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By Derek Link
Early in the AIDS crisis, when the epidemic's disastrous scope could not yet be imagined, AIDS activists pressed the Food and Drug Administration (FDA), the federal agency that regulates the testing, sale and promotion of drugs, for a faster and more humane response to this public health emergency. On October 11, 1988, thousands of AIDS activists from across the nation descended on the FDA's headquarters in Rockville, Maryland. They demanded faster approval of new AIDS therapies and focused public attention on the glacial pace of this federal bureaucracy. Over the last eight years, AIDS activists have continued to scrutinize the FDA's AIDS activities, serving as consultants on FDA advisory committees, issuing critical reports on its operations and winning many important victories along the way.
AIDS drugs are now approved faster, and access to them granted earlier, than anyone thought possible just a few years ago. Because of pressure and creative ideas from AIDS activists, the FDA pioneered accelerated approval and expanded access programs. One need only look at the recent past for a vivid example of the success of AIDS activists' efforts. Saquinavir, the first of the new generation of protease inhibitor drugs, was approved in a record three months, the fastest AIDS drug approval ever. All is surely not perfect at the FDA, but the agency has made substantial progress. AIDS activists still have a full regulatory agenda covering such issues as how best to use the accelerated approval process while insuring that sufficient information on drugs' actual potential is generated through post-marketing studies.
After the Republican landslide in the 1994 Congressional elections, the new Congress immediately took up the cause of FDA reform as one of its highest priorities. Accusing the FDA of murderous delays and inept bureaucracy, the new Congress adopted much of the confrontational language of AIDS activists in its debates on the FDA. The similarities between AIDS activists and Congressional Republicans end with the rhetoric, however. AIDS activists have helped to organize a national campaign in support of responsive and efficient drug regulation, but in opposition to ideological, political attacks on our nation's public health safety net. Congressional "FDA reform" could halt medical research and innovation, harm people with serious and life-threatening disease, and undermine the nation's health.
Reform of the FDA, AIDS activists recognized early, was a problem of policy, management, resources and administration. The FDA implemented faster drug approvals and expanded access programs without Congress ever passing a law. This is because the organization, policies and procedures of the FDA are not established by Federal law. With wide discretion over drug regulation, the FDA could approve drugs faster by implementing internal policy changes. This flexibility is perhaps its greatest asset; it gives the agency the ability to respond rapidly and in a non-political manner when public health emergencies, like AIDS, arise.
HIMA (the medical device manufacturers group), BIO (the biotech industry group) and PhRMA (the drug industry group) are the main industry groups pressing for substantial changes to the Food, Drug and Cosmetic Act. BIO's president, Carl Feldbaum, told the National Journal, "We're pushing [FDA reform] very hard. We have a lot of irons in the fire with the FDA."
Each of these groups has released FDA reform proposals, and has dispatched their lobbyists to the Capitol. "I think they'd like to eviscerate the FDA, but if they can't do that, they'd like to intimidate the FDA," Henry Waxman, a senior Democrat on the House Commerce committee and a leading consumer protectionist, told the National Journal.
Right-wing political organizations, with heavy funding from regulated industries, have gone on the offensive too. The Washington Legal Foundation (WLF), the Progress and Freedom Foundation and Citizens for a Sound Economy, are the three most prominent right-wing advocacy groups working on FDA reform legislation.
The WLF has run several full page ads in The New York Times and Washington Post harshly criticizing the FDA with the tag line, "The Problem with Health Care in America is the FDA." The WLF furthermore has filed several lawsuits over FDA regulations, mostly over the type of marketing strategies pharmaceutical companies can pursue. The Foundation argues that limiting the claims companies can make to the applications approved by the FDA is a violation of the First Amendment's protection of free speech.
The President of the WLF, Alan Slobodin, temporarily stepped down from his post to become a senior staff member of the House Commerce Committee, which has authority over the FDA and will draft reform legislation in the House. The Lilly Endowment, a foundation whose funds come from Indianapolis-based drug maker Eli Lilly, gave the WLF $150,000, making it one of the organization's largest financial backers.
The Progress and Freedom Foundation is perhaps the biggest player among the advocacy groups. The Foundation is closely associated with House Speaker Newt Gingrich. The Foundation is run by close Gingrich supporter Jeffrey Eisenach, and handles many of the Speaker's political activities, including organizing Progress Report, Gingrich's talk show on National Empowerment Television. Major industry contributors to the Foundation have included Burroughs Wellcome, Glaxo, Genzyme, Searle, Johnson & Johnson, Direct Access Diagnostics (now a Johnson & Johnson subsidiary), Health South Corporation, Amgen and Solvay. "This was an organization that looked like it was going to have some influence, and we wanted to have some influence with them," Lisa Raines, chief Washington lobbyist for Genzyme, has stated.
Speaker Gingrich has already interceded on behalf of some of these Foundation contributors. Last summer, Gingrich urged the FDA to move faster to approve Luvox, a Solvay drug for obsessive-compulsive disorders. Gingrich also has urged the FDA to move faster in approving an HIV home test kit manufactured by Direct Access Diagnostics. The House Ethics Committee is investigating Gingrich's relationship to Direct Access Diagnostics, as part of its overall ethics investigation of the Speaker.
Last year, the FDA proposed sweeping new regulations which would substantially change the way cigarettes are sold in the United States -- limiting advertising and restricting sales to minors. The new FDA regulations could have a devastating impact on tobacco industry profits -- almost all smokers start when they are teenagers.
The tobacco industry has responded with a full-scale assault on the FDA and the FDC Act. On January 2, it submitted to the FDA a 2,000 page document with 45,000 pages of supporting documents challenging its authority to regulate cigarettes.
The industry also launched an aggressive campaign contribution drive to the Republican party. In the first half of 1995, the tobacco industry pumped $1.5 million into Republican party coffers, over five times the amount from the same period in 1994, and a record level contribution of so-called "soft money" to a political party. In addition the tobacco industry has sharply increased donations to individual Republican Congressmen. Most tellingly, Thomas Bliley (R-VA), Chair of the House Commerce Committee -- the committee responsible for FDA reform legislation in the House -- received $126,476 from the tobacco industry, more than any other member of Congress.
Richard Burr (R-NC), who has received $11,350 from tobacco interests and also is a Commerce Committee member, wrote in Roll Call "I cannot understand why the FDA, which cannot efficiently perform its core mission, should be rewarded with historic jurisdiction increases [over the tobacco industry]." Although the tobacco industry has been a driving force that keeps FDA reform high on the Republican agenda, it has not been publicly identified with the reform effort. "A veteran tobacco industry hand said that Bliley has asked companies to lay low for their own benefit and his and that he doesn't want to be perceived as beating the FDA over the head because of tobacco. That message has come through loud and clear," reported the National Journal.
In response to the industry-driven assault on the FDA, patient advocacy groups have joined together in an historic coalition. The Patients' Coalition, which formed last summer, includes over 80 leading national organizations from prominent AIDS groups, such as the American Foundation for AIDS Research and GMHC, to the American Cancer Society, the National Organization for Rare Disorders and the National Health Council, which represent the largest voluntary health organizations in the country.
The coalition wrote a set of FDA reform principles informed by the common experiences of all patients with serious and life-threatening diseases. It also released a policy white paper on the real problems at the FDA. One much discussed proposal is a "sunshine law" that would permit the FDA to publicly discuss its private interactions with drug developers. Currently, companies frequently complain of FDA delays in processing their drug approval applications while the FDA refuses any comment on the grounds that such applications constitute proprietary information.
The coalition is working together on Capitol Hill and in the media, trying to ensure that FDA reform legislation serves patients' true interests. Such diverse patient groups have never worked together in such an intensive way. They have come together because all patients need federal regulations that encourage medical research and innovation while continuing to ensure that drugs are safe and effective.
FDA reform legislation has taken much longer to move through the Congress than many had predicted. Numerous hearings have been held on FDA reform issues in both the House and Senate during the first year of the 104th Congress. But legislation has been very slow to emerge. The Republicans now realize that FDA reform is more complicated than they first imagined, placing core values into question, and opening a Pandora's box of competing interests.
In both the House and Senate, there is no consensus on FDA reform. Nancy Kassebaum (R-KS), chairwoman of the Senate Labor Committee -- which has jurisdiction over the FDA in the Senate -- introduced a comprehensive ("Omnibus") FDA reform bill. Sen. Kassebaum's bill has no co-sponsors, indicating that both industry advocates and consumer protectionists in the Senate are dissatisfied with its provisions. The House Commerce Committee has had an even more difficult time with FDA reform legislation. The House committee has altogether given up drafting a single, "omnibus" FDA bill. Instead the Commerce Committee now plans many individual bills on discrete areas of the FDA's authority. The lack of consensus means the course and outcome of the FDA reform legislation is unpredictable and volatile. Individual bills or amendments to bills could be introduced that radically change the federal government's authority over drug development
and marketing.
The Congress now anticipates taking up FDA reform early this year. Sen. Kassebaum plans hearings on her bill over the next few weeks, and the House could start introducing bills as well. It is still unclear, though, if the Republicans can move such major legislation through while budget debates and election campaigns heat up. In any event, if a bill is eventually passed by Congress, it may bear little resemblance to the proposals being considered now.
As the first introduced, Sen. Kassebaum's FDA reform bill (S.1477) is worth a close look. Written primarily by senior staffer Jane Williams, the bill is considered a moderate proposal. Sen. Kassebaum's staff have been open to the concerns and views of the Patients' Coalition. When a draft of the proposal was circulated this fall, the coalition sent a detailed analysis, some of which was incorporated into the final version.
The bill does reject many of the most radical FDA reform proposals, and, as Ms. Williams said to a meeting of the coalition, "it's the best you're going to get." Be that as it may, the bill as it now stands would harm patients with serious and life-threatening diseases by undermining incentives for medical research and innovation.
The Kassebaum bill establishes that only one efficacy study of a new drug is necessary to meet the requirement of safety and efficacy. The FDC Act presently does not define how many studies are required, but the FDA has interpreted the law to mean that two are required. On a scientific level, two studies greatly increase the likelihood of making the correct interpretation of data, especially when results are ambiguous or marginal. The FDA in any case already uses a one efficacy study requirement for new drugs if the study is a large multi-center one, or the drug in question is a high priority or the results are unambiguous. Without the FDA's discretion over the number of required studies in drug development, less clinical research will be performed, reducing the scientific foundation for new therapies.
The bill sets strict approval schedules, requiring FDA action within 120 days on New Drug Applications. Strict time-lines sound wonderful, but they in fact can slow access to drugs for patients with serious and life-threatening diseases. If the FDA must approve everything rapidly, then resources will be pulled away from high priority approvals, like break-through drugs for serious diseases, to lower priority approvals, like fourth generation sleeping pills. The FDA has inadequate resources for every drug to be a high priority. The FDA must devote more resources and staff time to reviewing drugs for the sickest patients. This proposal also fails to acknowledge the FDA's progress. Saquinavir, the first of the new generation protease inhibitor drugs, was approved in 90 days, for example.
The bill also proposes increasing the authority of the FDA's advisory committees. The FDA maintains a host of independent advisory committees that review research data and make recommendations to the agency. The decisions of FDA advisory committees are not binding on the agency. Sen. Kassebaum's bill enhances the authority of the advisory committees, making their decisions binding on the FDA. The bill would also mandate that representatives of regulated industries be included as members of the committees, a move which is presently prohibited under conflict-of-interest regulations.
The Kassebaum bill ignores ample evidence of the mediocrity and ineffectiveness of advisory committees. A 1992 study of the FDA advisory committees by the Institute of Medicine found multiple problems with them. Well-qualified people often do not serve on FDA advisory committees because of long time commitments (members serve two year terms) and low pay for professionals ($150 a day). Sen. Kassebaum's bill does nothing to fix the recruitment problems for advisory committees, and instead aggravates it by extending service to three years. Breakthrough drugs should be evaluated by skilled FDA scientists and professionals, not mediocre, part-time committee members.
The bill's most radical proposal is to create a "presumption of approvability" for some new drugs. If a drug were approved in the United Kingdom, it would have an automatic "presumption of approvability" in the United States. The FDA would have thirty days to block the automatic approval of the drug in this country. This proposal ignores some key facts. The United Kingdom has a slower drug approval process than the United States. Many AIDS drugs -- d4T, 3TC and saquinavir among them -- are not yet approved in the U.K. Every AIDS drug has been approved first in the U.S.
The presumption that the U.K. is faster is simply wrong, and it abrogates the federal government's fundamental responsibility over the safety and efficacy of drugs marketed in this country. It also ignores that the U.S. has far fewer drugs withdrawn from the market for safety reasons than other countries -- just the classic case of thalidomide.
The bill also would allow drug companies to promote and advertise so-called "off-label" uses of their products. Promotion of off-label uses refers to advertising health claims for a product that are not approved by the FDA but that are considered part of standard medical practice. The bill seeks to solve a real problem. Many drugs -- especially for cancer -- are used in ways that are not FDA-approved. Many drugs have multiple uses, but some are approved for just a single specific purpose. While many off-label uses of drugs are standard medical practice, many others are ineffective or harmful. Sen. Kassebaum's bill would allow marketing of any "medically accepted" use of a product, without saying what constitutes "medically accepted." The bill cannot distinguish between legitimate and harmful off-label uses.
Advocates for rare diseases are especially concerned about off-label promotion. They fear Sen. Kassebaum's bill will undermine the incentives for research into rare diseases created by the Orphan Drug Act. The Orphan Drug Act establishes financial, tax and patent incentives for industry to research drugs for rare diseases.
Many of the drugs used to treat rare diseases are already approved for other, more common maladies. Say two companies make the same product, but only one company conducts research into the product's use in a rare disease. The Orphan Drug Act authorizes the government to grant the company that did the research an exclusive right to market the drug for this disease. If adopted, Sen. Kassebaum's bill may well undermine this exclusivity because any manufacturer could promote all the "medically accepted" uses of its drugs, even if the company did not conduct the research on the orphan indication.
Patient advocates agree that their goal for off-label drugs should be to encourage industry and the FDA to work together to submit data on off-label uses. Applications for secondary indications should be easier and cheaper to file.
More broadly, the Patients' Coalition sees the FDC Act as critical for sustaining the unprecedented era of medical research and progress, an era in which American science has been preeminent. The FDC is vital to the nation's, and indeed the world's, health because its high standards help protect the public against new therapeutic products backed only by dubious or fraudulent data.
Congressional meddling with the Act may well end up harming patients with serious diseases by reducing the amount of medical information available. Questionable, ill-advised treatment would become more likely in such circumstances.
Many AIDS activists have pressed for reform of the FDA, but not for changes to the Food, Drug and Cosmetic Act. These AIDS activists, along with their allies among patient advocacy groups, are continuing to call for an efficient and responsible FDA. At the same time, this coalition considers paramount the preservation of the federal government's crucial role in drug development and marketing.
Gilead Sciences has asked the Food and Drug Administration to approve intravenous cidofovir (brand name: Vistide) as a therapy for CMV retinitis. Cidofovir's primary advantage is that it need only be infused into patients on a weekly or biweekly basis compared to once or twice daily for current medications (ganciclovir and foscarnet). This dosing schedule furthermore removes the need for the in-dwelling catheter used with ganciclovir and foscarnet. If Gilead's application is accepted without modification, cidofovir would be on a par with the two older drugs and could be administered either as initial treatment or as a salvage therapy.
The case for the new drug application rests on data from two company-sponsored studies. One compares immediate treatment with cidofovir to deferred treatment. The other is a dose comparison study.
The first study enrolled 48 patients with CMV retinitis and no systemic CMV disease. Retinitis progression was defined as advancement of the edge of an existing lesion by 750 microns or the occurrence of a new lesion 750 microns or larger in diameter. Most of those randomized to deferred therapy experienced progression of their retinitis after a median 22 days, and were then crossed over to treatment. Those who received cidofovir immediately and who remained on treatment throughout the trial did not progress for a median of 120 days.
Many patients discontinued the study prior to progression and were not counted in calculating progression rates. According to Gilead's Vice President of Clinical Research, Howard Jaffe, M.D., though, even if those who discontinued were assumed to have progressed, the median time to progression would have been approximately 70 days at worst. The median time to progression had not yet been reached in the sixteen patients crossed-over to treatment from the deferred therapy arm, but, again, many patients have discontinued therapy.
The dose comparison study includes 100 people with relapsing CMV retinitis or intolerance to standard therapies. Although an interim analysis of data from the first sixty patients last April did not at that time show a statistically significant difference between the two doses (three mg/kg of body weight vs. five mg/kg), the median time to first progression was 49 days on the three mg/kg arm vs. 115 days on the five mg/kg arm. Complete data from this study should be ready sometime in February -- if there is a statistically significant difference between the doses, the case for approval of cidofovir will be stronger.
One other study and a treatment IND (expanded access) program provide additional data for the cidofovir application. The SOCA (Studies of the Ocular Complications of AIDS) network is running a three arm trial in 90 volunteers comparing two different regimens of cidofovir and deferred treatment. It is unlikely that any efficacy data from this study will be ready by the time the FDA reviews Gilead's application, but some safety data will be available. Adverse events also are being actively monitored in the treatment IND program as physicians must submit a report with every two doses of drug. At press time, 146 patients have re istered in the protocol. (For TIND information, call 415/573-4700.)
All three systemic intravenous CMV therapies are toxic. Like foscarnet, cidofovir can cause irreparable, life-threatening kidney damage. A few years ago, it appeared too dangerous to be useful as a systemic therapy until researchers learned that the toxicity could be attenuated with hydration therapy and four grams of probenecid on the day of the infusion. (Probenecid helps the kidneys excrete cidofovir safely. Researchers also reduced the cidofovir regimen.) Even with probenecid and hydration, the drug at standard dose should not be administered to patients with proteinuria (high levels of protein in the urine) or elevated serum creatinine levels, both indications of kidney impairment. Dose reduction studies are underway in patients with compromised kidney function.
Probenecid produces its own side effects, including transient (lasting one to two days) fevers, nausea and rashes in about fifty percent of the patients in the Gilead studies. A few patients can have life-threatening allergic reactions. In the dose-ranging study, at least two patients required resuscitation and hospitalization within hours of treatment. One had a major drop in blood pressure and the other had a fever of 104 F, low blood pressure and severe shortness of breath. Both patients had a history of reactions to sulfa drugs (to which probenecid is structurally related). Many investigators have been giving antihistamines along with the probenecid. Discontinuing pro-benecid or lessening the dose is not an option since cidofovir's kidney toxicity is so severe.
There is little drug interaction data available for cidofovir. There seems to be no interaction with AZT. Interaction studies with ddI and Bactrim will begin soon, and other studies are being designed.
Some in the community are concerned that if the FDA approves cidofovir, people may opt to use this drug before the better characterized ganciclovir or foscarnet because the dosing regimen is so much easier on patients than the daily regimens and indwelling catheters of the two older intravenous therapies. But the lack of studies directly comparing cidofovir to ganciclovir or foscarnet makes it difficult to determine which drug should be used when.
The picture is further complicated by the new availability of oral ganciclovir and the ganciclovir intraocular implants. These two approaches in combination may represent another attractive option. The implant would provide the advantages of localized therapy against CMV retinitis in the treated eye while the oral drug may provide a cover against breakthrough infections in the uninvolved eye or elsewhere in the body. Hard data on this combination will be available from an ongoing trial comparing the ganciclovir implant-oral ganciclovir combination to standard intravenous regimens. In the future, intraocular injections of cidofovir promises to provide another effective localized therapy against CMV retinitis. (For a review of the many new CMV treatments, see the July-August, 1995 Treatment Issues.)
The lack of comparative data is not an argument against FDA approval of cidofovir. Cidofovir appears to show clear clinical benefit in people who can tolerate it. But unless intravenous cidofovir is shown to be superior to other CMV therapies, or until there is more clinical experience with the drug most clinicians will relegate it to second or third CMV therapy, to be used when other approaches are failing.
Hoffmann La Roche, makers of saquinavir, the first protease inhibitor to receive FDA approval for treatment of HIV infection, has just launched a large trial to test a new, more promising formulation of the drug.
The old formulation, a hard gelatin capsule with a very low bioavailability (four percent), has been used in six previous clinical trials. The drug has displayed an antiviral effect that is low in comparison to other, soon-to-be-released protease inhibitors -- at least at the standard 600 mg thrice daily dosage. A study of high doses of saquinavir (3,600 and 7,200 mg per day) done at Stanford University did show a substantial improvement in the effect on HIV levels and CD4 count.
The new trial will try the soft gelatin capsule at a dose of 1,200 mg taken three times daily, which is predicted to provide exposures to the drug similar to 7,200 mg/day with the hard gelatin capsule. The study will be double-blind and placebo-controlled (in a two to one ratio of people on saquinavir to those on placebo) for the first sixteen weeks. Other concomitant protease inhibitors are excluded, but participants may take nucleoside analogue therapies as prescribed by their physicians. They will be required to maintain a constant anti-HIV regimen for these sixteen weeks.
After the first sixteen weeks, the trial participants will be given the option of open label therapy with the soft gelatin capsule at the 1,200 mg thrice daily dose.
Six hundred volunteers are expected to be enrolled at 35 to 40 centers in the United States. They will be stratified into three groups by CD4 cell count (0 to 50, 51 to 300 and 301 to 500). One quarter of the trial group must have plasma HIV levels of greater than 20,000 copies/ml. The primary endpoints of the study will be plasma viral load by quantitative PCR and an increase in CD4 cell count. For the location of trials sites around the country, call 800/TRIALS-A.
Unimed Pharmaceuticals has announced FDA approval of a compassionate use program providing very limited access to nitazoxanide (NTZ), an anti-crypto- sporidial agent currently in clinical trials (see Treatment Issues, September, 1995, page 14). The company is also opening a site in San Francisco at the Kaiser HIV Research Group (investigator: W.J. Fessel, M.D.) to speed the ongoing American phase II studies of the drug. Meanwhile, the Mexican licensee of the drug has initiated phase III clinical trials in that country for people with AIDS-related cryptosporidiosis. Data from this study should contribute to the eventual application for FDA approval of NTZ.
The compassionate use protocol is currently limited to 30 patients until the FDA is provided with additional safety data, but the size is expected to increase over time. Its purpose is to provide access to people with cryptosporidiosis who do not qualify for or cannot enroll in the ongoing study which excludes those who have other concurrent gastrointestinal infections such as microsporidiosis. Doctors wishing to enroll their patients in this protocol can call 800/864-6330. Twenty patients had already enrolled in this program as of early January.
An ongoing double blind study of AmBisome, the Fujisawa USA's liposome-encapsulated version of amphotericin B, is now open to people with relapsing cryptococcal meningitis (CM) that remains sensitive to fluconazole (which is used as maintenance therapy).
Previously, participation in the study had been restricted to people with primary CM. The study compares AmBisome to standard amphotericin treatment and currently has 50 patients enrolled. For information on trial sites, call the government's national clearinghouse at 800/TRIALS-A.
Liposomal versions of amphotericin are thought to be considerably safer than the unprocessed product (see Treatment Issues, April, 1994, pages 6, 9-12) A number of open-label studies have reported positive responses with AmBisome in people with CM who have failed amphotericin treatment.
Fujisawa also has opened a general compassionate use program to provide AmBisome to anyone with systemic fungal infections who is intolerant to amphotericin or for whom amphotericin would be contraindicated. The protocol is also open to patients with candidiasis resistant to the triazole antifungal medications such as fluconazole. (Maintenance therapy to prevent recurrence may require once or twice weekly infusions of AmBisome) For more information, call Fujisawa's Medical Information Line at 800/727-7003.
The first clinical trials of an HIV "integrase inhibitor," Aronex Pharmaceuticals' AR-177, are in progress at San Francisco General Hospital. Like reverse transcriptase and protease, integrase is an essential HIV enzyme. It binds to HIV DNA, which is created by the reverse transcriptase enzyme, and integrates that DNA into the host cell's chromosomes. AR-177 does not inhibit this integrating activity (compounds that do so are years away) but rather appears to keep the enzyme from binding to the newly processed DNA in the first place.
The drug is an oligonucleotide (string of nucleotides -- the building blocks of DNA). Most oligonucleotides cannot be administered systemically, because they breakdown and rapidly pass from the body. But AR-177 is unique -- formed by seventeen nucleotides (mostly guanine), it folds upon itself to form a stable structure less prone to destruction in the blood. In animal studies, the compound was not easily metabolized and was excreted very slowly. Some drug remained in the animals' bodies a week after a single dose.
Work on this compound began because similar oligonucleotides were found to bind to the V3 loop on the HIV envelope protein gp120, potentially interfering with entry of the virus into cells. But after adding AR-177 and HIV to cell cultures with HIV, researchers were still able to detect viral DNA in the cells. Nevertheless, the drug blocked viral replication, and the HIV DNA within the cells disappeared after several hours.
This observation suggested that HIV was getting into cells, but that AR-177 was keeping the viral DNA from being integrated into the cell's DNA. Subsequent studies showed that the drug blocked binding to and early processing of viral DNA by integrase.
The phase I single dose escalation study of AR-177, directed by James Kahn, M.D, began in October. The study has reached its second dose level (1.5 mg/kg of body weight) and has already achieved blood levels that correlate with activity in laboratory cell cultures. Higher doses will be evaluated. A subsequent study evaluating the pharmacokinetics, safety and antiviral effect of multiple dosing will begin in the second quarter of this year.
At present, AR-177 is an injectable drug. The company hopes that the compound's half-life will be long enough to allow for infrequent dosing. Meanwhile, preliminary data in rodents show that the drug does have some oral bioavailability. The company is now studying an oral formulation in primates.
Unimed Pharmaceuticals is starting a clinical trial of its new, rub-on testosterone gel in twenty HIV-positive men with wasting associated with low testosterone levels (hypogonadism). The ten-week dose comparison study will begin at Beth Israel Hospital in Boston, and an additional site may be added in San Francisco or Los Angeles. Call Richard Spark, M.D., at 617/667-2471 if interested.
Two testosterone patches -- Androderm, marketed by Smith-Kline Beecham, and Testoderm, from Alza -- already are approved for use in hypogonadal wasting. Testoderm must be applied to a shaved scrotum, while Androderm (just approved by the FDA in October) can be placed anywhere on the body. There is no data available to date on the use of either patch in people with AIDS, but results from at least one study should be released within the next few months.
Immune thrombocytopenic purpura (ITP) is a relatively frequent condition in people with HIV infection. Although most common early in disease, it can occur at any stage of disease. "Thrombocytopenia" refers to an abnormally low platelet count, platelets being the blood cell fragments involved in the clotting process. Low platelet counts are associated with easy bruising and spontaneous bleeding, which can be life threatening especially if the platelet count drops below 20,000 per cubic millimeter of blood.
Treatment of ITP has been limited in the past by short duration of response, high cost and sometimes serious side effects of the available therapies. But a therapy approved last March by the Food and Drug Administration promises to improve the management of ITP. This new treatment (brand name: WinRho) utilizes the therapy that protects against the classic illness that occurs in Rh-positive babies born to Rh-negative mothers.
Platelets coated with antibodies are cleared from the body, mostly by macrophages residing in the spleen and liver. This phenomenon is seen as the major factor behind ITP during HIV infection, although the source of the antibodies bound to the platelets is open to interpretation. In an individual with HIV, platelets may have particular surface antigens that become the targets of antiplatelet antibodies that make them targets for destruction. Platelets also sponge up antibody/antigen complexes as well as any free antibody floating in the blood, and both of these are present to a high degree during HIV infection.
Other factors in thrombocytopenia during HIV infection include reduced bone marrow production probably due to direct HIV infection of the megakaryocyte, the precursor stem cell of the platelet. These cells have CD4 receptors that allow HIV to adhere to the cells and alter their function. Other factors that may contribute to decreased platelet production include the low levels of interleukin-3 and interleukin-6, which serve as growth factors for megakaryocytes.
Treatment modalities for HIV-related thrombocytopenia include AZT, corticosteroids, immuno-globulin therapy and splenectomy (surgical removal of the spleen).
AZT has been considered the most effective therapy, with 30 to 90 percent of patients responding within twelve weeks of initiating the drug.1 ddI has also been tried but is much less effective. The newer antiretroviral agents have not been formally studied for this purpose, although theoretically they should provide a similar effect as AZT, by interfering with HIV infection of the megakaryocyte.
Corticosteroids can elevate platelet count in 40 to 80 percent of patients yet result in long-term remission in only ten to twenty percent of patients. They are associated with intolerable side effects in many people, including further immune suppression, reactivation of opportunistic infections such as candidiasis, herpes simplex and tuberculosis and increases in blood glucose, blood pressure and peripheral edema.
Splenectomy offers the most durable response but has some surgical risks and may increase the risk of infections with such encapsulated bacteria as pneumococcus, haemophilus influenzae, which are often effectively removed by the spleen. Patients who are to under splenectomy should be vaccinated against these two bacteria prior to surgery.
Other similar treatment modalities which have been partially successful include low dose splenic irradiation. Small studies have shown a 70 percent acute response rate and a durable response rate of 40 percent.
This procedure requires total doses of radiation of approximately 900 to 1,000 centigrays (centijoules per kilogram of body weight) administered over one month, which allows for some degree of splenic function to be preserved.
Finally, immunoglobulin (transfused antibody, also known as Ig or gammaglobulin) therapy is the quickest therapeutic approach and is used in cases of very severe thrombocytopenia and prior to surgery to rapidly lower the risk of bleeding. Immunoglobulins saturate the receptors on the platelet-trapping macrophages in the spleen, thus sparing the platelets from destruction.
The duration of response is only about one to three weeks and sustained remissions from a single course of treatment occur in less than ten percent of patients. The cost of immunoglobulin therapy is about $1,500 to $2,000 per treatment, which makes long-term therapy prohibitive.
WinRho, also called anti-D antibody therapy, consists of concentrated antibodies that bind to the Rh antigen on red blood cells. WinRho, like broader immuno-globulin therapy, is thought to act by overloading the reticuloendothelial system by increasing the number of antibody-coated cells to eliminate. WinRho will lead to some reduction in the number of red blood cells, but not enough to cause significant anemia. The treatment will not work in patients who are Rh-negative or who have had their spleen removed.
In one study by Bussell and others,
43 Rh-positive patients with ITP were treated with WinRho at a dose of 10 mg/kg of body weight followed by daily doses of 20 mg/kg until either their platelet count increased to a minimum of 20 to 30,000 per mm3 or hemoglobin levels decreased greater than 2 gm/dl of blood, indicating the onset of anemia. The mean platelet increase was 95,000 per mm3, with children having better responses than adults.
In the largest study to date, 267 patients treated at New York Hospital/Cornell University between 1987 and 1994, had mean platelet increases of 76,000 cells. Study participants with HIV had a poorer response (a mean increase of 49,000 platelets per mm3) than HIV-negative ones.
Again, younger patients (less than eighteen years of age) had a better response than older ones. Changing the dose of WinRho did not alter the response rate or the decrease in hemoglobin levels, which were on average 0.8 gm/dl. The HIV-positive patients had a lower decrease in hemoglobin than the HIV-negative patients. Concomitant use of AZT affected neither the platelet response nor the rate of red blood cell clearance. CD4 cell counts were not adversely affected by the WinRho treatment, nor was there any other evidence of acceleration of HIV disease progression.
Not long after HIV was identified, many researchers noticed that it was very difficult to culture the virus from the blood of many infected people, particularly those free of symptoms. Investigating this phenomenon, Jay Levy, M.D., of the University of California San Francisco, determined that activated CD8 lymphocytes in these cultures were responsible. Dr. Levy found that activated CD8 cells from HIV-negative donors, and SIV-infected primates, also halted the growth of HIV in cell cultures. This activity was not due to CD8 cells directly killing HIV-infected cells, as one might expect considering their commonly accepted antiviral role. Rather, something that these cells produced, which Dr. Levy referred to as the cell antiviral factor (CAF), was keeping the virus in check.
Since proportionally more CD8 cells are required to block the virus in cultures derived from patients with advanced HIV disease, Dr. Levy concluded that these CD8 cells were not producing as much CAF. He reported that CAF could be what is responsible both for the long period of clinical latency that most people with HIV experience and for the continued health of many long-term survivors. He also believes that production of CAF ebbs before CD4 cells become depleted and people develop symptoms.
CAF's exact chemical identity proved to be extremely elusive. Dr. Levy could isolate no one substance secreted by CD8 cells that could affect this dramatic suppression of HIV. His work languished, garnering little interest or support from the National Institutes of Health.
Last month, Dr. Levy's discovery regained the spotlight, when two groups separately claimed to have identified CAF. Researchers from the Paul Ehrlich Institute in Langen, Germany reported in a letter to Nature (December 7, 1995, page 563) that a cytokine called lymphocyte chemoattractant factor, or IL-16, has a strong suppressive effect on HIV. The other team, led by Drs. Paulo Lusso and Robert Gallo, formerly of the National Cancer Institute, argued that CAF was not one, but three different substances acting in concert to keep the virus in check (see Science, Dec. 15, 1995, pages 1811-5). Dr. Levy, though, does not believe that CAF has truly been identified by either group.
Dr. Paul Reinhard Kurth and the other German investigators have been working with a factor isolated from the CD8 cells of African green monkeys that suppresses SIV, the monkey virus similar to HIV. The Germans found that this factor is virtually identical to human IL-16. However, the observed HIV-suppressive activity of pure IL-16 was not as dramatic as that of the crude material extracted from the CD8 cell cultures.
In a review accompanying the Nature letter, Anthony Fauci, M.D., director of the National Institute of Allergy Infectious Diseases, suggested that IL-16 may be working together with other suppressive factors. How IL-16 works is unknown, but it does bind to the CD4 receptor and may inhibit CD4 cell activation. At the doses that Dr. Kurth's group used, IL-16 was not toxic to cells and so perhaps has some therapeutic potential.
Dr. Gallo's team took a CD8 cell line that was particularly effective at suppressing HIV, removed the actual cells and separated the remaining substances in the culture. They found three proteins, previously dubbed RANTES, MIP-1a and MIP-1b, that had potent anti-HIV activity at nontoxic levels in cell culture. These proteins belonged to the chemokine family, which heretofore were known to direct lymphocytes to the site of infection or inflammation.
The researchers then added antibodies that inactivate the individual chemokines to the cultures to see which chemokine was primarily responsible for the CAF activity. Only the antibody to RANTES seemed to partially reverse some of the suppressive effect. Yet when antibodies to all three chemokines were added, all of the anti-HIV activity was eliminated. The scientists observed the same result when the antibodies were added to cell cultures taken from people with HIV and concluded that all three of the chemokines are required to keep the virus under control.
Dr. Gallo's group is currently running the chemokines through various in vitro assays to determine which aspect of the viral life cycle is disturbed by the chemokines. They may act at an early phase in the viral life cycle, but Dr. Gallo says, "there may be more than one mechanism of action."
Dr. Gallo's paper concluded with the suggestion that the people with HIV should be studied to see whether those who produce higher levels of these chemokines have a slower rate of disease progression. Does production ebb as people progress? (Dr. Gallo says other factors may emerge that reduce the chemokines' effect in people with progressive disease.)
Another area to look at is whether vaccine-induced higher levels correlate with protection against SIV infection in monkeys. At present, there is little natural history data on the secretion of chemokines (or IL-16) in people with HIV disease.
High production of chemo-kines has been noted in a large number of autoimmune disorders, such as rheumatoid arthritis and lupus. This observation raises the question of whether people with a history of such conditions are less likely to become HIV infected, or, if they do become infected, whether they progress more slowly.
Researchers have noted that it is extremely unusual to find HIV and these other conditions together, but there are a few case studies in the literature. Rather than a slower progression of HIV disease, a remission of the autoimmune disorders was observed.
William Blattner, M.D., Deputy Director of the University of Maryland institute that Dr. Gallo now directs, says, "The first thing to do is get a better understanding of the way in which these [chemokines] occur in these different populations. A single marker may not tell the whole story -- ratios or combinations may be important. It is possible that there are some suitable populations for case control studies. Our first approach will be to look at levels of these markers in patients at different stages of HIV infection, and whether these markers correlate with protection in HIV-negative people with continued high-risk exposures. But again, the initial focus is standardizing the assays."
The extent to which any of these findings will lead to the development of new therapeutic agents remains to be seen. IL-16 may suffer from the same fate as other cytokines that have shown anti-HIV activity in the lab. Some of these compounds also concurrently stimulate the production of inflammatory cytokines such as TNF-a when administered in people, undermining whatever direct anti-HIV activity they might have had in the test tube. And generally, administration of the HIV-suppressor cytokines have been associated with severe side effects.
The systemic administration of chemokines poses certain problems. The most established purpose of chemokines is to direct white blood cells to the sight of the infection. If administered systemically, immune cells might wander aimlessly, confused by conflicting signals and be less likely to respond when secondary infections do occur.
Administering MIPs alternatively might make common infections life-threatening by magnifying the amount of inflammation present. In the lungs, excessive MIP-induced inflammation during pulmonary infection can lead to suffocation. Added RANTES, meanwhile, could cause side effects similar to arthritis.
Nevertheless, the chemokine levels effective in cell culture "are not showing toxic effects in the animal [rodent] toxicology studies," says Dr. Gallo. He hopes to administer the chemokines to green monkeys (the SIV model) within several weeks (although he notes that delays in the construction of his new institute make it difficult for him to say for certain).
Dr. Gallo also believes there may be some way to trigger the local secretion of chemokines. Presently, Dr. Sergio Romanagni, in Florence, is conducting experiments to determine how CD8 cells produce these chemokines, and what factors might stimulate their secretion.
Dr. Gallo's team also is manipulating the molecular structures of the chemokines to determine which subunits are responsible for the antiviral activity. Altered molecules might be developed that suppress HIV but do not have the potential side effects of the whole chemokine molecule.
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text:
With Sweep, Baseball Off to Best Start Since '97
BATON ROUGE, La. -- No. 3 LSU (22-2, 5-1 SEC) racked up 22 runs over three games and completed a sweep over Auburn (15-9, 0-6 SEC) with an 8-2 victory on Sunday afternoon in Alex Box Stadium.
The Tigers took Game 1 by a score of 9-4 and Game 2 by a score of 5-1. LSU will return to action on Tuesday as the Tigers travel to New Orleans to face Tulane at 6:30 p.m. The game will be televised live on CST and can be heard on the affiliates of the LSU Sports Radio Netowrk.
LSU has won 22 of its first 24 games, matching the start of LSU's 1997 National Championship team and the Tigers' 1986 squad. The 5-1 start to SEC play is the best conference start for LSU since the 2010 season.
Starting pitcher Cody Glenn (4-1) teamed up with a stellar defensive effort to efficiently work through 7.2 innings of work, which was the longest stint for an LSU starting pitcher this season. The southpaw allowed six hits and two runs and struck out three in the winning effort. .
"I was really proud of Cody for bouncing back the way he did after a rough outing last weekend," said LSU coach Paul Mainieri. "He ran in to some trouble early, but he kept his composure and worked into a rhythm through the middle innings. We played great defense behind him as we have all weekend, and today's game put the finishing touch on a very good weekend.
"I felt before the game that our players would perform with a purpose today, and they gave tremendous effort to earn this sweep."
Shortstop Alex Bregman crushed nine hits in the series, extending his hitting streak to 12 games, and has notched three hits in four consecutive games and three hits in seven games this year. Outfielder Mark Laird recorded eight hits and scored seven runs over the weekend.
First baseman Mason Katz, the SEC's leader in home runs and RBI, had seven hits and drove in five during the weekend. Leftfielder Raph Rhymes drove in six runs during the series.
LSU outscored Auburn by a combined 9-0 margin in the first inning of the three games of the series. In the bottom half of the frame Sunday, LSU exploded for four runs off of Auburn starter Will Kendall (0-1).
Rhymes plated rightfielder Chris Sciambra with a fielder's choice RBI after Sciambra led off the inning with a double. Second baseman JaCoby Jones drew a bases-loaded walk for the second run. Auburn inserted pitcher Terrance Dedrick, and designated hitter Chris Chinea greeted him with a two-RBI single to right.
Auburn responded in the top half of the second with a one-out double by Garrett Cooper and a RBI single by Blake Austin.
LSU kept the runs coming in the bottom of the second. Laird and Bregman knocked consecutive one-out singles. Laird scored from second on Rhymes' RBI single between first and second. A wild pitch scored Bregman to increase the lead to 6-1.
The Tigers added two runs in the bottom of the sixth on consecutive two-out doubles down the left field line by Laird and Bregman. Centerfielder Andrew Stevenson reached on a two-out walk after entering the game in the top of the third and scored the seventh run.
Auburn scored a run in the top of the eighth off of Ryan Tella's sacrifice fly. Right-hander Will LaMarche forced a line out to end the eighth after entering the game with two men on and two out. Chris Cotton pitched a scoreless ninth for LSU.
LSU 8, Auburn 2 (Mar 24, 2013 at Baton Rouge, La.)
Auburn.............. 010 000 010 - 2 6 1 (15-10, 0-6 SEC)
Pitchers: Auburn - Will Kendall; Terrance Dedrick(1); Conner Kendrick(5); Dillon Ortman(7);
Chase Williamson(8) and Blake Austin; Kody Ortman. LSU - Cody Glenn; Will LaMarche(8);
Chris Cotton(9) and Ty Ross; Michael Barash.
Win-Cody Glenn(4-1) Loss-Will Kendall(0-1) T-2:37 A-10960
Actual Attendance: 6,137

subset: commoncrawl


text:
This ING commercial comes from deep in the heart of Germany (via Tas Melas of TBJ).
Dirk Nowitzki walks into a butcher shop, eats some free meat, giggles with a bunch of jolly old women, and we all go home happy.
We'd probably have a better idea of what's going on if we spoke German, but it's amazing anyway:


text:
EDT:The EDT Team
Revision as of 08:53, 20 June 2011 by Smythew.us.ibm.com (Talk | contribs)
These are the current members of the EDT team. Go to the project summary page to see the list of committers.
- Tim Wilson (architect, project leader)
- Justin Spadea (IDE core, debug)
- Scott Greer (JavaScript generation)
- Matt Heitz (chief programmer, builds, webmaster, Java generation)
- Alice Connors (IDE)
- Jeff Douglas (core, Java generation, debug)
- Kathy Carroll (language test framework)
- Jing Qian (language test framework)
- Joe Vincens (services)
- Paul Harmon (core)
- Saul Margolis (documentation)
- Tony Chen (IDE)
- Xiao Bin Chen
- Zhi Zhu
- Forest Huo
- Ji Yong Huang (JavaScript generation)
- Lisa Lasher (project management)
- Will Smythe (strategy consultant, web presence)
- Aaron Allsbrook
- Brian Svihovec
- John Trevisan
- Bart Van Campenhout


text:
Express. Home of the Daily and Sunday Express.
Mancini plays down Tevez punishment
Manchester City boss Roberto Mancini does not expect Carlos Tevez's community service order to hamper the club in any way.
The Argentinian striker was this week ordered to undertake 250 hours of unpaid community work after being found guilty of driving while disqualified. The punishment comes at a time when Tevez has been in fine form on the field having scored six goals in his last seven appearances.
With City facing Manchester United in an eagerly-anticipated derby at Old Trafford on Monday, Mancini is hopeful that run continues. When asked if the community service was likely to cause a problem for City, Mancini said: "I don't think so, no. I didn't speak with him about this."
He added: "I think that Carlos made a mistake and he will pay for this. But usually he has good behaviour."
Another City player, Samir Nasri, has also been banned from driving this week.
Mancini does not think these incidents badly affect the image of the club.
He said: "I don't think this. This is their private life. We can do nothing about this. This can happen sometimes."


text:
To return to the main Release and Transfer process page, please click here
|Cal South Release and Transfer Process Instructions
A Step-by-Step Guide for Affiliate Member Registrars
|Step 1
In order to login to your affiliate member account, please go to www.calsouth.com and locate the Member Central Area on the center-right side of the page.
Click the button that says "Youth Soccer Login."
|Step 2
The second step will require you to sign in with the registrar account that has been provided to you by a Cal South League Account Management Department.
|Step 3
Understanding "Alerts"
|Step 4
Alert Action Link
|Step 5
Approval Process
a) Please make sure to mark either the "Yes" or "No" buttons in the section regarding whether or not a player pass has been collected.
b) If a player's pass was not collected, please make sure to leave detailed comments.
|Step 6
After selecting either the "Approved" or "Contested" button regarding release or transfer approval (and making sure that you have marked whether or not the player pass was collected), simply click the "Update" button.
During the Fall Roster Freeze period, a release with an accompanying transfer may be contested. If contested, the parent may appeal.
• The Fall Season roster freeze period is from August 1st through the 1st Monday after Thanksgiving
• A Release and Transfer is only allowed during this time period when initiated online by the parent and uncontested by both the releasing and incoming club
- There is a maximum of 7 days for the releasing registrar to contest the transfer request online, otherwise the request is deemed approved
• If contested, the parent may appeal. The parent must initiate the appeal process within 3 days and pay the $100 appeal fee (refundable if transfer is granted on appeal). Otherwise, the transfer is denied
• IMPORTANT NOTE: Your local competitive leagues (CSL, Presidio, SCDSL, Central Coast, Bakersfield, LA Futbol Circuit) may have more restrictive player transfer policies. These policies will take precedence during their respective season
|Step 7
Your release or transfer is now waiting for approval by Cal South.
a) After the release or transfer has been reviewed and approved, emails to the parent and registrar(s) will be automatically generated by the Cal South Online Registration System.
If you still have questions that aren't answered in the Step-by-Step Guide above, click below:
Frequently Asked Questions by Registrars about the Release and Transfer Process


text:
Bu oyunları da deneyin
Jelly CollapseMake combinations of the jolly jelly blocks and get enough points to pass the levels.
Atom & Quark: Farm FeverMatch fruits and vegetables to prepare for harvest time! Help Dr. Atom and Quark to complete the match 3 challenges in this fun action packed game!
Apple BlastClick on groups of 3 or more fruits to remove them! Use bombs and special power-ups to blast them all!
Jewel JourneyMatch jewels, solve puzzles and get ready for a spectacular adventure in this charming Match 3 game! Start the Jewel Journey and travel around the world with us!
Jewel AquariumDive into an underwater world of match-3 fun - 60 challenging levels with different goals are waiting for you! Make combinations of 4 or more fish to create powerful tiles which explode areas on the board.
Jewel Academy
Rate this game
Match gems, activate powerups and solve puzzles in this great new game! Jewel Academy is a gem-filled, action packed game with a ton of levels to complete. Updated with 40 new levels, 2 new worlds and 1 new magical pearl!!


text:
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Create a healthy home with De'Longhi's line of Air Purifiers. All De'Longhi air purifiers feature the unique AQS (Air Quality Sensors) technology. This intuitive system's sensors continuously monitor the air quality, providing you with the visual assurance to "see the clean air" through color changing LEDs. The De'Longhi AC150 air purifier model features 5 layers of filtration, trapping allergens, asthma triggers, odors, chemicals and even bacteria and viruses. With ultra low noise levels and easy to use display features, a De'Longhi Air Purifier is perfect for any room in the house, including living rooms and bedrooms. The De'Longhi AC150 air purifier model is suitable for rooms up to 150 sq ft.
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text:
Video: Ex-Pakistan Taliban members join IS group, behead man
ISLAMABAD (AP) — An online video released Saturday purports to show former militants of the Pakistani Taliban pledging allegiance to the Islamic State group and beheading a man they identify as a Pakistani soldier.
The video shows former Pakistani Taliban spokesman Shahidullah Shahid along with dozens of other militants in a wooded area. Shahid already announced his support for the Islamic State group in an audio message in October. He was later replaced by the Pakistani Taliban.
Other militant leaders who identify themselves as from Afghanistan and Pakistan also pledge their support to the Islamic State group. At the end of the video, the militants behead a man they identified as a Pakistani soldier.
The SITE Intelligence Group, a U.S.-based terrorism monitor, said the video was released by the Islamic State group on Twitter and jihadi forums.
The video is sure to raise concerns about whether the Islamic State group has found support in Pakistan and Afghanistan, a region already awash with dozens of militant groups. Taliban militants in Afghanistan and Pakistan owe their allegiance to Mullah Omar, a cleric who has led the Taliban since the 1990s and hasn't been publicly heard from for years.
The area where the video was shot was not identified but Taliban militants are known to operate in the rugged mountainous regions between Pakistan and Afghanistan. The militants frequently target Pakistani troops who have been carrying out missions in the country's northwest. There was no immediate comment from Pakistan's military or government.
The Islamic State group controls about a third of both Syria and Iraq. A U.S.-led coalition is targeting the group in airstrikes. On Saturday, the U.S. military said in a statement it carried out 12 strikes on the group in Syria and three strikes in Iraq. Eleven of the coalition airstrikes in Syria targeted Islamic State group positions around the border town of Kobani near Turkey.
Associated Press writer Bassem Mroue in Beirut contributed to this report.
Sorry we are not currently accepting comments on this article.


text:
We might just have to make a "Stop it, Buffalo" series.
On the heels of the success of the #BillsMafia, someone decided to copy-paste it into the Sabres game chat and try to make it a hockey thing.
#SabresMafia is going to be a thing? Well, we also get copycat serial killers. Not sure which is worse.
— Scott Michalak (@ScottyMCSS) January 30, 2013
Now breathe in, and do this with me:
GROOOOOOOOAAAAN/scream into pillow
I wasn't going to write about this Sabres "mafia," but it's becoming a Thing, so… here… we… go…
4 Hot Takes:
1. The Sabres Mafia is Gaining Traction
Which is embarrassing.
The hilariously NSFW Bruins blog "Days of Y'Orr" was all too happy to pick up on this copycat effort. Here's a few gems:
Continue Reading


text:
Reviewed By cortney s (Buffalo, WV) Reviewed for a 1996 Jeep Cherokee —12/12/2012 2:59 AM
the build aspect of these locks are great, have been running them for a good bit now, as seeing that i only contain one sway the front. i have placed these to help with DD on my 4.5 Cherokee. so far everything has been great. install was easy and fast. hardest part getting them set just right for my modified suspension already.


text:
A 59-year-old Burbank man was found dead Friday night in front of a house in his neighborhood near a dog, according to police.
Authorities found Artashes Sarkisians near the front lawn of a house on the 300 block of Via Montana around 7:30 p.m., said Burbank Police Sgt. Gerry Misquez.
There were no signs of foul play, but the cause of death is unknown as of now, Misquez said, adding that it's unclear if Sarkisians was walking the dog when he died.
Sarkisians' body was taken to the Los Angeles County Coroners office as the investigation into his death continues.
-- Brittany Levine, Times Community News
Follow Brittany Levine on Google+ and on Twitter: @brittanylevine.


text: On Fri, 26 Sep 2008, Donald Becker wrote: > But that rule doesn't continue when we move to higher core counts. We > still want a little observability, but a number for each of a zillion > cores is useless. Perhaps worse than useless, because each tool has to > make its own decision about how to summarize the values before using them. > A better solution is to have the reporting side summarize the values. Why is this a better solution? Might not applications NOT wish to summarize or aggregate? And why does the cutoff occur at 2 cpus (and not 1). And what do you choose to compute and return? Aggregated activity (not showing how it is distributed), or average activity (even worse, just showing a nominal percentage of total aggregate activity? And how do you differentiate (or do you) between a single processor dual core and a dual processor single core and a single processor quad core and a dual processor dual core, etc? I'd say that ONE solution is to provide a tool that does client side averages and aggregation, and I initially did it that way, in part to minimize the size of the return and make life "easy", or so I thought. I changed my mind, because I discovered that I DID want a lot of the information detail that was being aggregated and hidden. It actually was very useful. IMO at this point, it is "better" to provide the raw numbers per core (and network device) to the client (monitor program, head node, whatever) side and let IT decide what it wants to display or how it wants to use the numbers. Here is my reasoning. A network bottleneck on a system with multiple network interfaces shows up not necessarily as the aggregate being saturated, but as a particular interface being saturated. There may be multiple interfaces, and they may not even have the same speed characteristics -- "saturation" on one may be a small fraction of the capacity of another. A CPU bottleneck -- especially in a cluster that isn't doing "the same thing" synchronously on all the cores by hypothesis -- can be one processor core pegged at 100% but all the rest near idle (possibly waiting on the one that is pegged!). Even on an 8 core system -- again where it might be an 8 core server in a LAN with cores allocated among several completely distinct VMs (some of them running Windows and invisible to "direct" monitoring) or an 8 core node in a cluster -- if the cores aren't running a set of homogeneous tasks aggregates will not reveal a bottleneck or the reaching of a resource limit at a glance. mysql might be max'd out on a single core and several mysql clients might be tamely waiting on it, even though the AGGREGATE CPU is down there at < 20%, and with people wondering why everything is slow. When you make a toplevel design decision like this -- to aggregate and average, or not -- you are basically picking a set of assumptions concerning what people will need. However, people's needs vary and almost any assumption that you make will NOT fit the needs of some subset. That may be OK -- you make a tool that is right for a restricted subspace of things that DO match your assumptions, and that's fine. In the case of scyld, you tightly define the cluster architecture, so you MAKE it so the assumptions work on both ends. But the price is that it makes your tool all but useless to people with problems your assumptions hide but that would be revealed and solvable if you didn't hide them, or environments that don't match your assumptions ditto. I ran through similar considerations on the network side. One interface? All "ethernet" interfaces? Or just everything the kernel tags as "an interface"? Per interface, do I send back the raw packet counts, or just the rates? In other words, who does the dividing to turn packet count deltas into a rate? The interface decision was easy -- I started with just one, had a few systems with two where I needed numbers on both, and finally just broke down and send the information on all interfaces, and let the client decide which ones are "important". The rate issue was a tougher decision, because xmlsysd doesn't operate on a predetermined schedule. To get an accurate differential rate, one really should sample on a fine-grained time granularity -- average over a time order 1 sec, say. Again, one has the possibility of totally saturating the network for short bursts but having a relatively low AVERAGE rate. I tried various schema for doing node-side averaging and none of them were very satisfactory. Ultimately -- and this is a decision I could easily reconsider or make a client-controlled option, given a view of the TCP interface as being there primarily as a control interface and using UDP to actually back-transport the information -- I opted to just send the raw numbers again -- it is consistent and the client side can decide if 1, 5, 500 second averages are OK (and indeed can decide to sample twice 0.1 seconds apart to generate local deltas and then NOT sample for 10 seconds, so the numbers given are an instant snapshot of the rate, but that rate is only updated occasionally). Not necessarily the "ultimate" solution -- I still think of implementing a fixed-width window and doing a timed delta of perhaps 0.1 or 0.01 sec across it to make various rates -- but that requires two interruptions of the background work in place of one, and introduces a longish delay between polling the node and getting the answer, neither desireable on a TCP connection or for all possible sets of work the node might be doing. Incidentally, avoiding client-side arithmetic minimizes computational impact on the nodes, sometimes the expense of a larger return packet. This in turn could be mitigated by means of adding more controls to permit the remote and dynamic reconfiguration of the daemon, although I haven't yet done this as broadly as I could. I keep it simple unless/until there is a real need to add complexity, lest I get to where the tool itself becomes as complex as /proc itself. FWIW, the kernel does exactly this for (I'm sure) similar reasons: provide the raw, instantaneous numbers and let userspace clients do whatever selection, aggregation, and rate arithmetic they wish with them. It's not that difficult. All the procps tools do it (starting with a much uglier data interface to parse). It's not the only solution. It MAY not be the "best" solution. But it's not a bad one. > Again the problem with XML and other extensible systems is that people use > the flexibility to avoid thoughtful design. Sure, it's obvious how to just > add a few more records when we go from two to four core per socket. And > reporting system won't obviously break when we have 64 cores in each of 4 > sockets. But it really just shifts the re-design work to the tools and > applications. I absolute agree with the first and have been saying it myself, although I wouldn't say it is >>THE<< problem with XML, just >>A<< problem. There are obviously data structures for which XML isn't a good solution period, no matter how thoughtful you are, and IMO its BIGGEST problem is that one cannot easily switch between its default human readable but extremely "fat" encapsulation and a heavily compressed binary encapsulation, by means of toggling a single switch in the library. Toggle fat to debug, toggle thin, become efficient. Also, at the very least I'd qualify the "people" into "some people". But that's a UNIVERSAL problem, whether or not you use a library or data encapsulation standard. There's no substitute for thoughtful design, but equally true there's nothing obvious or easy about it either. It's why good programmers are (often) well paid. And truthfully I think it is clearly a BENEFIT (all things being equal) to have a reporting system that won't break (obviously or not) when going from 1 to N cores. Note well that whether or not this breaks the tools and applications depends on whether or not they were designed to scale across a variable number of CPUs from the beginning. The fact that design decisions on a client-server application pair can be obsoleted by changes beyond one's control on the server side is hardly a general conclusion one can use to indict extensible encapsulations of the data. One (fairly obviously) needs to be aware of and code client side applications to be able to manage variability where it exists, if you can TELL where it exists. The problem comes when something that wasn't variable becomes variable, or where something that was in a comfortable and familiar range suddenly isn't. I'll resist making up a car metaphor to illustrate the point, though...;-) When you have a "sudden" change in the kernel -- some resource that only existed on computers one at a time from time immemorial -- to a resource that now comes N at a time, things are going to break. Think of the 2.0.0 linux kernel -- suddenly there were two processors! Tools that KNEW there were never going to be more than one didn't know what to do! In general, everything was assumed 1, now it is N. Everything will have to be fixed (or ignore the change and report only one, or as if it were only one). You are absolutely correct that this change requires a client side change to manage, but that change needs to occur ONCE to make the CLIENT aware of the N whatevers and arrange for IT to be able to transparently manage 1-N of them as they appear in the return. If you do it badly, you say "well, now there are EITHER one or at most TWO processors per system. But I'll never need more than two, so all my loops and display and processing decisions can use two as a hard upper bound." The price you pay is that the day dual duals or single quads, or eight-ways appear, you can rewrite everything AGAIN -- expensive, especially if you DIDN'T use an extensible data encapsulation scheme (canned or homebrew) -- or tell yourself "well, I'll just hide the eight and average them somehow back to two so my API remains fixed and my client(s) do(es)n't break". Too bad if someone wants to know per core utilization on any system with lots of cores, not just aggregate utilization, because the aggregate number you fudge will not reveal the core saturation which could be just what you need to see on servers or nodes that can be rate limited by a saturated processor handling a single threaded task. It isn't always easy to know what level of detail is going to be useful to at least some users (including yourself, actually), so when one builds a tool like this one has a tendency to support what YOU need, for YOUR purposes -- right now. Putting in "everything" is clearly expensive but gives you everything -- lets you run a true "cluster-top" or "cluster-ps" that requires access to "all" the contents of /proc on all the nodes to function. Putting in just load averages is cheap but omits lots of detail that many people will need. There is no unique and obviously best solution to this problem, only tradeoffs. The closest one can come to best is "one that satisfies most of the people, most of the time" where satisfaction has to take into account having all the data they might need at a "cost" in resource utilization they are willing to pay." And it is again obvious that that best solution usually going to be a somewhat VARIABLE solution -- one that provides at least a bit of choice to the user to be able to select the best tradeoff for their personal needs out of the available (limited) choices -- and one that is extensible in dimensions (like core count or interface count) where extension is likely to occur. rgb -- Robert G. Brown Phone(cell): 1-919-280-8443 Duke University Physics Dept, Box 90305 Durham, N.C. 27708-0305 Web: http://www.phy.duke.edu/~rgb Book of Lilith Website: http://www.phy.duke.edu/~rgb/Lilith/Lilith.php Lulu Bookstore: http://stores.lulu.com/store.php?fAcctID=877977


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Information Commons Computer Help Desk
Student IT Consultants are available at the Information Commons Computer Help Desk to assist with software applications, printing, scanning and other questions relating to computers services offered in the Information Commons.
Consultants are available most hours that the Bartle Library is open. For specific hours see the hours page.
Consultants also maintain hours at the Science Library Information Commons (607 777-2166) and the UDC Library Information Commons (607 777-9225). Call these locations for specific hours.


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Sorry I missed last week; a combination of real-life duties and a bad cold took me out of commission. But I'm back this week with a look at a vanished rum brand: Dagger. A product of J. Wray and Nephew, Dagger is sadly defunct. I say "sadly" because a fellow member of the Cocktail and Spirits Online Writers Gang managed to dig up a bottle and mixed it into Mai Tais, and it sounds fantastic. Hat tip to you, Tiare. Click over if you want to see what the bottle looked like in color.
Anyway, here's a collection of Dagger ads from 1930s-era Life magazine. Enjoy!


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By Ronna Kelly | Illustrations By Carl DeTorres
On a cloudy day in December, a dozen venture capitalists from around the Bay Area crowd around a table 12 stories above the bustling streets of Downtown Berkeley, grilling student and alumni entrepreneurs about their fledgling business ideas.
"Besides money, what do you need?" " Is this a stand-alone company or part of a larger company?" "What motivated you to push this product on the market?" " Who owns the intellectual property?"
Oblivious to stellar views outside that span the Berkeley Hills to San Francisco Bay, the VCs pepper team after team with such questions for hours. Hoping to get their business ideas off the ground, the teams are vying for four spaces at Skydeck, a one-year-old startup accelerator that provides mentorship, coaching, and office space to UC Berkeley students and recent alumni.
Located in the penthouse of Berkeley's tallest building, Skydeck is becoming a hub of UC Berkeley's entrepreneurship ecosystem?and the most visible symbol of the Haas Schools new approach to entrepreneurship. Like entrepreneurs who must respond to a rapidly changing business landscape, the field of entrepreneurship is undergoing a seismic shift in response to market forces—and the Haas School is at the forefront of that movement with initiatives like Skydeck.
Call this new era Entrepreneurship 2.0 or the Lean Startup, says Haas alumnus and Lester Center Executive Director Andre Marquis, MBA 96. Marquis knows all about version 1.0: His class of 1996 boasts several notable Internet entrepreneurs who founded the startups behind Google Earth, Yahoo!s search engine, and the largest online apartment rental site. Marquis own experience includes work on startup teams for Accept.com (acquired by Amazon), a startup inside Eli Lilly that cut drug development time in half, and an incubator he created with classmates while still earning his MBA.
"We all believed that the Internet would change everything," says Marquis. "Its taking a while longer than we thought, but it is, and one of the things its changing most is entrepreneurship."
Plummeting software and hardware costs combined with the Internet have enabled entrepreneurs to rapidly build prototypes, easily and quickly connect to customers and experts worldwide, test, refine, and test and refine some more.
"Entrepreneurs can literally start companies on their laptops with a credit card," says Haas Lecturer Steve Blank, a serial entrepreneur who is pioneering a new way of teaching entrepreneurship with an experiential course called Lean LaunchPad.
In addition, the pace of change is rapidly increasing, which means entrepreneurs no longer can spend months drafting a 50-page business plan before pitching VCs or developing products. (See Risk Takers articles.)
As a result, the Lester Center is evolving its business plan competitions into startup competitions, requiring teams to submit a one-page business model canvas instead of a business plan and encouraging students to start businesses while still in school.
The Lester Center won a major endorsement of its approach last month with the award of a $3.75 million grant from the National Science Foundation (NSF). Teaming up with Stanford and UC San Francisco, the Lester Center will spearhead the creation of a Bay Area/Silicon Valley I-Corps Node—one of three being created by the NSF? to train the next generation of entrepreneurs and encourage partnerships between academia and industry. All three I-Corp Nodes will teach Blanks Lean LaunchPad framework.
"The NSF has built an incredibly smart program to bring together the best of science and technology invention with all the advances business schools have made in teaching entrepreneurship over the past decade," says Marquis.
Creating Community
Marquis top priority is helping Haas students start more companies that are more likely to succeed. Since his arrival in 2010 as the second executive director in the Lester Centers 21-year history, Skydeck has become a key vehicle to accomplish that goal. Marquis is joined by Professor Toby Stuart, who left Harvard Business School this year to become the second faculty director in the Lester Centers history and is now working on revamping the schools gateway entrepreneurship course for MBA students. (See Q&A with Stuart.)
"The best way to create entrepreneurial leaders is to give them the experience of building startups while they are here," explains Marquis. "When our MBA students go back to work, its almost certain they will be innovating by putting business models and technologies together in cross-functional teams. Thats what a startup does. While at Berkeley Haas, they get the theory and the practice."
Because entrepreneurship is a cross-disciplinary endeavor, Skydeck is similarly a cross-disciplinary collaboration of Haas and the Lester Center, the College of Engineering, and the UC Berkeley Vice Chancellor for Research Office. Students and recent alumni from across Cal can apply to work on their startups at Skydeck. But they get much more than free office space: Teams are matched with mentors, gain access to an extended network of startups, and can attend workshops and events at Skydeck, including hackathons designed to build technology solutions in 24 hours.
"I'm not a big believer in space," explains Marquis, noting that Facebook and Genentech didn't need office space to get off the ground. "I believe in community."
Skydeck is unique among accelerators because of the unique UC Berkeley community it taps into: world-renowned researchers and a strong culture of independent thinking, notes Haas Lecturer and Skydeck mentor Mark Coopersmith, BA 82, MBA 86, who built a $150 million consumer products and online commerce division for Sony and now advises VC-backed and large companies. "We have to leverage that Berkeley culture because that combination of intellect, discipline, and creative nonlinear thinking is what makes successful entrepreneurs," he says.
One of the first startups at Skydeck was Go Overseas, a Yelp-style website for programs abroad started by Mitch Gordon, MBA 12. Gordon moved into Skydeck from Haas previous business incubator in the basement of the Bancroft Hotel.
"We literally went from the basement to the penthouse," Gordon quips. "Skydeck gives me more legitimacy with customers right away."
Gordon had the idea for Go Overseas before enrolling in Haas. "The first day I was here I went straight to the Lester Center to get started on it," he says. "My business wouldn't be where it is today without Haas."
Springboard for Success
Melissa Millan, MBA 13, who won a spot in Skydeck in Decembers competition, tells a similar story.
"One of the reasons I came to Berkeley was to be in Skydeck, to be surrounded by similar-minded people following their entrepreneurial aspirations," says Millan, who founded Androgyny, a company that sells premium women's dress shirts.
Millan also is a testament to the success of the Haas Schools entrepreneurship curriculum, and Coopersmiths Workshop for Startups class in particular. She was one of five students who received funding within three months after taking Coopersmiths class and one of two students from his class to be accepted into Skydeck in December.
"Our entrepreneurship curriculum prepares our student entrepreneurs to get to that next level, as reflected by which teams were most prepared to move into Skydeck," notes Coopersmith. "Skydeck is a place for people to get business done, make connections, and take their ventures to the next stage. It becomes a springboard for growth, learning, and success."


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Girlfriend Allegedly Beaten
East Hampton Town police received a call at about 10:15 Saturday night from a woman who had run out of her East Hampton house with her daughter after being beaten by her boyfriend, a police report said.
According to the report, the woman told police through an interpreter that she had been at home when her boyfriend, Domingo Mejia Augustin, 26, of East Hampton returned from work drunk and began arguing with her.
The argument turned physical, with Mr. Mejia Augustin hitting the woman on the face and body, in front of their daughter, police said. Mr. Mejia Augustin then allegedly grabbed her by the neck, but she managed to break free, taking her daughter and running to a neighbor's house. Police were called.
Police took her to headquarters, where, with aid of the interpreter, she made a statement about the alleged beating.
Police went to the couple's house, but Mr. Mejia Augustin had fled, police said. He was later found at a friend's house and arrested and charged with harassment in the second degree. The county's child protective services bureau was notified. Bail was set the next morning at $350.
On the morning of April 9, town police said, they got a call from the stepfather of a 16-year-old girl in the Northwest Woods section of East Hampton. The man told police that the girl had left the house the previous day and had not returned or called since.
He told them that in October he and his wife had obtained an order of protection for their daughter from Town Justice Court against Lucas M. Ward, 19, of East Hampton, according to the police report.
Police interviewed Mr. Ward, they said, and he gave them a written statement that said he had sent text messages to the girl the previous day and had picked her up at her house. He was arrested and charged with criminal contempt in the second degree for disobeying a court order. He was released on his own recognizance the following day.
Too-tinted windows led to an East Hampton Village arrest last Thursday at about noon. An officer at the intersection of Woods Lane and Main Street noticed a black 2004 Mazda with dark windows. The officer stopped the car and, using a tint meter, determined that the windows had only 26 percent visibility, the police report said.
The officer then asked the driver, Jamie R. Jappa, 31, of East Hampton for his license but was given a passport instead. Mr. Jappa allegedly told the officer that he did not have a driver's license.
The officer then arrested Mr. Jappa and took him to headquarters, where, after running his fingerprints, it was determined that, under the name Oscar R. Solano, he had previously had his license suspended three times between 2005 and 2006, twice for alcohol-related offenses, police said. Mr. Jappa reportedly told the police he had used that name before.
He was charged with three counts of driving without a license, two of which were aggravated, and two counts of driving a vehicle with nontransparent windows. Bail was set at $250.
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Sara loves baseball so for her birthday, her family gave her tickets for this weekend's major baseball league game. She went with a friend, the weather was hot and sunny, but she had good seats with a great view of the game. Both teams played very well with some exceptional hits and plays. Determine the full names of four of the players, the position each played, and each player's best hit of the game.
1. Alec played the center field position. Sam Crisp didn't get the grand slam.
2. Brad, whose last name wasn't Reach, didn't play the 1st base position.
3. The player who got a double wasn't the player who played the 3rd base position.
4. Mr. Ember didn't play in the center field position but he did get a single hit.
5. Mr. Mann got a triple. Will, whose last name wasn't Mann, didn't get a single.
6. The player in the catcher position got the grand slam.
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text: When you think of Fastening the name Bostitch comes to mind. Staples are one of the most recognized and useful items that have been invented. The Bostitch group came around in 1896 and invented the world's first stapler. It used a small coil of wire and formed its staple into the item. It was called the Boston Wire Stitcher. Little did they know but this one machine would spawn a wide world of invention. In 1914, the first desk model hand operated stapler was made. Back then, the staples were shipped loose but only a decade later, Bostitch created the first cemented strip staples; which are the standard type for consumer consumption today. In 1948, the Boston Wire Stitcher Company became Bostitch and the rest, as they say, is history. Staples continue to be a main part of the company, as evident with the model GRSHCR38 staples, but they also manufacturer Glue Guns and Slammer Staplers. In 1986, Bostitch was acquired by Stanley from Textron Corp. Since then, Bostitch continues to provide advancements in the fastening industry by not only improving on current fastener designs but also by inventing new fasteners and fastening devices.


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MONMOUTH Town have confirmed the signing of former Newport County AFC, Cheltenham Town and Swansea City striker Julian Alsop until the end of the season.
The 40-year-old 6ft 4ins striker will be in the squad for Saturday's visit of Haverfordwest County..
Alsop played for the Exiles in the Conference South under boss Peter Beadle from 2006 to 2008, twice narrowly missing out on play-offs and appearing in two FAW Premier Cup finals.
County won the 2008 final but Alsop was released at the end of the 2007–08 season.
He is most associated with Cheltenham having made his debut for the Robins in 2000 and scoring in a 2-2 draw with Mansfield.
He eventually scored 47 goals for the club in 171 League and FA Cup appearances from 2000-2003 and 2009-2010.
Nuneaton -born Alsop also played for Swansea from 1998 to 2000, making 92 appearances and scoring 34 goals, and hit the quickest hat trick in history for Tamworth in the 1995 clash against Armitage by bagging three goals in just over a minute.
Alsop made five appearances for the England C team from 1995 to 2005, playing against Belgium, France, Norway, Croatia and Scotland and played with Monmouth striker Dan MacDonald at Carmarthen Town before temporarily hanging up his boots.
Monmouth Town boss Steve Jenkins, who knows Alsop from his County days, is confident Alsop can offer the Kingfishers something different and provide a boost for the rest of the season.
"Jules is a great character and a very experienced player," he said. "We sometimes need a different option when we're playing against tighter defences and Jules will give us that. If we need to mix it with teams he can do that too."


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City of Sand Point: Religious Organizations
St. Nicholas Russian Orthodox Church / Phone: 907.383.6637
Sand Point's St. Nicholas Russian Orthodox Church, nestled among the trees surrounding the harbor, is a picturesque reminder of the Russian history of Sand Point. The island, originally settled by Russian explorers, is naturally tree-less and the few trees seen today on the island are additional reminders of the Russian influence. Saturday: Vespers at 6:30pm / Sunday: Divine Liturgy at 10:00am
Sand Point Baptist Chapel / Phone: 907.383.4551 / Mailing Address: Post Office Box 329
The Sand Point Chapel overlooks the water in the heart of Sand Point.
Sunday School: 10AM
Worship: 11AM
Evening Worship: 6:30PM
Bible Study: 6:30PM