to the genome and short-range and long-range contiguity. If a program is already in use in the applicant's project, evidence of its usefulness must be presented in the Progress Report.
Production-Related Technology Development/Implementation: One of the goals of the NHGRI sequencing program is continually to improve the efficiency and decrease the cost of production sequencing. This will facilitate completion of the human genome sequence in the shortest possible time and at the lowest possible cost, as well as build the infrastructure that will be needed to continue sequencing multi-megabase regions of DNA from both the human and other organisms after the first human DNA sequence is completed. Applicants must present a plan to address this issue and discuss how their proposed project will balance further technology development and sequence production. As much as 10% of the requested budget may be budgeted for technology development/implementation for this purpose, but the cost must be included in the total cost of the sequence produced, as discussed above.
Mouse Genomic Sequence: While the focus of activity in the sequence production centers must be on human genomic DNA sequence, as much as 10 percent of the effort may be devoted to sequencing genomic regions of the mouse that are syntenic with regions of the human genome that have already been or are being sequenced. The applicant must present a plan for obtaining the sequence-ready maps for the regions of the mouse to be sequenced and a coherent scientific strategy/rationale as to why the target regions were chosen.
Management Plan: The management of a sequencing center requires a significant commitment by the P.I. of the project. Accordingly, he or she is expected to devote at least 30 percent effort to the project. The applicant must propose a management plan for the project that takes into account the changes that will occur as the project scales up.
ARBITRATION PANEL: A panel that is formed to review scientific or programmatic disagreement (within the scope of the award) that may arise between award recipients and NHGRI. It will be composed of three members: a designee of the Steering Committee chosen without the NHGRI staff voting, one NHGRI designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of an individual disagreement, the first member may be chosen by the individual awardee. The Arbitration Panel will help resolve both scientific and programmatic issues that develop during the course of work that restrict progress.
AWARDEE: The institution to which the cooperative agreement is awarded.
COOPERATIVE AGREEMENT: An assistance mechanism in which there is anticipated substantial NHGRI programmatic involvement with the recipient organization during the performance of the planned activity.
RESEARCH NETWORK: A group of scientists, each funded by a separate cooperative agreement, working together to complete the DNA sequence of the human genome by 2005.
NHGRI PROGRAM DIRECTOR(S): A scientist(s) of the NHGRI extramural staff who provides normal stewardship for the award and who, in addition, has substantial scientific/programming involvement during conduct of this activity, as defined in the terms and conditions of award. This involvement includes coordinating NHGRI's participation in the Research Network, functioning as a peer with the Principal Investigators, facilitating the partnership relationship between NHGRI and the Research Network, helping to maintain the overall scientific balance in the program commensurate with new research and emerging research opportunities, and ensuring that the Research Network program is consistent with the NHGRI missions and goals.
PRINCIPAL INVESTIGATOR (P.I.): The person who assembles the project, is responsible for submitting the application in response to this RFA, and is responsible for the performance of the project. The Principal Investigator will coordinate project activities scientifically and administratively.
STEERING COMMITTEE (SC): A committee that is the main governing board of the Research Network. Membership includes the NHGRI Program Director(s), the P.I. of each awarded cooperative agreement (including the sequence production centers, specialized sequencing centers and the quality control center), and three research scientists with relevant expertise, but who are not affiliated with any of the projects participating in the Research Network.
SCIENTIFIC ADVISORY PANEL (AC): A committee that evaluates the progress of the Research Network and provides recommendations to the Director, NHGRI about continued support of the components of the Research Network. The Advisory Committee will be composed of four to six senior scientists with relevant expertise and who are not P.I.s of a cooperative agreement involved in the Research Network. The AC will meet at least annually.
The following terms and conditions will be incorporated into the award statement and will be provided to the Principal Investigator, as well as the appropriate institutional official, at the time of award. The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92 [Part 92 is applicable when State and local Governments are eligible to apply], and other HHS, PHS, and NIH grant administration policies:
The administrative and funding instrument used for this program will be the Cooperative Agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during the performance of the activity. Under the Cooperative Agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the study will be shared among the awardee(s) and the NHGRI Program Director(s).
P.I. Rights and Responsibilities: The P.I. will have the primary responsibility for defining the details for the project within the guidelines of the RFA and for performing the scientific activity. The P.I. will agree to accept close coordination, cooperation, and participation of NHGRI staff in those aspects of scientific and technical management of the project as described under "NHGRI Program Staff Responsibilities".
The P.I. of a sequence production center will:
The P.I. of a specialized sequencing center will:
The P.I. of the quality control center will:
In collaboration with the research network,
NHGRI Program Staff Responsibilities: The NHGRI Program Director(s) will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination such as participating in the design of Research Network activities, advising in the selection of sources or resources, coordinating or participating in collection and/or analysis of data, advising in management and technical performance, or participating in the preparation of publications. However, the role of NHGRI will be to facilitate and not to direct the activities. It is anticipated that decisions in all activities will be reached by consensus of the Research Network and that NHGRI staff will be given the opportunity to offer input to this process. The NHGRI Program Director(s) shall participate as a member of the Steering Committee having one vote.
The Program Director(s) will:
The Steering Committee will serve as the main governing board of the Research Network. The Steering Committee membership will include the NHGRI Program Director(s), the P.I. from each awarded cooperative agreement (including those of the production centers, the specialized sequencing centers and the quality control center), and three research scientists with relevant expertise, but who are not affiliated with any of the cooperative agreements. The rest of the steering committee will appoint these three members by majority vote. One of these three members will be nominated to serve as the Chair of the Steering Committee and will be appointed by the Program Director(s). Additional members may be added by action of the Steering Committee. Other government staff may attend the Steering Committee meetings, if their expertise is required for specific discussions.
The Steering Committee will be responsible for discussing progress within the Research Network, and for advising NHGRI as to how the Research Network can complete the human DNA sequence within the stated goals of time and accuracy, and within budget. The Steering Committee will work with the quality control center to develop uniform procedures for data quality assessment. Members of the Steering Committee will be required to accept and implement the common guidelines and procedures approved by the Steering Committee.
Within one month after award of the cooperative agreements, the NHGRI Program Director(s) and the P.I.s will meet (perhaps by telephone conference) to select the three outside committee members and to nominate a chair from among those three. The Program Director(s) will appoint the Chair and schedule the first meeting of the Steering Committee once the Chair has been selected. The Chair of the Steering Committee will be responsible for coordinating the Committee's activities, preparing meeting agendas, and chairing meetings. A meeting schedule will be developed at the first meeting. Two meetings will be held each year, either in Bethesda or at one of the sites. One of the meetings will partially overlap with the annual meeting of the Advisory Committee. The purpose of meeting jointly will be to allow direct interaction between members of the Research Network and the Advisory Committee, prior to the latter's annual evaluation of the Research Network's progress. Subcommittees will be established by the Steering Committee as it deems appropriate.
The Advisory Committee will be responsible for reviewing and evaluating the progress of the Research Network toward completing that portion of the human DNA sequence for which NHGRI is responsible. The Advisory Committee will be composed of four to six senior scientists with relevant expertise. The Director, NHGRI, will select the members and Chair. The membership of the Advisory Committee may be enlarged permanently, or on an ad hoc basis as needed.
The Advisory Committee will meet at least once a year. The first part of this meeting will be a joint meeting with the Steering Committee to allow the Advisory Committee members to interact directly with the members of the Research Network. Annually, the Advisory Committee will make recommendations regarding progress of the Research Network and present advice about changes which may be necessary in the Research Network program to the Director, NHGRI.
Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and the NHGRI may be brought to arbitration. An Arbitration Panel, composed of three members - one Research Network Steering Committee designee, one NHGRI designee, and a third designee with expertise in the relevant area and chosen by the other two designees, will be convened. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16.
Awardees will be asked to define yearly milestones at the time of the award and to adjust these milestones annually at the anniversary date. In accord with the procedures described above, NHGRI may withhold or reduce funds for projects that substantially fail to meet their milestones or to maintain the center at the state of the art.
It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43).
All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy.
Prospective applicants are asked to submit, by August 1, 1998, a letter of intent that includes a descriptive title of the overall proposed research, the name, address and telephone number of the Principal Investigator, the number and title of this RFA, and a list of the key investigators and their institution(s) and projects. Any applicant planning to submit an application for more than $500,000 direct cost in any one year must contact the NHGRI staff listed under the INQUIRIES section in order for the application to be accepted by NIH.
The letter of intent should be sent to:
Dr. Jane L. Peterson
Program Director, Large Scale Sequencing
National Human Genome Research Institute
National Institutes of Health
38 Library Drive, MSC 6050 Building 38A, Room 614
Bethesda, MD 20892-6050
Propsective applicants are invited to attend a briefing on this Research Network program on May 13, 1998 in the Plimpton Room of the Beckman Center at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY. NHGRI staff will explain the purpose of the program, provide detailed instructions about the application process and answer questions. Applicant institutions are urged to send a representative to this briefing. For further information about the meeting or accommodations in the area, please contact the program staff listed in this RFA.
The research grant application form PHS 398 [nih.gov] (rev. 5/95) is to be used in applying for these grants. Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, E-mail: email@example.com; and from the program administrator listed under INQUIRIES.
The RFA label available in the PHS 398 (rev. 5/95) application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked.
Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies, in one package to:
Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Suite1040 - MSC 7710
Bethesda, MD 20892-7710
Bethesda, MD 20817 (for express/courier service)
At the time of submission, two additional copies of the application must also be sent to:
Dr. Rudy Pozzatti
Scientific Review Administrator, Office of Scientific Review
National Human Genome Research Institute
National Institutes of Health
38 Library Drive, MSC 6050 Building 38A, Room 609
Bethesda, MD 20982-6050
Telephone: (301) 402-0838
Applications must be received by October 9, 1998. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed.
Upon receipt, applications will be reviewed for completeness by CSR and responsiveness by the NHGRI. Incomplete applications will be returned to the applicant without further consideration. If NHGRI staff find that the application is not responsive to the RFA, it will be returned without further consideration.
Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NHGRI in accordance with the review criteria stated below. As part of the initial merit review, a process (triage) may be used by the initial review group in which applications will be determined to be competitive or non-competitive based on their scientific merit relative to other applications received in response to the RFA. All applications will receive a scientific review and summary statement, although applications judged to be competitive will be discussed and be assigned a priority score. Applications determined to be non-competitive will be withdrawn from further consideration and the principal investigator/program director and the official signing for the applicant organization will be promptly notified. The second level of review will be provided by the National Advisory Council for Human Genome Research.
All applications will be judged on the basis of the scientific and technical merit of the proposed projects and the documented ability of the investigators to meet the RESEARCH OBJECTIVES of the RFA.
The application must be directed toward attaining the programmatic goals as stated under RESEARCH OBJECTIVES. The following criteria will be used by peer review groups to evaluate these applications:
For sequence production centers:
For the specialized sequencing projects:
For the quality control center:
The second level review will be conducted by the National Advisory Council for Human Genome Research.
Awards will be made on the basis of scientific and technical merit as determined by peer review, including the significance of the projected contribution toward meeting the NHGRI program goal of contributing to the completion of the human DNA sequence by the year 2005, program needs and balance, adherence to NHGRI policies on human subjects, data release and intellectual property, and the availability of funds.
Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify issues or questions about the RFA from potential applicants is welcome.
Dr. Jane L. Peterson
Dr. Adam Felsenfeld
Division of Extramural Research
National Human Genome Research Institute
National Institutes of Health
38 Library Drive, MSC 6050
Building 38A, Room 614
Bethesda, MD 20892-6050
Phone: (301) 496-7531
Fax: (301) 480-2770
E-mail: email@example.com
E-mail: firstname.lastname@example.com
Ms. Jean Cahill
Grants Management Office
National Human Genome Research Institute
Building 38A, Room 613
38 Library Drive, MSC 6050
Bethesda, MD 20892-6050
Phone: (301) 402-0733
Fax: (301) 402-1951
E-mail: email@example.com
Public Briefing at Cold Spring Harbor, NY: May 13, 1998
Letter of Intent Receipt Date: August 1, 1998
Application Receipt Date: December 10, 1998
Scientific Review Date: Feb/March 1999
Advisory Council Date: May 1999
Anticipated Award Date: July 1999
This program is described in the catalog of Federal Domestic Assistance No. 93.172. Awards are made under the authority of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 122372 or Health Systems Agency review.
The PHS strongly encourages all grant and contract recipients to provide a smoke- free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.
Letter of Intent Receipt Date: August 1, 1998
Application Receipt Date:December 10, 1998
National Human Genome Research Institute
The purpose of this notice is to inform the scientific community that the National Human Genome Research Institute is revising the RFA Research Network for Large-Scale Sequencing of the Human Genome, which appeared in the NIH Guide on January 9, 1998. NHGRI remains strongly committed to the goal of completing a high quality, complete sequence of the human genome by the year 2005. However, recently there has been discussion in the scientific community of the potential benefit of generating an intermediate rough draft sequence by 2001. During the next three months, NHGRI will be considering this possibility, and will be addressing questions about the utility of and best strategy to develop different types of a rough draft sequence. By the end of this period, NHGRI will decide whether to pursue a rough draft and, if so, what characteristics of that intermediate product would make it most useful and strategically practical. Once a decision is made, another Guide Notice will be published to inform prospective applicants about the NHGRI strategy for obtaining the human genome sequence. It is expected that this Notice will be published no later than September 30, 1998.
NHGRI recognizes that, if the scope of the RFA were to change, applicants would need time to adjust their strategies and to produce preliminary results in support of their applications. Therefore, the submission date for the applications has been changed from October 9, 1998 to December 10, 1998. Applications will be reviewed in March 1999, considered by the National Advisory Council for Human Genome Research at its May 1999 meeting and awards for the cooperative agreements that will participate in the Research Network will be made on July 1, 1999.
The date for the Letter of Intent remains August 1, 1998. The letter of intent should include a descriptive title of the overall proposed research, the name, address and telephone number of the Principal Investigator, the number and title of this RFA and a list of key investigators and their institution(s) and projects. NHGRI recognizes that the nature and perhaps the titles of the projects may change as a result of any changes in the scope of this RFA that may be announced. NHGRI staff plan to contact each investigator submitting a letter of intent during the period between the submission dates for the letter of intent and the application to discuss any changes in the RFA. Any applicant planning to submit an application for more than $500,000 direct cost MUST contact NHGRI staff in order for the application to be accepted by NIH.
The letter of intent should be sent to:
Dr. Jane L. Peterson
Program Director, Large Scale Sequencing
National Human Genome Research Institute
National Institutes of Health
38 Library Drive, MSC 6050
Building 38A, Room 614
Bethesda, MD 20892-6050
Direct inquiries regarding programmatic issues to:
Dr. Jane L. Peterson
Dr. Adam Felsenfeld
Division of Extramural Research
National Human Genome Research Institute
National Institutes of Health
38 Library Drive, MSC 6050
Building 38A,Room 614
Bethesda, MD 20892-6050
Phone: (301) 496-7531
Fax: (301) 480-2770
E-mail: firstname.lastname@example.com
E-mail: firstname.lastname@example.com
Direct inquiries regarding fiscal matters to:
Jean Cahill
Grants Management Office
National Human Genome Research Institute
Building 38A, Room 613
38 Library Drive, MSC 6050
Bethesda, MD 20892-6050
Phone: (301) 402-0733
Fax: (301) 402-1951
E-mail: firstname.lastname@example.com
Release Date: September 29, 1998
Application Receipt Date: December 10, 1998
National Human Genome Research Institute
The purpose of this notice is to inform investigators who have expressed an interest in applying for the above-referenced RFA that the National Human Genome Research Institute (NHGRI) is revising the scope of the RFA in light of recent advice from the National Advisory Council for Human Genome Research (NACHGR). The NACHGR has approved a new NIH-DOE plan for the Human Genome Project (HGP) in the U.S. for the years 1999-2003. (The full NIH-DOE five-year plan will be published in the October 23, 1998 issue of Science.) The new plan calls for the completion of a finished, high quality human DNA sequence by 2003; in addition, the plan calls for generation of a 'working draft' of the sequence -- consisting of at least 90% coverage and at least 99% accuracy -- by 2001. The sequence data on which the working draft will be based will be held to quality standards aimed at ensuring that the data can later be directly used in assembling finished genomic sequence. Therefore, assembly of the working draft should not create loss of efficiency or increases in overall cost. Finally, the plan also calls for finishing one-third of the human sequence by 2001, focusing on gene-rich regions of the genome.
Investigators who plan to respond to this RFA must address the new NHGRI sequencing goals in their applications. Applications for large-scale sequencing centers should focus on production of finished sequence, but may also propose to generate additional draft-quality sequence in their research plan.
The primary objective of the specialized centers remains contributing, in any of a variety of ways, to the completion of the human DNA sequence by providing flexibility, capabilities or services that the sequence production centers cannot. The following are examples of activities that would be appropriate for specialized sequencing projects in light of the new goals for the genome project: producing finished and draft-quality sequence, albeit at a smaller scale than the production centers; collaborating with another sequencing center by finishing some portion of the draft-quality data being produced by the collaborating center or by producing draft sequence for finishing by the collaborator. As stated in the original RFA, investigators may also propose to organize specialized sequencing centers around the sequencing of difficult regions of the genome or the testing of a new technology or strategy.
Award criteria for the large-scale sequencing centers and specialized sequencing centers have been revised as follows:
Awards will be made on the basis of scientific and technical merit as determined by peer review, including the significance of the projected contribution toward meeting the NHGRI program goals of: contributing to the completion of the finished, high quality human DNA sequence by the year 2003, generating a draft- quality sequence covering at least 90% of the human genome and at least 99% accuracy by 2001, and completing finished, high quality sequence representing one-third of the human genome by 2001. Award decisions will also take into account program needs and balance; adherence to NHGRI policies on human subjects, data release and intellectual property; and the availability of funds.
It is expected that, under the terms of the Cooperative Agreement as specified in the RFA, there will be effective collaboration and coordination amongst the successful applicants. Applicants should address in the application, the role they will play in the Cooperative Agreement.
Funds Available: It is anticipated that as much as $120 million may be available for support of the Research Network in FY 1999. The funding level will be dependent upon the availability of funds.
Quality Control Center: NHGRI has determined that it will not accept applications for a quality control center as part of this RFA, but will instead issue an RFP for a contract to perform sequence quality assessment in the near future.
Review Schedule: In response to the accelerated timetable for completion of the human genome sequence described in the new NIH-DOE 5-year plan, the NACHGR advised NHGRI to accelerate the review and funding of applications submitted by groups that have already demonstrated the capability to contribute large amounts of finished, high quality human DNA sequence. Therefore, applications from groups that have sequenced and deposited in a public database by December 10, 1998 at least 15 Mb of completed genomic sequence (in contigs greater than 30,000 bp) will be reviewed on an accelerated timetable and considered by the NACHGR at its February 1999 meeting. Approximately one-half of the funds available for the RFA will be available to fund these projects after the February Council meeting. All other applications for large-scale sequencing centers and specialized sequencing centers will be reviewed on the timetable outlined in the original RFA, but should be submitted for the December 10, 1998 receipt date, not October 9, 1998. In July 1999, the remaining funds will be used to support additional efforts that can sequence human genomic DNA rapidly and efficiently, or to increase support for the most efficient production efforts.
Quality Control Exercise for RFA: As announced in the RFA, as part of the review of the applications, NHGRI will conduct a quality control exercise for all applicants who have deposited completed sequence in GenBank. This exercise will commence November 1, 1998. NHGRI staff will contact those who have already submitted letters of intent to discuss the details of the quality control exercise.
Web-based Progress Report: The set of questions that must be addressed by applicants as part of their progress report of their applications has been revised. A new addition to this set is a format for presenting sequencing costs which must be used to report sequencing costs for the previous year and for the years of support requested in the application. The budget should also be submitted in the usual format requested in the Form PHS 398.
Direct inquiries regarding programmatic issues to:
Dr. Jane L. Peterson
Dr. Adam Felsenfeld
Division of Extramural Research
National Human Genome Research Institute
38 Library Drive, Room 614, MSC 6050
Bethesda, MD 20892-6050
Telephone: (301) 496-7531
E-mail: firstname.lastname@example.com
E-mail: firstname.lastname@example.com
Direct inquiries regarding fiscal matters to:
Ms. Jean Cahill
Grants Management Office
National Human Genome Research Institute
38 Library Drive, Room 613, MSC 6050
Bethesda, MD 20892-6050
Telephone: (301) 402-0733
E-mail: firstname.lastname@example.com
Last Reviewed: March 7, 2012


text:
© Cooler Master Technology Inc.
This website is for consumer products of Cooler Master Technology Inc. only. For OEM/ODM products please go to Cooler Master Co., Ltd.
Stephen Hoad
Modder /
This is my entry into the Cooler Master Case Mod World Series and believe it or not I started with a Cooler Master Elite 110 Mini ITX case…
Alex Ciobanu
Modder /
My case mod is inspired by Mass Effect and it is based on the spaceship from the new Andromeda game, TEMPEST! …
Graffiti Artist /
It was magical to see Tech Modified (previously known as Oz Modz) and LeFunky collaborate on the Cosmos II 25th Anniversary Edition…
Sign in and register your product to enjoy the exclusive offers, giveaways, services and information.
I like to hear all the latest from Cooler Master

subset: commoncrawl


text:
Difference between revisions of "Mylyn/Context/Modeling Bridge"
m (→Status)
|Line 9:
|Line 9:
The initial release is completed. The Modeling Bridge will be contributed to a newly proposed project [[Mylyn/Modeling/ProjectProposalDraft Mylyn Context Modeling]].
The initial release is completed. The Modeling Bridge will be contributed to a newly proposed project [[Mylyn/Modeling/ProjectProposalDraftMylyn Context Modeling]].
==Known Issues==
==Known Issues==
Revision as of 14:11, 30 September 2011
Currently, Mylyn for Modeling supports EcoreTools diagrams and Project Manager integration as well as Papyrus UML2 class diagrams. The supporting modeling bridge is designed to be relatively easy to extend to support arbitrary GMF supported diagram editor.
This work is developed by Tasktop Technologies and sponsored by Ericsson in the context of the Modeling Platform Industrial Working Group
Watch Mylyn for Modeling in Two Minutes (Screencast).
- 1 Status
- 2 Known Issues
- 3 Users
- 4 Developers
- 5 Future Work
- 6 Project Details
The initial release is completed. The Modeling Bridge will be contributed to a newly proposed project Mylyn Context Modeling.
Known Issues
- Ecore Tools does not work correctly when Papyrus is installed. Install either Ecore Tools or Papyrus but not both. (This isn't a Mylyn Modeling bug but affects our users.) [1]
- Papyrus support is much less mature than for Ecore Tools.
- The Diagram editor outline view "Focus on Active" task button doesn't do anything. [2]
- When you select the "Remove from Context" context menu item in a diagram, the entire editor closes. [3]
- Items in containers -- for example Ecore packages -- are not managed. [4]
Other tracked issues (if any) can be found by clicking this link.
Currently, the features can be installed from the automated build update site. Note that the Modeling Bridge is still in active development and expect frequent updates.
Select either "Mylyn for Ecore Tools" or "Mylyn for Papyrus". We'd recommend starting with Ecore Tools, as the tools are more mature and have less dependencies. A Papyrus issue currently prevents the EcoreTools project explorer support from functioning. (See known issues.) Mylyn for Modeling has minimal dependencies defined on these tools, so you should probably install the target tools separately if you don't already have them.
Please note that the project has not yet been contributed to Eclipse and so has not passed formal review.
User Guide
Mylyn for Modeling works in the same way as other Mylyn tool integrations such as for Java. See the Mylyn User Guide for more details. Modeling specific features are described here.
Task-Focused Interface
To reveal unfocussed items, we provide a "fade effect" to reveal diagram items. As you move the mouse though the diagram, nearby unfocussed nodes and edges will be revealed. Just click on a node to add it to your current context.
Unselecting the Focus Button in the toolbar will cause all model elements to be shown as they are in an non-Mylyn enable editor.
To landmark a node, right-click on it and select "Mark as Landmark". Remove an element using "Remove Model Element from Context". Remove the entire diagram from the active context by clicking "Remove from Context".
Project Explorer
If you're working with EcoreTools or other supported EMF-based models you can also use "Alt-Click" in the Project Explorer to reveal and select nodes. This works for both model and diagram elements.
Tip: You can use the Outline View to help identify and navigate to the nodes you've revealed.
We've tried to design the modeling bridge so that it is easy to make your own GMF and other EMF-based editors and views Mylyn savvy. There are a number of artifacts to take care of but much of it is boiler-plate. (It would be straightforward to support this with a simple meta-model and code generation -- let us know if you'd like to participate in or support that effort!) And please let us know if you have any difficulties or improvements for the below steps.
Users aren't interested in the diagram objects, they're really interested in the underlying domain or model objects. In the Mylyn Java integration, for example, Java classes and methods are tracked, and then revealed in various ways in different editors. So for an EcoreTools model for example, we don't want or need to keep track of the diagram Node objects or any other reference in the various foo.gmf.. files for, we want the domain object itself, e.g. EClass, EPackage, etc.. in the corresponding foo.ecore resource. What we need to do is to define what the user might be interested (or not interested) in and then map that to the diagram editors and other editor types.
Integrating Mylyn for Modeling with custom GMF editors
Copy Existing Project
The best thing to do is just start with one of the two existing projects. We'd recommend org.eclipse.mylyn.modeling.papyrus.ui. org.eclipse.mylyn.modeling.ecoretools.ui will give you some ideas about how to work with a more complex scenario.
Refactor Artifacts
Rename files and other artifacts with the appropriate names. For example in your GMF "Foo" Diagram tool:
- Uml2DiagramDecoratorProvider -> FooDiagramDecoratorProvider
- In Plugin.xml
<decoratorProvider class="org.eclipse.mylyn.internal.modeling.papyrus.Uml2DiagramDecoratorProvider">Becomes:
<decoratorProvider class="org.you.foo.FooDiagramDecoratorProvider">
- etc..
Define Model Specific Behavior
Here's where the non-boiler plate stuff is.
Structure Bridge
In FooStructureBridge, you'll define domain objects which should be managed by Mylyn. This is how it is implemented in UML2StructureBridge:
@Override public Class<?> getDomainBaseNodeClass() { return Element.class; } @Override public Class<?>[] getDomainNodeClasses() { return new Class[] { Classifier.class }; } @Override public Class<?> getDomainBaseEdgeClass() { return Relation.class; } @Override public Class<?>[] getDomainEdgeClasses() { return new Class[] { Relation.class }; }
See DomainModelContextStructureBridge for API details .
Diagram Bridge
In FooUiBridge, you'll define diagrams and views which should be managed by Mylyn. In UML2UiBridge, the important bits are:
@Override public boolean acceptsPart(IWorkbenchPart part) { return part instanceof PapyrusMultiDiagramEditor; } @Override public boolean acceptsViewObject(Object domainObject, Object part) { if (domainObject instanceof Classifier) { return part instanceof ClassEditPart; } if (domainObject instanceof Package) { return part instanceof PackageEditPart; } //Edges if (domainObject instanceof Relationship) { return part instanceof ConnectionNodeEditPart; } return false; }
See DiagramUiBridge for details.
Future Work
Below are some ideas for further improvements and extensions. Please feel free to add your own, and let us know if you'd like to contribute solutions to any of these.
Support other Model Editors
It's quite easy to implement editors for other model types. It would be great to have more examples.
EMF Tree Editors
Support for arbitrary EMF generated editors. See this bug.
Easier Integration with Generic GMF Models
Code generation for Mylyn enabled GMF and EMF tree-based based editors. Ideally this would be completely transparent, but it's very likely we would need a project for each generated GMF model diagram. This isn't really an issue as generating code is part of the GMF diagram creation workflow anyway. This is actually a relatively simple plumbing task, as we already have good example projects to build tempaltes from.
Show Focussed Collaborations
The current approach works well for object collaborations that are already close together or that are composed of several related clusters. Our intuition is that this will generally be the case. To the extent that focussed nodes are spread out across the diagram, the current approach will be less effective. Note that the situation is still much better than without Mylyn as in the default case, you'd have to find the other nodes of interest amidst all of the other diagram clutter! There are a number of approaches we might take to this issue:
- Use "signposts" where distant but off screen nodes are indicated.
- These signposts when clicked on could auto-navigate to the related distant node.
- Depict simple collapsed overview diagrams of just the focussed element collaborations either as an inset caption or a separate navigation view.
Project Details
Project Proposal
We're preparing a proposal for a Mylyn Context project sub-project to contain this and related efforts. Please read the draft and give us your feedback.
Release bug:
All related bugs:
Bug Reports
- Product: Mylyn Incubator
- Component: Experiments
- Deescription: Include "[modeling]" as keyword.
Git Repos
URL: email@example.com:MilesParker/mylyn.incubator.git
This is a temporary home only, we hope to contribute it to Eclipse git soon.
Projects: org.eclipse.mylyn.modeling.*
Automated Build
Please use: mylyn-incubator-dev. Discussion also on EMFT-dev.
Related Documents
- Blog Post by Miles Parker on the current effort.
- Blog post by David Green, Tasktop's VP of Engineering, for model-driven development diagrams based on a model similar to, but not based on, EMF.
- Mik Kersten's PhD thesis on Mylyn. See especially Section 5.4.1.
- Miles Parker for Tasktop -- Development
- Benjamin Muskalla Tasktop -- QA, Testing and Builds
- Steffen Pingel Tasktop -- QA, Testing and Builds


text: www.6mmwarfare.com - Top Site List - Hostirian Webhosting - Rate this Site: Home Forum Photo Gallery Blog Shoutbox News TopSite Last Shout - Posted by: Shadow - Sunday, 28 September 2014 19:24 StF8 done and gone. What a successful comeback of a legendary (crappy) OP. Thanks to everyone that came and helped make this one of the best. Main Menu Home Forum Photo Gallery Blog Shoutbox News Personal Menu Welcome Guest User: Pass: Auto-Login: Register! Ads and Afilliates Online Users 42 Users online: 39 Guests0 Anonymous3 Visible: Bing [Bot], Google [Bot], Majestic-12 [Bot] Last click Rate Rate this Site: Hostirian Webhosting Rate this Site: Hostirian Webhosting (Max Rating: 5) 1 2 3 4 5 Total users browsing Top Site List: 1 (0 Members 1 Guests and 0 Anonymous Members)Members are: MKPTopSite ©2003-2008 mkportal.it Board Menu New posts Users Help last_forum_post Re: TSD Type96 Rifle by: Sofiabern on: Friday, 17 October 2014 23:21 Re: Back from the dead by: Geo on: Sunday, 12 October 2014 19:01 Re: Back from the dead by: Shadow on: Sunday, 12 October 2014 11:15 Re: Back from the dead by: Geo on: Saturday, 11 October 2014 19:05 Re: Still there guys!?! by: Shadow on: Friday, 10 October 2014 23:01 Last Shouts by: Shadow StF8 done and gone. What a successful comeback of a legendary (crappy) OP. Thanks to everyone that came and helped make this one of the best. by: Shadow R&R mode engaged after BHIII. To all the STL (and surrounding) Who fought for the coalition. My hat goes off to you. You fought the good fight and while the UFS might have pushed us back this time, It will only fuel the fire to burn them down with next year. Gamblers are already preparing! by: Shadow Oct 5th, Hunt for Juba! No NSA none of us are real taliban, relax it's just a game. by: refuge Operation: Broken Arches 13-14 July. Be ready. by: Shadow The admins (especially myself, and refuge) will be very busy for a while preparing for BH2 so it may take a few days to answer or reply to PM's and threads. Please be patient. In the meantime ranger is around frequently and he can relay things to us if need be. by: Shadow Updated reg procedure. Spambots shouldnt be able to get through anymore. If anyone has any other problems with log in or posting let shadow or refuge know. by: refuge Because of problems with spambots, registration has been closed down to only admin activation. If you are trying to register on the site, please email refuge or shadow @6mmwarfare.com with your username, and we will activate you. by: Shadow Just ignore the spambots. Refuge will deal with them in a more efficient manner than I can. by: Shadow *Taps plays for StF* Goodbye old friend. by: Shadow Tomorrow midnight is the cutoff so unless some surprise miracle happens stf will die. Calendar Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec 2016 2017 2018 2019 2020 2021 2022 Su Mo Tu We Th Fr Sa 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Site Stats 28397 Posts: 2676 Topics 25721 Replies 0 Blog: Created by Members 0 Files: Inside the Downloads Area 1 Sites: Inside the Top Site List 281 Reg. Members: Last: dnthrshmdrio Browsed Pages: MKPortal ©2003-2008 mkportal.it


text:
How the Immune System Fights Disease
September 18, 2008
The immune system is a complex network of cells and chemicals. Its mission is to protect us against foreign organisms and substances. The cells in the immune system have the ability to recognize something as either "self" or "invader," and they try to get rid of anything that is an invader. Many different kinds of cells, and hundreds of different chemicals, must be coordinated for the immune system to function smoothly.
The immune system can mount a variety of responses to attack specific invader organisms. One of these responses is coordinated by T-helper cells (also known as T cells, T4 cells, or CD4 cells), which act as a kind of orchestra conductor. The T-helper cells tell other cells what to do when this response is triggered. We are interested in this immune response because it is the one that is most disrupted by HIV infection. As HIV succeeds in destroying more and more of these important cells, the ability to fight off other infections gradually declines. If the "coordinator" of the process, the T-helper cell, is no longer functioning, other cells in the immune system cannot perform their functions, leaving the body open to attack by opportunistic infections.
Normal T Cell Response to Infection
Let's look first at how the immune response coordinated by the T cells is supposed to work. Please keep in mind that we will be explaining only one of the body's immune responses.
Any infectious agent (Figure 1) that enters your body will eventually be taken up in your lymphatic system.
After displaying the agent's antigens, the macrophage will send out a message to a T-helper cell to read and recognize the antigens (Figure 4).
HIV Interferes With Normal Immune Response
With HIV infection, this procedure does not work adequately. Initially, macrophages recognize the HIV, T-helper cells initiate the response, and B cells produce antibodies. However, although effective at first, the antibodies do not eliminate the infection. Although some HIV might get killed, many more viruses will actively infect T-helper cells -- the very same cells that are supposed to coordinate the defense against the virus. Infected T cells become virus factories which, if activated, will produce more copies of the virus instead of triggering the production of more antibodies against HIV.
Besides T cells, HIV is capable of infecting other cells (e.g., macrophages, B cells, and monocytes) and can cross the brain-blood barrier, infecting nervous system cells. Most immune cells cannot cross that barrier, which surrounds the brain and spinal cord, so HIV can retreat where the immune system cannot follow.
The immune system is very complex and many of its processes are still not understood. This brief explanation of the immune response coordinated by the T-helper cells will help you understand issues surrounding immune monitoring and treatment for HIV disease. Some of the tests that are used to monitor the health of HIV positive people show how well the immune system is working (e.g., T cell or CD4 cell counts), while others show the number of copies of the virus in the body (viral load). Monitoring and early treatment can be crucial in determining the course of HIV disease and making informed choices about treatment.
This article was provided by San Francisco AIDS Foundation. It is a part of the publication AIDS 101. Visit San Francisco AIDS Foundation's Web site to find out more about their activities, publications and services.


text:
Accommodation Statements for Events/Activities
Equal opportunity cannot be achieved unless individuals with disabilities are aware
that accommodations and adjustments are available on campus. It is recommended that
accommodation and alternate format statements are included, where applicable, on publications,
event announcements and websites. The statements should be printed in an easy-to-read
font size and placed in a location that is noticeable.
Sample accommodation statements are provided below
- Limited Accommodation Statement (Use this version for fliers or other announcements, where space constraints are severe.)
All participants are welcome. If you need special accommodations please call (insert telephone number of the sponsor).
- Fuller Accommodation Statement (This statement should be printed in any publication that describes a specific program
or special event, e.g., seminar, film, speaker, performing arts series, employment
programming, etc.)
Fresno State encourages persons with disabilities to participate in its programs and activities. If you anticipate needing any type of accommodation or have questions about the physical access provided, please call (telephone number of the sponsor) in advance of your participation or visit.
- Abbreviated Accommodation Statement
Persons with disabilities who anticipate needing accommodations or who have questions about physical access may call (telephone number of the sponsor) in advance of the program (or film, event, etc.).
Request for Printed Information in Alternate Format
In most cases, a request for alternate format of printed material, whether for brochures, pamphlets, or event announcements, requires that a text-only electronic version of the publication or announcement be made available. Individuals can then access the information through screen reading software, or by modifying the font size, color, etc., of the printed text.
For information on creating alternate format of materials campus staff can visit the website "For Professional Development of Accessible Technology in the CSU", http://teachingcommons.cdl.edu/access/
Should you have an unusual request for alternate format (e.g., Braille, CD, printed version with extra-large font); call the Services for Students with Disabilities office at 559.278.2811, to discuss options.
Accommodations Statements for Publications
It is recommended that a statement informing individuals with disabilities that the information is available in alternate formats be included on your campus publication, flyer or event announcement.
Sample Alternate Format Statement
- This publication is available in alternate formats on request. Please call (insert
telephone number of sponsor).
The statement should be printed in an easy-to-read type size and placed in a location that is easy to notice.


text:
Go from ordinary to extraordinary.Catch those summer evening shots around the bonfire, or freeze the action of the winning goal. Fast, responsive and boasting an incredible 14x optical Zoom-NIKKOR ED glass lens, the Nikon COOLPIX S8200 will help you capture images you may previously have missed. Its 16.1-MP CMOS sensor crisply renders your view of the world?whether low light, far off fast action or sweeping panoramas. Capture sharp, clear photos and Full HD (1080p) movies using Nikon's incredible optics. Spice up stills and movies with special effects, and view everything on a 3-inch, ultra-high resolution (921,000 dot) display.
Capture what most cameras cannotIf your old camera never quite captured the moment, the S8200 will! It boasts a high-resolution, 16.1-MP CMOS sensor so you get superb image quality-even in low light. With fast, versatile, continuous shooting modes, you can capture those spontaneous moments shot after shot. Then show family and friends your movies and still creations on the 3-inch ultra-high resolution (921,000 dot) display. Stylish and compact, the S8200 tucks into a pocket but packs brilliant performance and advanced features.
14x optical Zoom-NIKKOR ED glass lensDespite a slim profile of approximately 1.3 inches, the S8200 delivers amazing versatility with an incredible 14x zoom (25mm to 350mm equivalent). Imagine creating macro images of a bumblebee in a spring flower, then zooming out to frame a mountain range for a panorama. With the S8200, you can go from wide-angle to telephoto to macro/close-up views in an instant, preserving photos or movies of most everything from grandstand crowds to a stage performer's smile.
Full HD (1080p) movies with stereo soundA single photo may not always be enough to recreate the moment; sometimes memories are best shared with a movie. Portable and ready when important things happen, the COOLPIX S8200 lets you create stunning Full HD (1080p) movies with stereo sound at the touch of a button. You'll love its ability to zoom in and out at will?while keeping subjects in focus. Stylize your story with one of various special effects or by recording in 15, 60 or 120 fps for fast/motion effects. Life doesn't stand still; neither should your memories.
Easy Panorama, Night Modes, HDR and more!Maybe you've wanted to create panoramic photos but thought they were too difficult. Maybe you've tried shooting photos at night but they never turn out. The S8200 takes the guesswork out of shots like these and more with handy Scene Modes at the ready. For sweeping panoramas, simply pan the camera and let it detect and automatically combine images to build a gorgeous vista. Going out at night? The S8200 takes great low-light photos. You can even create amazing HDR shots in-camera. The S8200 does the work.
In-camera effects for unique resultsLet the artist in you go from ordinary to extraordinary! With a variety of in-camera effects, such as Low Key, High Key, Hard Monochrome, Nostalgia Sepia or Selective Color, your world takes on a new dimension. The S8200 provides you the tools to fashion photos and movies with more than just your great eye?just select an effect and go! For your still photography, bring out your creative side with a fisheye, miniature or even an artistic look. Finally, you can make the kinds of photos and movies you've always wanted to make.Flattering portraits every timeNikon's Smart Portrait System includes Smile Timer, which automatically recognizes when a subject is smiling and releases the shutter, Face-Priority AF, which finds and focuses on up to 12 faces, Blink Warning, Red-Eye Fix, Skin Softening and more.
Steady even when you?re notThe S8200's four advanced Vibration Reduction (VR) image stabilization functions automatically reduce the streaky images associated with shaky cameras.
High-speed continuous shootingYou'll never miss a shot with the S8200 because it starts right up, has a quick autofocus and shoots five shots in approximately one second at full resolution.
Strength in numbersYou'll always get a great shot with Nikon's Best Shot Selector. Press the shutter once, and the S8200 takes up to ten shots and then selects and saves only the sharpest image.
Dimensions: Height: 2.4 in. (59.3mm) x Width: 4.1 in. (103.7mm) x Depth: 1.3 in. (32.7mm)
Receive Our Latest Deals
Connect With Buydig


text:
by Joe Tressa
If you see a bald eagle flying around in Chestnut Hill, you're not imagining it. The national bird of America has been spotted nesting in the Wissahickon Creek area, near the Valley Green Inn.
Northwest Philadelphia is not the only part of the state (or country) where bald eagles have been seen. The eagles have been spotted in other parts of Pennsylvania, and they have also been seen throughout other parts of the nation.
The eagles' return comes shortly after they were officially removed from the federal list of threatened and endangered species in August of 2007. The return has been a long time coming, since the eagles were put on the U.S. Fish and Wildlife Service's endangered list for the first time in 1967 and were officially classified as endangered in all fifty states in 1978.
Willow Grove resident Ruth Pfeffer, who is known for her bird walks and lectures, many of which are held in the Wissahickon, said she is thrilled to have some bald eagles nesting in the area.
"It is amazing to have the bald eagles return and be so plentiful throughout our state," said Pfeffer. "It is so much fun to be with a group of birders and spot a bald eagle. The smiles appear on every face and the first spoken word is wow. The bald eagle has a magical effect on our spirits."
Pfeffer, who claims bald eagles have also been spotted in Chester, Montgomery, and Bucks counties, says residents should soon see the bald eagle's fledgings.
"We will begin to see the fledglings in our area soon," she said. "They have a different plumage than their parents. It takes five years for an eagle to acquire itswhite head and feathers."
The U.S. Fish and Wildlife Services have helped in the attempt to bring back America's bird. They have prohibited the killing of any eagles; they have improved the quality of water in many lakes and rivers, and they have made an attempt to protect the nest sites of eagles.
Pfeffer also gives credit to The Pennsylvania Game Commission for playing a role in restoring the bald eagles' population in Pennsylvania. According to Pfeffer, they began their attempt to restore the bald eagle population about 25 years ago.
Researchers from the state went to Saskatchewan, Canada, in order to remove a few eaglets from their nests and bring them back to Pennsylvania. These eaglets were brought back to the state and were housed in hacking towers where they were fed and taken care of. They were eventually released back into the wild, which gave them opportunities to mate and produce more eaglets.
This project has been credited with helping increase the bald eagle population in the state of Pennsylvania.
Bald Eagls first became endangered with widespread use of the harmful insecticide Dichloro-Diphenyl-Trichloroethane, better known as DDT, in the 1950s, according to the U.S. Fish and Wildlife Service's website. The problem that DDT caused was that it affected the eagles' reproduction, which caused failure in attempts to give birth to more eaglets. The eagles who were exposed to this chemical would lay thin-shelled eggs that would crack before the eaglets could hatch.
According to a report, the Environmental Protection Agency noticed this was a problem and it eventually banned the use of DDT in 1972. A second reason for the endangerment classification was the loss of habitat. Many forests were cleared, leaving the eagles with nowhere to nest.
The increase in population has taken some time, but the results of the Pennsylvania Game Commission's Project have recently paid off. As of 2011, 217 bald eagle nests have been spotted in the state, according to the Game Commission's website. This is a huge increase over time, as only three nests were known to exist in Pennsylvania in 1980. Also, many of these nests have produced eaglets.
From the years 2003 to 2011, more than 70 percent of nests produced eaglets. This is an outstanding number, and it gives more hope that the bald eagle population will flourish in years to come.
Also, the Game Commission has come up with a 10-year plan for the eagles. This plan will attempt to maintain the bald eagle population for the foreseeable future. The 52-page Bald Eagle Management Plan for Pennsylvania can be found on the Pennsylvania Game Commission's website.
Persons who may come across bald eagles are cautioned to refrain from agitating them. It is best to observe the birds from a distance, preferably with binoculars. Loud noises and sudden movements will disturb the eagles, which may cause them to become dangerous.
So if you're in the Wissahickon, keep an eye open for the Eagles. With the fledgings due, you may be even more likely to see the birds in the park.


text:
9-Year-Old Football Star Samantha Gordon Bests Hall of Famers
We met Samantha Gordon last week, when a highlight video of the nine-year-old dominating her otherwise all-boy football league went viral.
The folks at NFL GameDay were just as blown away as we were with her smooth moves, and invited her to be on Sunday's show.
Her appearance began with Steve Mariucci breaking down Samantha's now famous tape. The former San Francisco 49er coach enthusiastically praised the elementary school student from Utah but that wasn't even the highlight of Sam's day.
The gang asked if Samantha like offense or defense better, and she said she liked defense because of the tackling. However, she next showed her prowess with the ball by "juking" former All-Pro lineman Warren Sapp not once, but twice.
Finally, she got her chance to prove her defensive skill by tackling Hall of Fame running back Marshall Faulk. The former Ram looked worried when Sam began to line him up, and he had good reason to be as she eventually felled him with a mighty blow.
Despite her youth league dominance, it's a long shot that Samantha will ever make it to the NFL. But at least now she will always have this tape of her squaring off against a couple of NFL legends. Check out the cute video below.


text:
Oatmeal, Chocolate Chip and Pecan Cookies
Makes about 3 dozen cookies
8 tablespoons unsalted butter, at room temperature
3/4 cup sugar
1 cup light brown sugar, firmly packed
1 teaspoon salt
1 teaspoon vanilla extract
2 large eggs
1 1/2 cups flour
1 teaspoon baking soda
1/2 teaspoon ground cinnamon
1/4 teaspoon ground nutmeg
1/8 teaspoon ground clove
1 cup quick-cooking oats
2 cups chopped pecans
2 teaspoons freshly grated orange zest
12 ounces semisweet chocolate chips
Preheat oven to 350°F. Line a large cookie sheet with parchment or a Silpat (rubber nonstick baking mat). Using an electric mixer, beat the butter in a bowl until light and fluffy. Add both sugars, salt, and vanilla, and beat until well mixed, about 3 minutes. Stir in eggs, one at a time. Sift together the flour, baking soda, cinnamon, nutmeg, and clove in a separate bowl. Add half of the flour mixture to the butter with the mixer on low speed. Once the flour has been incorporated, add the second half. Stir in the oats, pecans, orange zest, and chocolate chips. Drop the dough, by the tablespoon, onto the cookie sheet and bake for 10-12 minutes or until golden. Remove from the oven and cool the cookies on a rack. Store at room temperature in a cookie jar or other airtight container.


text:
WARNING! Normal Blood Pressure May Be High Blood Pressure!May 2005
By William Davis, MD, FACC
Recent advances in medical science make previous notions of hypertension barely recognizable today. Although hypertension is widely misunderstood, often ignored, and generally under-treated, this incredibly important facet of health and well-being can be your passport to cardiovascular disease prevention.
High blood pressure can be imperceptible, insidious, and sometimes inscrutable.
Too often, people deny that they have high blood pressure. "I'm nervous," or "I fought traffic to get here," or "Wait until I relax a little while and it'll come down," are common reactions of those advised that their blood pressure is too high.
If you truly have high blood pressure, you are not alone. Without intervention, high blood pressure is likely to affect most of us at some point in our lives. With age and declining health, high blood pressure can be as inevitable as death and taxes. Even if you are non-hypertensive at the age of 55, the Framingham Heart Study predicts a 90% likelihood that you'll be hypertensive within your lifetime.
Too often, discussion about hypertension degenerates into a mandate for prescription medication, once the obligatory comments about eating a healthier diet, reducing salt intake, and quitting smoking are out of the way. It is no secret to the medical community that conventional blood pressure treatment does not fully eliminate the risk of suffering cardiovascular events from hypertension.1 In other words, threats to health from high blood pressure often remain uncorrected even when blood pressure appears to be fully controlled by medication.
From Bloodletting to Metabolic Syndrome
In the late nineteenth century, Dr. Carl Ludwig first devised a technique for measuring blood pressure that required the insertion of a tube into an artery, allowing blood to flow into a manometer. Not until the turn of the twentieth century did the sphygmomanometer became available. This device for measuring blood pressure did not require puncturing a blood vessel and was therefore useful for everyday purposes. In 1912, the Massachusetts General Hospital in Boston began mandatory blood pressure measurements for all patients admitted to its wards.
Progress in treating high blood pressure has lagged behind techniques for measuring it. Even in Ludwig's day, some practitioners advocated bloodletting to allow high pressure to dissipate. As recently as the 1960s and 1970s, hospital wards were filled with patients suffering uncontrolled, perilous levels of hypertension ("hypertensive crises") due to the broad failure of the medical community to recognize and treat earlier phases of high blood pressure. Treatment choices were likewise limited and flawed.
Our understanding of blood pressure has advanced considerably since these early observations. Today, medicine has improved, though it is certainly not foolproof. Even better, breakthroughs in the science of regulating blood pressure are revealing many promising nutrition-based approaches for preventing and controlling high blood pressure. Some of the most exciting recent insights revolve around the role of nitric oxide, a master controller of blood pressure, and the frightfully common cluster of health disorders known as metabolic syndrome, an eminently correctable factor in blood pressure control.
What Is Normal Blood Pressure?
In the 1960s and 1970s, the medical profession used arbitrary guidelines that grossly underestimated the perils of hypertension. For example, a rule practiced in the 1970s held that an "allowable" blood pressure value could be calculated by adding 100 to a person's age. By this formula, a 60-year-old adult woman would be permitted a systolic blood pressure of 160 mmHg before her physician would become concerned. We all know now that a blood pressure like this virtually guarantees complications of high blood pressure—such as stroke, dementia, and kidney failure—within a few short years.
Why such confusion about acceptable blood pressure levels? The dilemma arises in part because blood pressure is variable. In the morning, just before arising, your systolic/diastolic blood pressure might be 104/78 mmHg. After eating breakfast and having coffee, it could change to 128/74 mm Hg. While sitting at your desk at work, having more coffee, answering email, and making phone calls, your level could rise to 149/79 mmHg. An annoying comment from a customer could push your blood pressure to 164/68 mmHg. After blowing off steam with a friend, walking 200 feet to another part of the building, looking at the picture of your family on your desk, and reminding yourself that there is more to life than work, your blood pressure might then drop to 130/70 mmHg.
No one's blood pressure stays constant at the optimal level of 120/80 mmHg or lower. Blood pressure fluctuates widely, even in people with normal levels. People without high blood pressure will fluctuate into clearly abnormal ranges during periods of emotional stress, overindulgence in unhealthy foods or alcohol, and physically demanding activities. This does not mean they have high blood pressure.
Then how do we define high blood pressure if even those with normal blood pressure occasionally trespass into high levels?
High blood pressure does not necessarily mean constantly and persistently high. People with high blood pressure tend to fluctuate more widely. Differences of 60-80 mmHg within just a few minutes are common. The "give me a few minutes to calm down" comment that allows systolic blood pressure to drop from 180 to 120 mmHg simply reflects this phenomenon in a hypertensive individual. High blood pressure also stays higher longer and rises above normal more frequently. In other words, for hypertensive people, the peaks and valleys of blood pressure are higher, broader, and more numerous than for those with normal pressure. The ideal way to measure blood pressure is to have somebody follow you throughout the day and measure your blood pressure under all sorts of different circumstances. Unfortunately, this approach is impractical.
One practical way to gauge overall blood pressure behavior is to wear an ambulatory blood pressure monitor. This device is worn for 24 hours, and automatically measures and records blood pressure every 15 minutes. Its readings are then reviewed by a physician. Another way is a stress test, since graded exercise's effects on blood pressure can be observed while the patient walks on a treadmill. Both tests show the extremes of blood pressure fluctuations and offer a good idea of whether you truly have high blood pressure when faced with the stressors of everyday life.
The last option is to simply measure your blood pressure the old-fashioned way, while sitting in your doctor's office. You can improve on this by adding measures of your own (with an automatic blood pressure cuff or measured by a friend) at different times and under varied circumstances, such as at home, upon awakening, and following exercise. This will gives you a reasonable idea of everyday fluctuations in your blood pressure. However, you should expect variations in pressure, regardless of whether you have high blood pressure.
Another reason for confusion over elevated blood pressure arises from its "silent" nature. Only occasionally does high blood pressure cause symptoms like headache or fatigue. The vast majority of those with lurking hypertension feel just fine, with no symptoms at all. Perhaps that is why we question, argue with, and resist a diagnosis of high blood pressure.
Blood Pressure's Ebb and Flow
What exactly is blood pressure? Put simply, it is the force with which blood is propelled through your arteries. Unlike a river, which flows continuously downstream, blood flow is pulsatile, with the ebb and flow driven by the pumping heart muscle. The heart muscle squeezes forcefully, propelling blood forward. The heart then relaxes and blood flow ebbs momentarily. This cycle repeats itself with each heart-beat, 60 or so times each minute.
Blood pressure, therefore, is the pressure contained within your arteries, with a forward burst of flow from heart contraction called systolic pressure, and the receding flow of heart relaxation called diastolic pressure. A blood pressure measurement of 120/80 mmHg signifies a systolic value of 120 and a diastolic value of 80, measured in the pressure units of millimeters of mercury.
You can deduce many of the causes of high blood pressure just by understanding this basic process. For instance, pour a greater volume of fluid into the system, and systolic pressure goes up because each contraction of the heart delivers greater volume, and the diastolic pressure goes up because there is more volume to fill the arteries and less room to dissipate pressure during heart relaxation. Several disorders cause fluid retention in your circulatory system and thereby cause high blood pressure. These include excessive salt intake, poor kidney function, and high levels of certain hormones like renin, angiotensin, and cortisol.
Another factor is arterial flexibility or stiffness. Normally, arteries are flexible and "give" with pulsatile blood flow. However, when these vessels are stiff, they are less able to expand with bursts of flow, and pressure increases. This is common in arteries lined with semi-rigid atherosclerotic plaque, also known as "hardening" of the arteries.
Regardless of their cause, all forms of blood pressure can eventually lead to the same undesirable effects. High blood pressure pounds your organs with each heartbeat, hour after hour, day after day. Over the years, the effects of this relentless trauma begin to show. In the kidney, the ability to filter the body's waste products and separate excess fluid from blood weakens. In the heart, coronary arteries develop plaque that leads to heart attack. Heart muscle becomes overly thick and muscular, internal heart pressure increases, and you become breathless and retain fluid, a condition called diastolic dysfunction. The arteries of the chest and abdomen, and particularly the major artery of the body, the aorta, also develop plaque. The aorta enlarges, essentially "inflating" under the increased internal pressure of hypertension, leading to the formation of aneurysms. In the brain, the relentless pounding of high blood pressure can lead to deterioration of brain tissue, eventually leading to a form of dementia called multi-infarct dementia that arises from many mini-strokes.
Is "Normal" Blood Pressure Too High?
"We have taken it as the natural human condition that blood pressures are as high as they are. We have arbitrarily defined 'normal blood pressure.' But that does not mean that normal is optimal."
—Dr. Henry R. Black, Rush University Medical Center
At what point does blood pressure begin to have demonstrable effects on cardiovascular complications and mortality itself? At a systolic pressure of 150 mmHg? How about at 140 mmHg? In fact, measurable complications of blood pressure begin to appear at just 115 mmHg! That is, systolic pressures above 115 mmHg are sufficient to generate damage to arteries and other organs, with measurable impacts on morbidity and mortality over a period of several years.2
Every additional increment in blood pressure of 20/10 mmHg doubles one's risk of developing cardiovascular disease. For this reason, the most recent national guidelines for blood pressure issued by the National Heart, Lung, and Blood Institute recommend maintaining a systolic blood pressure under 120 mmHg and a diastolic pressure below 80 mmHg. Values at or above 140/90 mmHg are considered hypertensive, requiring medical intervention. The new guidelines provide for a category called "pre-hypertension"— defined as systolic pressures of 120-139 mmHg and diastolic pressures of 80-89 mmHg—that justifies lifestyle modification for improvement.1
The recent release of the Camelot Study conducted by Dr. Steven Nissen of the Cleveland Clinic has fueled the argument that lowering blood pressure even moderately yields substantial health benefits. In this study of nearly 2,000 participants with heart disease, lowering blood pressures within the borderline range from 129/78 to 124/76 mmHg led to significant reductions in heart attack, death, and hospitalization. This blood pressure reduction also decreased arterial plaque growth, as measured by intra-coronary ultrasound.3 It is interesting to contemplate what the potential effects of lowering blood pressures to 100 mmHg would be, and perhaps future clinical trials will answer this question for us.
Hypertension: A Twenty-First Century Epidemic
Look down the aisles at your neighborhood grocery store and you will see why 47 million adults in the US, or about one of every four, have the cluster of disorders dubbed metabolic syndrome. Ninety percent of the products on the supermarket shelves are highly processed foods that are rich in unhealthy fats, loaded with sugar, and depleted of fiber. Combine these foods with lifestyles marked by inactivity, sleep deprivation, and stress, and you create a constellation of physiological phenomena that includes abdominal obesity, low levels of beneficial HDL (high-density lipoprotein), high levels of harmful triglycerides, elevated blood sugar, and high blood pressure. So many adults in the US meet the diagnostic criteria for metabolic syndrome that the total number now afflicted nearly equals the number of "baby boomers."4
If you have hypertension, there is a high likelihood that you have at least some of the characteristics of metabolic syndrome, particularly resistance to insulin, a condition that precedes development of full-blown diabetes. In fact, the association is so strong that hypertension should be regarded as a significant risk factor for future diabetes, with a greatly increased risk of diabetes in your future.5
Moreover, the estimate of 47 million US adults with metabolic syndrome is based on the rather lax definition of hypertension as a blood pressure greater than 140/90 mmHg. Many truly hypertensive people will be uncounted using this guideline. As noted earlier, blood pressure is, by its nature, labile and variable. It is also clear that blood pressure begins to affect mortality rates at levels above 115 mmHg. Most people are shocked when they hear this, having been accustomed to hypertension guidelines specifying levels of 150/90 mmHg and higher. To remind ourselves of what optimal blood pressure should be, we need only look at blood pressure levels in primitive cultures that lack access to processed foods and are engaged in physical activity much of the day. People in these cultures, who rarely suffer from cardiovascular disease, have blood pressures of around 90/60 mm Hg.2