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STEP Perspective
Letter from the Editor
As we learn more about antivirals, more questions arise about how and if we can restore the immune system. In this issue we continue our investigation of researchers studying immune restoration with an interview with Dr. Ronald Moss of the Immune Response Corporation. The immune restoration drug in development here shows great promise and has a unique approach on how it attempts to rebuild the immune system.
With summer weather heating up we take a look at managing body weight and preventing wasting with BIA testing. Our story on Bioelectrical Impedance Analysis (BIA) explains this new test, why it is important, and how to use it to monitor your health and catch wasting syndrome early. In our Just For Women Column, we explore the effects of HIV drugs on oral contraceptives, and we get a personal story of what it is like to be a woman in a rural community trying to remain compliant.
Rebuilding the Immune System
Promising New Therapy Uses the HIV Virus Itself to Awaken the Damaged Immune System
In this article, the second interview in our series exploring immune restoration, we look at a different approach to immune-based therapies. In these therapies, the outer shell of the HIV-virus is removed and only the inner proteins of HIV are used. These proteins act to stimulate the memory cells that create more of the HIV-fighting T-cells that were killed off early in the disease process. These concepts originated with Dr. Jonas Salk in the 1980s, and have been both praised and dismissed since then.
Today, Salk's concepts are gaining more attention and their development is continuing under the direction of Ronald Moss, MD, Senior Director of Medical and Scientific Affairs at the Immune Response Corporation.
Dr. Moss: Absolutely. I think the misnomer was referring to this immunogen as a vaccine; it's not a therapeutic vaccine. The term vaccine implies a preventative type of a procedure -- that one could give a particular type of injection and prevent a disease. We are [also] working on the area of preventative AIDS vaccine, but Remune itself is a way of stimulating the memory response of the immune system.
The goal is to stimulate the body into producing the special T-cells that early in the infection period fight and kill HIV. We know that early in the disease there is a progressive loss of the ability of the immune system to recognize HIV. Early in the infection period the immune system does battle the virus through the cell-mediated arm of the immune system. This is the arm that includes T-cells, cytotoxic T-cells [T-cells that directly kill HIV-infected CD4 lymphocytes], and other various factors that have direct activity against the virus. So the body initially intends to fight the virus using these and eventually the virus wins and overcomes the immune system. But the fact that the immune system has already had an initial battle with the virus means there are memory cells in the immune system that can be re-stimulated to re-emerge and battle the virus again.
The excitement now about Remune is how it can work in conjunction with combination therapy to possibly create immune systems in people that can look like the immune system of a non-progressor. Current drug combinations can lower viral loads to very small levels yet leave these memory cells intact. Remune can stimulate the body into producing more of these fighting cells that can then attack the already depleted virus. I believe that data will soon show that individuals immunized on drug therapy with Remune will have immune systems that look very much like a non-progressor immunologically. The work by Dr. Bruce Walker and others proves that the immune system can be stimulated to control the virus under the proper conditions. And, clearly the proper conditions are in individuals taking highly active antiretroviral therapy [HAART].
STEP: So there's been some confusion around the terminology of vaccines and immune-based therapies, and people not making the distinction?
Dr. Moss: I think so. I think there's no doubt about it that it's a struggle. We've begun using the terminology "immune-based therapy" because I think that is the most appropriate word. You talk to Dr. Walker and he's still using the word therapeutic vaccine. The other difference between Remune and a preventative vaccine is that with Remune we are re-stimulating the memory response in an infected person. So, immunizations have to continue in order to keep this immune response up and that is very different from a preventative vaccine. I think we really do have to try to change that terminology a great deal.
STEP: In Dr. Walker's work he was able to show that long-term non-progressors maintain high levels of these HIV-specific memory cells and that rapid progressors lost them very quickly.
Dr. Moss: I would argue with that -- some studies show that there isn't really a loss of these cells. They're just overwhelmed by virus and not able to function properly. I'm actually more optimistic than Dr. Walker. With proper immune stimulation we can get some sort of anti-HIV response in individuals who have had evidence of clinical progression so long that they're on some sort of drug therapy that's controlling the new virus replication.
STEP: Would it be fair to say then that Remune would be a therapy that, if it works well, will allow the immune system to go back and fight the fight like it would if it were healthy?
Dr. Moss: Exactly. With some of the earlier studies there were a lot of questions including why we were seeing vigorous immune responses in some individuals and not in others. Now with the ability to control the virus we're seeing a much more consistent vigorous immune response in Remune-treated individuals. So it may be that Remune can help turn the clock back in terms of progression just like the drugs (HAART) have turned the clock back.
The other issues about anti-HIV drugs and Remune is that there are certain reservoirs of virus that the drugs can not reach and kill. If the goal is total eradication of HIV, one probably will get closer to that goal by using therapies like Remune. We believe that this type of therapy would be able to capture some of the reservoirs left over from the drug therapies. In one sense it may allow people to be on a particular drug regimen for a longer period of time. That's one of the many things that we're testing in our studies. In my clinic switching drug therapies is a constant battle. If you were able to stimulate the immune system to the point where you could keep the individual on a fairly well tolerated and simple drug regimen for a longer period of time, that would be a significant contribution for better care for patients.
STEP: I know that there were concerns expressed 3 or 4 years ago about Remune -- that you didn't see a strong antibody response. Could you address why you don't see that type of response with Remune?
Dr. Moss: Sure. The original concept about HIV-infected individuals was that one needed to develop strong antibody responses, particularly neutralizing antibodies. And there were a number of immunogens put together to invoke those neutralizing antibodies. The so-called envelope immunogens [vaccines which used the outer shell or envelope of the HIV cell] developed some very strong neutralizing antibody responses. But what they found later was that these antibody responses inhibited only laboratory strains of the virus but did not inhibit the patient's own virus. [So] the thought that antibody was the essential part of controlling the disease has somewhat lost favor. Dr. Salk all along thought that the cell-mediated arm of the immune system was much more important. As I mentioned earlier, that's the arm that is involved with the cytotoxic T-cells, cytokines, chemokines, and of course the virus itself. So he devised an immunogen to enhance the cytotoxic T-cells and the cell-mediated arm of the immune system. This has been validated recently by the data from Dr. Bruce Walker's study looking at cell-mediated immunity.
We know, and Dr. Salk knew, that different doses of an immunogen could cause the body to produce different types of antibodies. We chose a regimen that would cause the body to produce primarily the HIV-specific killer T-cells, or cell-mediated immunity. And I think this is really the important arm in controlling this disease.
STEP: You talked about Dr. Salk and a lot of people probably won't know his role with Remune. Do you want to cover that?
Dr. Moss: Well, in the last years of his life Jonas Salk was obsessed with HIV infection and ways of dealing with it. He was the one who developed the concept of immune-based therapy. At the time (in 1987, prior to drug therapies) we didn't know a lot about the immunology of AIDS. But he saw that from the time an individual was infected to the time symptoms develop was about 10 years. He rationalized that there must be some kind of immune response to the virus that is different from a fatal disease like meningitis where one would succumb within 24 hours. So he wanted to parallel what was going on during the asymptomatic period. His thinking was that the immune system needed something to stimulate its memory, like an immunogen in slightly altered form. So, it was [from] this conception that Remune was developed.
At the time there was a lot of interest in envelope immunogens. The NIH [National Institutes of Health] was quite sure that immunization with the outside of the virus, both for preventative and therapeutic purposes, was going to prevent the disease. The NIH poured a lot of funding into this arena and there was not a lot interest in Dr. Salk's suggestion, and he published this in 1987 in a review article. So he ended up hooking up with the Immune Response Corporation to develop this [idea]. Until his death Dr. Salk was intimately involved with the day-to-day science of the program. I was very fortunate to work with him.
STEP: So you're saying that Remune will actually help the body to create more of the HIV-specific T-cells?
Dr. Moss: Yes. I'm saying that we do have data. We will be showing exciting new data from a placebo control study comparing a group using Remune plus drugs, to a group using drugs alone. Both groups had very good drops in virus, but the Remune plus drug group had dramatic increases in HIV-specific immune responses compared to the drug alone group, which during the study was a flat line. With the current drugs we are seeing a greater magnitude in the immune responses after the immunization with Remune. The drugs are allowing the immune system to digest immunization to a greater extent than when the virus was still there without drug therapy.
STEP: Can you summarize in just a couple of sentences what the major benefits of Remune are right now?
Dr. Moss: Well, I can't let the cat out of the bag, but there will be new, exciting data in Geneva, presented on at a satellite symposium. With Remune the goal is to generate HIV-specific T-cells that kill the virus,[but] that are lost very early in the disease. There's going to be a study out by Dr. Gallo looking at the mycobacterium avium complex (MAC) cohort where he looked at our HIV antigens in Remune.
Essentially, when he looks at healthy people there are some HIV-specific responses there, but when he looks at people with full-blown AIDS the HIV-specific responses are completely gone. So the goal of a therapy like Remune is to stimulate those responses, to mimic the responses seen in non-progressors. The goal with Remune is to bring some sort of additional immune surveillance that may not and is not brought back by drug therapy alone. The drug therapy alone, as I mentioned, is extremely good at dropping the viral load and, you'll see in Geneva, that we have data showing that the drugs alone are not bringing back the HIV-specific responses.
The other way that Remune might be shown to have a benefit is its ability to keep individuals on a particular drug regimen for a longer period of time. Some sort of delay in resistance might afford patients to be on a drug for a longer period of time because Remune itself is getting some sort of immune surveillance against the virus. This is the way that I envision Remune to potentially provide some clinical benefit in the future.
STEP: How is Remune given, and are there side effects?
Dr. Moss: It is a fairly simple type of treatment. It's an intra-muscular injection in the arm given every 3 months, so adherence and intolerability are not really a problem. The main side effect we see has been local injection site reaction, similar to what one sees in a pediatric vaccine -- redness and swelling and warmth at the injection site, which resolves within 24 hours.
STEP: Based on the fact that there are no agreed-upon surrogate markers, how do you think we're going to be able to tell if immune-based therapies are really working?
Dr. Moss: We are working on a couple of things. As I mentioned, we need to validate immune function markers in the same [way] that RNA was validated and I think Dr. Gallo's (MAC) study is the first of many studies that will be looking at this question. We really have to get the assistance and help of many different diagnostic companies. That's number one. Number two is we have a skin test we're using in large trials. We know that it indicates some sort of response against the virus. We really need to help a diagnostic company get into this area.
STEP: If I'm on a hot regimen that was successful and decided to add Remune and I don't have these types of surrogate marker tests available, what type of things would I look for to decide whether the therapy was beneficial?
Dr. Moss: I think that's a difficult question. Most things would be subjective. You would look for your viral load to be stable for a long period of time. You wouldn't be able to tease out whether or not that would be due to Remune or the drugs or the combination of the two. You would look at all of your clinical parameters. We've seen weight increases in Remune patients. But I don't think any of those parameters would be able to differentiate Remune from the drugs unless you had a marker of HIV-specific immune function.
But, as I said earlier, data that will be presented in Geneva look towards the concept that the drugs alone may have some effect on the non-specific immune system but have very little impact on HIV-specific immune function. So that would be a dilemma. But we do have folks who have been on Remune for over 10 years [and] who continue to take it and believe it. It is just anecdotal, and we don't know for sure whether Remune is responsible for keeping them healthy. We do see some immunological changes in them. We need the skin testing or some other HIV-specific test and I think it would be great for the community to try to get some of the diagnostic companies involved in this arena as they did with RNA testing.
STEP: Is Remune available now to people?
Dr. Moss: We have what's called an expanded access program. We haven't really publicized it a great deal but it's out there. And I imagine there will be increasing interest after Geneva. We will have to decide internally what to do about the expanded access program at that point. It's available and there are multiple studies still on-going. We will be starting, for example, a study with Dr. Walker that will be enrolling patients. We will be starting a primary infections study with Eric Darr in Los Angeles and we are open to hearing from investigators and the community about new studies that they'd like to see with Remune as well.
STEP: Is there a certain type of patient that you would recommend to get on Remune? In terms of somebody who's HIV-positive but asymptomatic with a nondetectable viral load versus somebody with full-blown AIDS?
Dr. Moss: I have a theory on this that's not very scientific. I think there is two types of individuals. One is an individual who may not want to go on drug therapy very early on and Remune might be something to go on before one really needs drug therapy. Before viral load is detectable, for example.
The other type of patient who would benefit from Remune is someone doing well on drugs, who has a viral load no greater than 100,000. Controlling the virus somewhat is probably important for Remune to work properly. I'm not saying that one needs absolute control of virus to use Remune. I think that there needs to be some control of virus before immunization with Remune to really see the true benefit immunologically. So I would not recommend someone with 500,000 copies trying Remune, but perhaps for someone under 100,000 copies it would be worthwhile. And clearly people with a very low viral load would probably get the strongest immune responses entering immunization with Remune.
STEP: There are some current trials looking at the possibility of maintenance therapy where you hit somebody with three or four drugs early on and once you get the virus down, you see if you can maintain that with a two-drug regimen. Have you thought about trials with Remune in a situation where people could scale back their HAART regimen to a maintenance regimen?
Dr. Moss: We haven't really thought about that completely. It's obviously a good concept though. I would think that would make sense. The other possibility is looking at adding another antiretroviral and seeing if Remune has an impact. I think that those are all good ways of looking at it. I think if Remune works there's a lot of possibilities to tease this apart further.
STEP: As a last question, can you give our readers an idea of how long the vaccine's been studied and then talk about the clinical endpoint study that's going to be coming to an end probably in March of 1999?
Dr. Moss: The vaccine has been around since 1987 so we have individuals who have continually gotten immunized since 1987 from those early studies here in California. We crept our way up the ladder and did our Phase I and Phase II studies. And this always has been controversial -- number one, because Dr. Salk was the person who initiated this, and secondly, we came up at a time when many of the envelope vaccines supported by the government were failing. And I think people threw Remune into the same boat as some of the envelope vaccines. I hope that I've expressed to you that this is really a different animal.
This particular immunogen has the conserved parts of the virus, the parts of the virus that are same regardless of what type of virus one is dealing with. We have shown scientifically that we can immunize patients with Remune and they can develop immune responses to different types of HIV antigens. This was never shown for envelope vaccines because they were always showing good responses to their own antigens but never to other viruses. So Remune is very different than the envelope vaccine.
We continued to move on to two different types of studies. One was a surrogate marker study that you'll hear about in Geneva. There are multiple studies going on in Europe and Asia [now] , and South America shortly, and 2 years ago we initiated one of the largest studies ever conducted in the United States. It's a Phase III clinical endpoint study and we have another year to go. It's the only immune-based therapy that was given the green light by the FDA to do a Phase III study for infected individuals.
We feel confident that we are in the right place at the right time. The irony is that advances in drug therapy will increase the ability to show clinical benefit using something like Remune in combination with an immune system that has better control of its virus. We're fairly close and not overly confident, but we believe that the data will tell the story in the long run.
Coverage of the 5th Conference on Retroviruses and Opportunistic Infections
All summaries by Jeffrey Schouten, MD, Chairman, Scientific Review Committee, STEP, unless otherwise noted.
Opening Session HighlightsPresenter -- Dr. Ashely Haase
Dr. Ashley Haase delivered both good and bad news with his data showing that lymph nodes remain the main reservoir of HIV, even after highly active antiretroviral therapy (HAART) therapy. The lymph nodes contain lymphocytes with no viral RNA, but with viral DNA incorporated into their genetic code.
Referring to the M (or "mystery") cells that harbor HIV DNA, Dr. Haase stated that these cells remain in the lymph nodes even after 2 years of no detectable viral load in the blood on HAART. Thus, the realization over the last 6 months is that HAART will probably not lead to viral eradication. On a more positive note, he noted that there is evidence of rehabilitation and rebuilding of the immune system on HAART, and that even after only 6 months of HAART, there is evidence of restoration of normal lymph node architecture.
Keynote LecturePresenter -- Dr. David Baltimore
Dr. David Baltimore delivered the Keynote Lecture, discussing the challenges of making an HIV vaccine. He is head of the federal government's AIDS Vaccine Research Committee (AVRC). Vaccines work by generating antibodies, generating cellular immunity (cytotoxic T-lymphocytes [CTL]), and/or some undefined third non-immunologic mechanism. He suggested that the third process could be that a non-pathogenic virus could be developed to occupy a space needed by HIV to establish infection, thus blocking infection by HIV. He noted that it is rare for a person to become infected with a second strain of HIV once they are infected with one strain of HIV.
Dr. Baltimore believes there is total commitment on the part of the federal government to expend whatever resources are needed to develop an AIDS vaccine. The vaccine need not necessarily prevent HIV infection, but rather prevent disease caused by HIV. It must be very safe, well tolerated, durable, transportable, easily administered, and protect against different routes of infection, such as via mucus membranes or via injection.
Dr. Baltimore noted that the Macaque monkey can be completely protected by live simian immunodeficiency virus (SIV), which is deficient in a regulatory gene (the NEF gene). It has been shown that a few people in the United States and Australia have been infected with a NEF-deficient strain of HIV and they have normal immune systems after long-term infection.
Dr. Baltimore reviewed the limitations of antibody vaccines, which do not immunize against wild type (real world) virus. There is cell-mediated killing of HIV-infected lymphocytes. The half-life of HIV-infected T-cells is about 2 to 3 days. However, one of the challenges is to figure out how HIV prevents CTL from killing infected cells. Dr. Baltimore is not in favor of giving a live-attenuated HIV virus to human volunteers, and feels that there needs to be a much better understanding of how HIV can be prevented by the various techniques discussed above.
Session 2: State-of-the-Art Lecture Monitoring the Epidemic of HIV/AIDS in the United StatesPresenter -- Dr. Kevin Decock, CDC
Dr. Decock reviewed the epidemiology of HIV/AIDS in the United States. Transmission is closely linked the following factors: Socioeconomic status Substance abuse Exchange of drugs for sex Presence of other STDs Of concern were data from public health clinics that showed HIV-positive persons had a relatively high incidence of sexually transmitted diseases (STDs). STDs increase the risk of HIV transmission by 4- to 5-fold. He emphasized that better control of substance abuse and STDs is critical to controlling the spread of HIV. In 1997, there was a 12 percent decrease in incidence of AIDS compared to 1996. Dr. Decock presented a slide that showed the flow of HIV into one bucket, representing HIV cases, which then flowed into a second bucket, AIDS cases, which then flowed out of the second bucket to account for AIDS deaths.
With decreasing AIDS cases, the number of people in the first bucket, HIV cases, is increasing. This was his justification for the CDC's call (a "technical opinion") for mandatory names reporting.
He noted that 31 states require HIV names reporting, but these states represent only one-third of all HIV cases. He said that there have been no breaches of confidentiality. (NOTE from the reviewer: Apparently, Dr. Decock is not aware of the major breach in Florida. Nor did he even mention the option of using unique identifiers to gather the same data, which would better protect confidentiality and while not discouraging HIV testing.)
Session 7: Immunopathogenesis Symposium
This session reviewed data concerning the quality of the increased number of T-cells in people on HAART. The big question is whether or not the increased T-cells are only memory cells (already programmed to respond to one antigen, or pathologic organism), or are there increases in naïve T-cells (new T-cells capable to responding to a new pathogen, or disease-causing organism). The good news is that there appears to be increases in both memory T-cells and naive T-cells in people on HAART therapy. The memory cells increase in the first few weeks, then plateau (usually at 300 to 400), while the naive cells slowly increase over several months.
Session 9: Chemokine Receptor SymposiumPresenter -- Dr. Moore
There was a great deal of detailed biochemistry presented about the chemokines. Chemokines are secreted by certain cells in the immune systems, and allow HIV to enter a healthy cell and infect it. The chemokine receptors appear to be necessary for the HIV to bind to the CD-4 lymphocyte and infect the cell. Generally, the CXCR4 receptor is on the T-cell, and the CCR5 receptor is on memory cells.
The chemokines became a major focus of HIV research in the last 2 years when they were identified as important co-receptors allowing for HIV entry into the cell. Additionally, some people have a genetic mutation causing them to not produce CCR5 receptors and are therefore immune to HIV infection. Also, people who lack one but not both genes for the CCR5 receptor (called the heterozygous CCR population) appear to have a slower rate of disease progression.
Dr. Moore explained why there have been some apparently conflicting data concerning the rate of progression of HIV disease in the heterozygous CCR5 population. Studies that have followed progression from time of diagnosis have shown a slower rate of progression among the heterozygous CCR5 population. However, studies that look at the number of heterozygous people at one time during the course of the infection, not at the initial time of infection, have not shown a difference in rate of infection. This is because the effect on disease progression is not that strong, so the effect will only be apparent in patients followed from the time of diagnosis.
Session 5: Antiretroviral Chemotherapy I Slide SessionSummary by Brian Coppedge, Treatment Information Specialist, STEP
The first slide session provided the first look at data on antiretroviral agents. The three following presentations focused on combinations that would no longer be recommended when following the new treatment guidelines. These guidelines could provide information that would be useful when choosing two reverse transcriptase inhibitor (RTI) drugs to be used as part of a triple combination.
Daniel Kuritzkes, MD, of the University of Colorado, presented data from the ACTG 306 study. When this trial began (December 1995) there was some question whether 3TC had a unique relationship with AZT, or if the same benefit could be seen when 3TC was added to ddI or d4T. To determine this, people were placed into random groups. These groups then received d4T alone, a combination of d4T/3TC, AZT/3TC, ddI alone, or a combination of ddI/3TC or AZT/ 3TC. At 48 weeks, the results suggest that the combination of 3TC and d4T is at least as effective as 3TC and AZT. It was also shown that d4T/3TC was more potent than d4T monotherapy (big surprise -- I think we have known that for a while).
The study also showed that when 3TC is added to ddI, the combination is not more potent than ddI monotherapy. Dr. Kuritzkes made a point of stating that 3TC can be combined with either d4T or AZT but that the two drugs should be used as part of a combination that includes a protease inhibitor.
Having shown that 3TC can be used successfully with d4T, researchers have been inquiring whether d4T can be used successfully with AZT. Many people have been under the impression that d4T and AZT should not be used in a combination because they were antagonistic (when taken together, there is less benefit than when either is taken alone).
Dr. Havlir presented the results of the ACTG 290 study, which investigated whether AZT and d4T were antagonistic. After looking at 144 people (all of whom had been on AZT before) who were randomized into groups receiving a combination of AZT/d4T, d4T alone, a combination of AZT/ddI, or ddI alone, the investigators came to three conclusions. First, AZT/d4T should not be used in combinations because AZT/d4T does not have a more potent antiviral effect than d4T monotherapy, and AZT/d4T is associated with a drop in CD4 cells in people who have taken AZT before. Second, ddI produces a greater level of viral suppression than d4T when taken by people who have used AZT previously. Third, the combination of AZT/ddI in people who are AZT-experienced had no more benefit than ddI monotherapy.
Next was a presentation that actually looked at a new compound, abacavir (1592, an RTI), in combination with five different protease inhibitors. John Mellors, MD, from the University of Pittsburgh, presented the results of a study that randomized 80 people into groups that received abacavir (300mg every 12 hours) in combination with either indinavir (Crixivan), ritonavir (Norvir), saquinavir (Fortavase), nelfinavir (Viracept) or the new protease inhibitor, 141W94. The drugs performed well, with 50 to 85 percent of the participants seeing their viral load reduced to below 400 copies at 16 weeks, and 40 to 70 percent to below 50 copies at 16 weeks. (Dr. Mellors noted that the group receiving saquinavir produced inferior results). Some participants (2 to 5 percent) developed a rash from abacavir that was seen 3 to 42 days after beginning therapy. It is important not to re-start abacavir after discontinuing the drug (rechallenging) because of the development of a rash. Five people were hospitalized and one person died after they were re-challenged with abacavir.
Finally, what does the future of dual protease therapy look like? Dr. Eron from the University of North Carolina presented a humorous and informative piece on dual protease therapy that evaluated amprenavir (141W94) with one of three other protease inhibitors: indinavir, saquinavir, and nelfinavir. Although the data presented was only for a very small study group (16 people) the results helped to provide an idea of which combinations should be studied in larger trials. After 16 weeks, all participants had viral loads below 400 copies.
Dr. Eron concluded by stating that the regimens were well tolerated and this study suggests that dual protease inhibitor therapy is a viable alternative to triple combinations. He noted that it is perhaps a bit too early to compare these regimens to triple therapy, considering the short study period and the fact that no participants were tested using ultra-sensitive tests that detect viral loads below 400 copies.
Studies of HIV Infection in WomenDonna Rochon, Editor, RITA! The Center for AIDS, Houston, TX
A welcome addition to the hundreds of presentations and posters was a varied assortment that addressed treatment issues specific to women. Although a few studies presented data on trials designed to assess the effect of anti-HIV drugs on women, most of the research being conducted continues to look at the effect of antiretroviral or prophylactic (preventative) therapy on pregnant women and their newborns.
While methods for reducing the risk of transmission from the mother to her newborn are still an extremely important and essential area of investigation, it would be refreshing if researchers took a more serious interest in improving the health of HIV-positive women, regardless of their childbearing capabilities.
The Women's Interagency HIV Study (WIHS) is one of the few large-scale studies that focuses on women's health, and several pharmaceutical companies, to their credit, are beginning to enroll women in trials to evaluate drug efficacy in women. Several key posters and presentations are highlighted below.
Researchers have found that HPV DNA is found in almost all cases of cervical cancer. In women with HIV infection, cervical HPV is more persistent than in HIV-negative women, and there is a higher proportion of abnormal new growth in cervical intraepithelial tissues (neoplasia) in HIV-positive women. Further, increased rates of progression to severe abnormal growth (dysplasia) have been noted in women with HIV infection, with lower CD4+ cell levels associated with greater risk. While CD4+ cell count was found to be an inconsistent predictor of HPV disease, plasma HIV RNA levels greater than 10,000 copies posed a greater risk for HPV that causes tumors.
Quantitative HIV-1 RNA and Other Factors Associated with Survival in the Women's Interagency HIV Study (WIHS). The objective of this ongoing study is to determine factors associated with survival in HIV-positive women. To date, data has been analyzed for 2,058 women who are HIV-positive and 567 HIV-uninfected women recruited in five cities in the United States between October 1994 and October 1995. Clinical, virologic, and immunologic evaluations were performed every 6 months. There were 242 deaths in the 1,890 HIV-positive women, with low CD4+ cell count and high viral load the contributing factors, as well as the occurrence of an AIDS-defining illness. There was a trend toward poorer survival in older participants, but survival was not associated with race, ethnicity or route of HIV exposure. Thus, women with low CD4 counts and viral loads greater than 500,000 had the greatest risk of death.
Benefits of Vitamin BSummaries by Paul Simmons, RN, The Center for AIDS, Houston, TX
In a presentation that is sure to have advocates of complementary therapy saying "I told you so," Andrew Kanter of the WITS Medical School, Johannesburg, South Africa, and colleagues presented fascinating data on the role of multivitamins and B-complex vitamins in delaying progression to AIDS and death. The data presented here are drawn from a retrospective chart review of over 2,100 HIV-positive individuals treated at the Johannesburg General Hospital HIV Clinic.
The median time from infection to full-blown AIDS in patients taking a multivitamin was 71 weeks, compared to 33 weeks for those not taking a multivitamin. Even more striking was the AIDS-free time associated with a B-complex vitamin. The median time to progression for those taking vitamin B-complex was 152 weeks, compared to 32 weeks among those who didn't. The data were less impressive but still important for those with a diagnosis of AIDS.
Median survival among AIDS patients taking vitamin B-complex was 62 weeks, compared to 42.5 weeks in those who did not. These results did not change even after controlling for CD4 count and antiretroviral therapy.
Since this data was obtained from a retrospective chart review and not a controlled clinical trial, it is possible that other intervening variables influenced the results. For example, the vitamin takers may have been individuals who generally took better care of their health than the non-vitamin takers. I asked Kanter about this and he acknowledged that the vitamin takers did visit the clinic more often than their counterparts. But anyone reading this report is likely to be among people with HIV who care about their health, and may therefore benefit by taking a daily multivitamin supplement with the B-complex vitamins in it.
Switching Protease InhibitorsPresented by Pamela Bozek of the University of Maryland, Baltimore.
Bozek and her colleagues examined the questions of how long people stay on their initial protease inhibitor and if they change protease inhibitors, why. Bozek reviewed the treatment of 49 inner city patients who attended a university clinic. Ten of these patients were naïve to all antiretroviral therapy when they started their first protease inhibitor (PI). Most of these individuals had IV drug use as their risk factor for acquisition of HIV; more than half of the 49 were male.
Indinavir was the first choice PI for 25 (51 percent) of the study participants. Nelfinavir followed as the first choice of 14 (29 percent). Five (10 percent) selected saquinavir as the initial PI. One patient started on ritonavir, while four began with a combination of saquinavir and ritonavir.
At the end of 1 year, almost half of the patients, 49 percent, had dropped their first PI in favor of another. Of the 25 who started with indinavir, only 36 percent were still on it at the end of a year. Among the 64 percent who changed, most cited intolerance of the drug or an inability to adhere to it as the main reasons for switching. Data for the patients starting with nelfinavir were available for 6 months only, because of the drug's more recent introduction to market. Of the 14 who selected nelfinavir as their first PI, 86 percent were still on it at 6 months. The three who dropped it did so due to an adverse experience, intolerance, or lack of efficacy. The one patient who began with ritonavir stopped taking it because of intolerance. Four of the five who chose saquinavir as the initial PI abandoned it, with lack of efficacy as the most common reason given.
So what did patients switch to when they dropped the first PI? Of the 39 percent who rolled over to a new PI, more than half (57 percent) chose nelfinavir , with only 14 percent choosing indinavir. Of the remaining patients who dropped their first PI, 21 percent went to the dual combination of saquinavir/ritonavir as second-line PI therapy, and 29 percent took the opportunity to simply discontinue treatment. The rest selected some other form of treatment (for example, two nucelosides).
These data support the notes of caution heard in many quarters about the rigors and toxicity of PI-containing regimens. Moreover, the data underscore the importance of choosing a treatment regimen with careful attention to side effects and ease of use.
Viral Load PredictorsL.P. Jacobson of Johns Hopkins School of Public Health, Baltimore and colleagues sought to answer two questions.
Does viral load predict survival in severely immunosuppressed men and does antiretroviral therapy improve survival among these men if they are treatment naïve at the time therapy is started? The answer to both is yes.
The study involved 500 HIV-positive men whose CD4 cell count had fallen to 50 or below. For men in this group with viral loads of less than 100,000 copies, median survival was 2 years; for those with viral loads between 100,000 and 250,000, median survival was 1.9 years; and for those with viral loads above 250,000, median survival was 1.3 years. Interestingly, there was no difference in survival time between those with viral loads above 250,000 and those with viral loads above 500,000.
But for patients in each of these groups, antiretroviral therapy significantly delayed time to death. Among those with viral burdens above 250,000 copies, treatment delayed time to death by 2.04 years. Among those with viral loads between 100,000 and 250,000, it delayed time to death by 2.41 years. And for those with viral loads under 100,000, treatment delayed time to death by 1.26 years. The presenter explained the odd finding that survival time was shortest in those with the lowest viral load as a probable result of statistical difficulties, noting that the number of patients in the under 100,000 group was relatively small at 11.
Virtually everyone would agree that the patients in this study waited too long to start treatment. Nevertheless, this data supports previous findings that antiretroviral therapy provides a clinical benefit even for individuals with profound immune suppression.
Ask Dr. Jeff
Yes. Viral load tests (HIV RNA) measure the amount of HIV in the blood. All of the tests currently available have a certain level below which they cannot accurately measure the amount of HIV present. So, when your health care provider tells you that your viral load is "undetectable," what that really means is that the amount of HIV in the blood, or plasma, is below the detection limit for that viral load test. The most commonly used test for viral load has a detection limit of 500 copies of HIV per milliliter (ml) of blood.
So, based on the amount of blood that the average person has in their body, 5 liters, if you had 400 copies of HIV per ml of blood, you would have a "undetectable" viral load, but still have about 2,000,000 copies of HIV in your blood alone!
Additionally, it is known that most of the HIV resides in lymph nodes, not the blood. Newer viral load tests, which are not yet FDA approved, can detect as few as 20 to 50 copies of HIV per ml of blood. These tests are referred to as "ultrasensitive assays," and are used in most anti-HIV drug trials. They may be useful in deciding when to add or change drugs to a treatment regimen.
Secondly, it is still not known (and there are many studies ongoing), how closely the level of HIV in the blood, or plasma, correlates with the level of HIV in genital secretions. Some studies have shown a good correlation with plasma and genital secretion HIV levels, while others have not. Most studies have shown that when the level of HIV in plasma drops significantly, the level of HIV in genital secretions also decreases. Thus, a person may be (and probably is) less infectious when their viral load is undetectable, but they may still be able to transmit HIV via genital secretions.
Co-infection with hepatitis C and HIV present some very serious treatment challenges because of the interactions of the different drugs used to treat each condition, and their effect on the other infection. Hepatitis C may become the next public health crisis after HIV. Recent estimates of the number of people in infected with hepatitis C in California are 500,000 and in Britain, 250,000, where it is estimated that the number of deaths from hepatitis C will exceed those due to HIV by the year 2000.
Before I discuss treatment specifics, you might need to know more about hepatitis C. Hepatitis C is primarily spread by blood-to-blood contact, either by transfusion or injection drug use. However, hepatitis C can also be spread by sexual contact. Since 1992, all blood products have been screened for hepatitis C. Hepatitis C is a silent, chronic viral infection causing ongoing hepatitis in up to 85 percent of all persons infected. It is usually diagnosed as part of an evaluation when someone has abnormal results on a liver function test.
It is recommended that all persons who received blood transfusions prior to 1992 get a test for hepatitis C. Many injection drug users are infected with hepatitis C, many more than are infected with HIV. With the increasing incidence of HIV infection among injection drug users, co-infection with HIV is becoming much more common.
Hepatitis C infection causes a chronic inflammation of the liver (hepatitis) which persists for decades, and some people progress to cirrhosis (hardening, or fibrosis, of the liver) and even liver cancer. Studies have shown the hepatitis C infection does not appear to affect survival of people infected with HIV.
Back to the treatment question. The major proven therapy for hepatitis C is alpha interferon injections. The initial recommended dose is 3 million units subcutaneous (needle injection beneath the skin), 3 times per week for 12 months. However, with alpha interferon therapy, only about 10 to 15 percent of people have sustained disappearance of the hepatitis C virus although more than 50 percent may have some transient benefit. (As with HIV, there are antibody tests for exposure to hepatitis C and for hepatitis C viral loads.) However, viral loads for hepatitis C do not correlate with the amount of liver damage present, and liver biopsy is recommended before being interferon therapy.
Recently, studies have shown better results when oral ribavirin is combined with interferon. People with CD4 counts above 200 have a better chance of benefiting from alpha interferon therapy. However, HIV viral levels increase significantly, and CD4 cells decrease, with alpha interferon therapy.
All of the approved protease inhibitors (PIs) cause significant, temporary worsening of liver function tests in most people who are co-infected with hepatitis C. Ritonavir metabolism is decreased in people with hepatitis, so a reduced dose of ritonavir should be considered for patients with both HIV and hepatitis. It is possible that the liver toxicity of the nonnucleoside reverse transcriptase inhibitors (NNRTIs) may be less.
Alcohol has been proven to accelerate the course of hepatitis C infection, so more than one drink per day is strongly discouraged and abstinence is recommended.
This is a difficult question. It would be important to know what your viral load was at the start of treatment, and how low it got, and for how long. But I'll assume you had a level significantly higher than 3,000 before treatment, and you have been stable at 3,000 for a while now. The underlying issue is how important is it to get your viral load below detection? All the major treatment guidelines recommend that you change therapy if it fails to lower your HIV RNA below 500, and you have some treatment options available. These recommendations are based on two factors.
First, it makes scientific sense that stopping HIV RNA replication significantly decreases the chance of drug resistance, and thus drug failure. This is because the virus can only become resistant if it is actually dividing, which is when a random mutation could occur. Random mutation is what allows the virus to develop resistance to the drugs you are on. Secondly, as noted in the above answer, the lower the HIV RNA at the start of treatment, the greater the chance that your viral load will stay at an undetected level for a longer period of time.
The really big unknown question is whether it is necessary for all people to get the viral load to an undetectable level (whether defined as below 500 or below 50). Most anti-HIV drug trials now define treatment failure in one of three ways: (1) failure to get to undetectable HIV RNA levels,whether at 500, 200, or even 20 copies per ml; (2) failure to reduce the level of HIV RNA by one-tenth; or (3) an increase in HIV RNA to a total of five times the lowest achieved level. The problem with using these strict criteria is that many people would run out of drugs before they ran out of virus.
At STEP's community forums, we have heard from many people in a similar situation who are maintaining levels of HIV RNA that are stable, low, but not below detection. The standard "party line" is that you should change therapy to get the HIV RNA lower. But that recommendation must be tempered by two critical items. First, what treatment options do you have available, and second, how committed are you to the goal of getting the HIV RNA to below detectable levels? If a person is not totally committed to the goals of therapy, then adherence may become a very large problem. With your specific treatment history, you have some good options. You could change to two new reverse transcriptase inhibitors (RTIs), such as d4T and ddI, and add either a non-nucleoside RTI (NNRTI), such as nevirapine, or a different protease inhibitor (PI). (The potent NNRTI, efavirenz, which is currently available in expanded access, should be approved by the FDA later this year.)
One of the advantages in selecting saquinavir as your first PI is that the chance of cross-resistance to other PIs is less with saquinavir than if you had chosen one of the other approved PIs, so switching to one of the other PIs now is a good option for you. Should you decide to change regimens at this time, you should have a thorough discussion of all options with your health care provider and make sure that he or she is very experienced in treating HIV.
Anna's Story
In 1994, when my partner and I were diagnosed with full-blown AIDS, there were no protease inhibitors, so we were placed on a mono-therapy of AZT. I would take many drug holidays, not understanding what I was doing to my body. Back then, I didn't feel sick, and I didn't totally understand that the therapy couldn't work unless I took my drugs as prescribed, whether or not I felt sick. AZT also meant a daily reminder of my disease -- that it was for real!
In 1995, my CD4 count started dropping fast and I was getting very sick. I quickly made the connection between the meds, HIV, and my health because I had immediate reactions and side effects from the AZT.
Being a parent and being sick did not go over well either. I remember my son often wanted me to drive him somewhere when I was lying on the couch with a horrible fever. Many times I would force myself into doing it, but there were also times when I had to say "Mommy is sick today." Funny how kids just don't understand mommy being sick most days.
Of course when I was taking drug holidays, I would feel good a lot more. But it was always the same when I went back to taking my meds. I'd feel sick and I would have to tell my sons, "Mom just took her medicine," hoping that they would understand. It didn't work with them though, because kids quickly see through things. They soon retorted, "If your medicine is making you so sick then why don't you stop taking it?" My children needed a mom and I wanted to be a mom again. And without a lot of support to take the meds, not to mention the disincentives of side effects, I stopped. After stopping I became sick off and on, but it was better than being sick all of the time.
In August of 1997 I started the protease inhibitor Viracept. It hasn't been easy. I take it three times a day and sometimes I forget the afternoon dose. Also, I have a very hard time taking it in the morning because it gives me a stomachache, so I take it later in the morning or at least try to take it by noon. Many times I forget my evening dose because I fall asleep if I have to stay up until midnight or later to take it at the right interval. Taking this medicine is hard, but I know that if I want to be alive to see my children graduate and to be a grandma someday, then I have to take this medicine no matter how hard it gets. Even though I've missed doses of my Viracept, lab tests indicate it is still working. So far so good.
Living in Olympia I felt alone, like I was the only woman in town with this disease. I got a lot of support from all of the wonderful gay men I met at what was then called the Olympia AIDS Task Force, and is now known as the United Communities AIDS Network (UCAN). I attended their support group every week, but felt I needed another woman to talk with, someone who could identify with having kids.
Living with HIV and being a full time mom and housewife is and was not easy. I had no one to talk to who could understand what I was feeling, so I put together a support group with a wonderful friend of mine. Together we made it happen. Today I am the president of Positive Friends of Washington, a support group for women living with HIV.
Our group got a lot of support from our local health department, from our case manager Deb Sentella, and from our local AIDS service organization UCAN. With the help of Executive Director Kevin Corbin and the Client Service Manager Miranda Craig, we have built the group until we now have seven women who come, and we are all very good friends. I'm hoping that more women in our community will find out that we are here. We want them to know that they are not alone in Olympia and that what we share is something that only other women living with HIV can understand.
Sincerely, Anna B.
Pregnant Pause
While various anti-HIV drugs, from AZT to protease inhibitors, have been evolving, little research has been done on the interaction of these drugs with birth control pills. The research that has been done on pharmaceutical interaction is not widely published, and with so many anti-HIV drugs in use, women are bound to become confused.
The level of interaction between anti-HIV drugs and birth control pills depends on which drugs you are taking. If you are on the protease inhibitors Norvir (ritonavir) or Viracept (nelfinavir), the level of contraceptive in your system may be lowered, causing the contraceptive to work less effectively. In a study conducted by Abbott, women who were taking oral contraceptives added ritonavir into their medication regimen. After the introduction of ritonavir, the amount of contraceptive in their bodies was lowered by up to 40%. Nelfinavir has been shown to reduce the level of contraceptive in women's bodies from 18% to 47%. While studies on Crixivan (indinavir) are limited, those that have been done show a decrease in oral contraceptive levels between 14% and 17%. The protease inhibitor Invirase (saquinavir) has not shown the same result, but it has not been studied thoroughly.
So why do these drugs act this way? The purpose of taking birth control pills is to maintain a level of hormones in your system so that you will not get pregnant, your period will come on time, and you will experience less painful menstruation. These hormones are metabolized gradually by your body throughout the day and after 24 hours they need to be replaced. That's when you take another birth control pill. When you start taking protease inhibitors, the protease inhibitors speed up the process by which hormones are metabolized. The hormones are metabolized up to twice as fast and therefore you have less of the contraceptive in your system. This can lead to being twice as likely to get pregnant, having an irregular period, or experiencing more cramping.
Other drugs commonly used by HIV-positive women can affect blood levels of oral contraceptives as well. Rifabutin, a preventative treatment for Mycobacterium (MAC) has been shown to decrease blood levels of birth control medications as a result of its effect on liver enzyme production.
For HIV-positive women -- and men -- using steroids or testosterone hormone replacement therapy to increase energy levels, manage depression, or gain weight, antiviral drugs can have the same decreasing effect on those therapies. Drugs that are not specific to the treatment of HIV, but that are commonly used in HIV management, may be similarly affected by oral contraceptives. These include acetaminophen, benzodiazepines, theophyllin, and some antidepressants.
We will soon have more information about the interaction of birth control pills and anti-HIV drugs. Roxane Laboratory is currently enrolling HIV-positive women in New York City and San Francisco to study the interaction of anti-HIV drugs and oral contraceptives.
A study by Boehringer Ingelheim Pharmaceuticals on the interaction of Viramune (nevirapine), a non-nucleoside reverse transcriptase inhibitor, and Ortho-Novum was recently completed, but the results have not yet been released. Here in Seattle, the University of Washington's AIDS Clinical Trials Unit is recruiting women to participate in a study on the effects of an AZT/Crixivan (indinavir) combination on oral and injectable contraceptives. If you are interested in participating in this study, contact the screening nurse, Karen Novak, at (206) 731-0206.
In summary, if you are taking both antiretroviral drugs and birth control pills you should talk with your provider about your options for increasing the birth control dosage and/or other means of preventing pregnancy, reducing cramping, or regulating your period. As a common sense precaution, however, never increase or "double up" birth control pills unless under the supervision of your provider. Doing so can be dangerous to your health. If you are wondering what other drugs might alter the effectiveness of your birth control, consult the package insert of both drugs, and then talk to your provider about your options.
Muscle Madness
The loss of body cell mass is a strong indicator of wasting and has been closely tied to disease progression. And the loss of body cell mass has been shown to be a strong predictor of disease progression and death. Bioelectrical impedance analysis (BIA) is a test that measures your body's cell mass, the metabolically important tissue contained in your muscles and organs. It can tell you, with reasonable accuracy, how much muscle and fat you have in your body. It will also tell you if you are well hydrated (have enough water in your body) and whether your cells appear healthy.
Why have your muscle mass measured? Many studies have shown that individuals living with HIV/AIDS who maintain their muscle mass within a normal level have a greater chance of suppressing viral replication, supporting the immune system, avoiding opportunistic infections, and enjoying a greater sense of well-being and energy.
Wasting remains a risk for people living with the virus because as the virus replicates, the body increases its rate of metabolism and thereby burns more calories, protein, and overall energy, which often leads to weight loss and smaller muscles. The metabolisms of people with HIV/AIDS burn calories at a rate 10 to 35 percent higher than normal, which ultimately destroys muscle tissue and lean body mass. Especially if you are on protease therapy, maintaining your muscle mass is essential to supporting your immune system and may offset the tendency to gain a lot of weight around your gut (a condition sometimes called "protease paunch").
By having a BIA test done at 6-month intervals, you will see if you are gaining, losing, or maintaining your essential muscle. Although one measurement will give you an idea of how you are doing, a more accurate way to assess your body is to have BIA measurements performed every 6 months. The BIA measurements are most accurate when trends are observed over time.
How is it done?
To have a BIA test, all you need to do is to remove one shoe and sock so an electrode can be attached to your foot. Another is attached to your hand. A painless electrical current is passed through your body and the speed of the current is measured. The faster the current travels from your hand to your foot, the more water is in your body. Muscle has more water than fat and therefore a faster current indicates more muscle is present and a slower current indicates more fat is present. The BIA machine is hooked up to a computer that can analyze the results and determine your hydration status, percentage of muscle, and fat mass.
How do I prepare for this test?
Be sure that you have been drinking enough water during the 24 hours before the test. If you are dehydrated, your test results will be inaccurate. You need to drink at least 10 cups of water or juice each day. For each cup of coffee, alcohol, or caffeinated beverage, be sure to drink 2 cups of water. Also, do not exercise strenuously within 12 hours of your scheduled test. This too can make you appear dehydrated and may make your results inaccurate.
Avoid eating too much salty food such as chips and pretzels the day of your test since salt can also dehydrate your body. On the day of your test, do not put lotion on the hand and foot to be tested because the electrodes won't stick.
What results do I get?
Results of this test will look like this:
Call Sabina the dietitian at Chicken Soup Brigade at 206-320-0213.


text:
The violence highlighted escalating political tensions
between Malagasy President Marc Ravalomanana and rival Andry Rajoelina, the
mayor of the capital,
An hour later, protesters burned down the studios of Malagasy Broadcasting System, a station owned by President Ravalomanana, according to local news reports and local journalists. A 14-year-old demonstrator and a policeman died in clashes at the scene, according to local reporters.
Earlier, at around 3 a.m., about a dozen armed government security agents disabled the transmitter of Viva Radio, a station owned by Rajoelina, according to local journalists. Communications Minister Bruno Andriantavison had threatened to shut down the station last week, saying that the commentary on a morning call-in program had incited civil disobedience and undermined "the public's trust towards national institutions," the local media quoted an official letter as saying.
"Media outlets have become the undeserving targets of
political feuding and violence between the government and opposition forces,"
In a prior incident, on January 9, two unidentified attackers threw a small bomb with a warning note about the program in the home of veteran journalist Harry Laurent Rahajason, better known as Rolly Mercia, according to local journalists. No one was injured, the journalists said.
Media outlets owned by Rajoelina and independent stations providing coverage of his political activities have been the targets of government censorship since December 13 when authorities shut down Viva TV, a sister station to Viva Radio also owned by Ravalomanana, according to CPJ research. An order signed by Communications Minister Bruno Andriatavison and obtained by CPJ accused Viva TV of broadcasting "statements likely to trouble security and public order" after the station aired a November full-length interview with exiled former president Didier Ratsiraka, according to local journalists. The government deemed the remarks likely to "incite civil disorder." Andriatavison subsequently withdrew the license of Viva TV and and security forces seized the station's transmitter on January 18.

subset: commoncrawl


text:
Starting line tech
Moderator: Team
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Starting line tech
Been doing some math after reviewing this years run records. I run a stock 305hp@6500 rpm 2012 V6 Mustang with 3.55 gears and BMR lower trailing arms. Otherwise it's stock. No mods. My 60' on stock tires is 2.059 with RTs in the .050 range common. I'm leaving about 3000 rpm to avoid spin. My engine makes max torque at 4300. So, I know I'm leaving a lot at the line. I definitely need a drag radial to get that 4300-4500 leave without spin. Going to add an Aluminum driveshaft also. Currently shifting manual trans at 6800-6900. The car MPHs at 102 and there really isn't anything left there. Any ideas on what might help the ET. Thanks, Richard
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text:
Everyone wants to be rich. Big homes, fast cars, exotic trips - what's not to like?
There's no harm in dreaming big, but setting unrealistic goals for your new business can make it hard to stay motivated.
Instead of worrying about your first million, think about what you could do with an extra $100, $500 or $1,000/month. Even a (relatively) small amount of extra income can make a big impact on your quality of life.
Unconvinced? I'll prove it to you.
Browse Exchange for a business to buy
Exchange is Shopify's marketplace for buying and selling stores. Browse a growing list of stores for sale, across over a dozen categories, with traffic and revenue data straight from Shopify.See stores for sale
How to Spend an Extra $100/month
It may not sound like much, but an extra $100/month can significantly improve your long-term financial health. Here are a few helpful suggestions for newly-successful business owners.
Put it in a college fund
College and university are expensive, so give your kids a leg-up by putting your new earnings in a high-interest savings account. Joel Larsen, a certified financial planner, points out that "[saving] $100 a month over 20 years at a 7% rate of return [...] would amass $52,092.67." Not a bad head start!
Grow your retirement savings
Don't need a college fund? Start putting your newfound income towards your future and ensure a comfy retirement. T. Rowe Price, a global investment management firm, calculated that "if a young adult retiring in 40 years makes an initial contribution of $1,000 to a Roth IRA and adds $100 a month until retirement, he could have more than $250,000—all tax-free under certain conditions."
Re-invest in your business (with upgrades)
An extra $100/month can help take your business to the next level. Spruce up your store with a premium theme, time-saving app or fancy logo.
Start a rainy day fund
Cars need repairs, roofs need patching, and pipes need fixing. It's bound to happen at some point, and it pays to be prepared. Experts suggest putting away 3-6 month' salary for an unexpected emergency, so start saving.
Take more time for yourself
See a movie every weekend, have a monthly couple's night out, or upgrade your cable package to finally get HBO.
How to Spend an Extra $500/month
Bringing in an extra $500/month has the potential to significantly raise your standard of living. Debts start to shrink, broken things get fixed or replaced, and your confidence as a business owner starts to grow. Here are a few good places to start.
Accelerate your mortgage payments
Putting an extra $6,000 towards your mortgage every year can really lower the amount of interest you pay in the long run. According to the RBC, "when you select an accelerated weekly or bi-weekly payment option, you are essentially making the equivalent of one additional monthly payment each year which will help pay off your mortgage faster."
Pay off your debts
We've already mentioned accelerating your mortgage payments, but other things like credit card debt and student loans should really come first. Learn how to prioritize your debts and make the most of your payments.
Re-invest in your business (by investing in yourself)
Making $500/month is a great start, but if you want to build a successful business, you'll need to start learning the ropes. Buy books, attend conferences, and read, read, read!
Build a home office
Nothing says "startup" like running your business from a laptop in your kitchen. Investing in a home office will help you get more done and add legitimacy to your growing empire.
Upgrade/renovate your home
Update your old bathroom with a new sink one month and a fresh coat of paint the next. The home you've always wanted is now within reach.
How to Spend an Extra $1,000/month
An extra $1,000/month can be life-changing. These suggestions are geared towards successful business owners who have already paid off outstanding debts and consider this money disposable income.
Pick up a few best-selling books about investing and start putting your money to work. Don't want to go it alone? Speak to a financial advisor about how you can make the most of your extra income.
Travel the world
See exotic places, visit family, or just spend some much-needed down time on a far-away beach. Wherever you're headed, you can definitely afford the trip. Plus, it's important to take some time to relax and recharge.
Re-invest in your business (with ads)
By now you've upgraded your store and learned a little about online marketing, so start acquiring new customers with Google AdWords, Facebook Ads and Pinterest!
Splurge (in moderation)
Every successful entrepreneur deserves to treat themselves every now and again. Whether it's a pair of designer shoes or an 80" big-screen, $1000/month can buy you big-ticket items you never thought you'd have.
Buy a new car
Is your gas guzzler on its last legs? An extra $1,000/month is more than enough to cover payments for a new, fuel-friendly ride.
Further Reading: How to Find Time to Build Your Ecommerce Empire While Working a 9 to 5
That's what we'd do with the money, but what about you? Tell us how your life would change with an extra $100, $500 or $1,000/month in the comments section below.


text:
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text: On Tue, 2005-11-22 at 08:17 -0700, ctierney at hypermall.net wrote: > New is relative. Comparing it to FC or other high speed interconnects (Myricom, > Quadrics, Dolphin) it is new. It is certainly new to the enterprise space. > I look foward to when that market adopts IB, so that we in HPC can reap the > benefits of commoditization. > It is worth having a look at this talk by Arie van Praag: http://www.ecmwf.int/publications/library/ecpublications/proceedings/hnf-europe-oct2002/1000Arie.ppt


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|Prep Time
|10 minutes
|Cook Time
|13 minutes
|Passive Time
|10 minutes
Born in Venezuela, Chef Maria developed her passion for food as a young girl. In her early 20's she came to the United States and entered the restaurant business in Boston MA. Later in San Diego CA she opened El Tucan Restaurant. It was in San Diego that Chef Maria was challenged by the culture and regional ingredients that ultimately contributed to the inventive style she's known for today. Also during this time in San Diego, Chef Maria was introduced to organic produce importance of nutrition.


text:
出典(authority):フリー百科事典『ウィキペディア(Wikipedia)』「2014/11/12 06:41:27」(JST)
[Wiki en表示]
A laboratory (/ləˈbɒrətəri/ or /ˈlæbərətri/; informally, lab) is a facility that provides controlled conditions in which scientific or technological research, experiments, and measurement may be performed.
Laboratories used for scientific research take many forms because of the differing requirements of specialists in the various fields of science and engineering. A physics laboratory might contain a particle accelerator or vacuum chamber, while a metallurgy laboratory could have apparatus for casting or refining metals or for testing their strength. A chemist or biologist might use a wet laboratory, while a psychologist's laboratory might be a room with one-way mirrors and hidden cameras in which to observe behavior. In some laboratories, such as those commonly used by computer scientists, computers (sometimes supercomputers) are used for either simulations or the analysis of data collected elsewhere. Scientists in other fields will use still other types of laboratories. Engineers use laboratories as well to design, build, and test technological devices.
Despite the great differences among laboratories, some features are common. The use of workbenches or countertops at which scientists may choose to either sit or stand is a common way to ensure comfortable working conditions. Cabinets for the storage of laboratory equipment are also found in laboratories. It is traditional for a scientist to record an experiment's progress in a laboratory notebook, but modern labs almost always contain at least one computer workstation for data collection and analysis.
Scientific laboratories can be found in schools and universities, in industry, in government or military facilities, and even aboard ships and spacecraft. A laboratory might offer work space for just one to more than thirty researchers depending on its size and purpose. Recently, a new type of laboratory called Open Laboratory has emerged.[when?] Its format allows the sharing of space, equipment, support staff between different research groups and also fosters information exchange through communications across fields. There is also an open source lab, which is a lab that is made up of open source scientific hardware.[1][2]
Chemistry laboratory of the 18th century, of the sort used by Antoine Lavoisier and his contemporaries
Thomas Edison in his laboratory, 1901
A laboratory in the 1970s
Laboratory techniques are the sum of procedures used on natural sciences such as chemistry, biology, physics in order to conduct an experiment, all of them follow scientific method; while some of them involves the use of complex laboratory equipment from laboratory glassware to electrical devices others require such specific or expensive supplies.
Laboratory equipment refers to the various tools and equipment used by scientists working in a laboratory. These include tools such as Bunsen burners, and microscopes as well as specialty equipment such as operant conditioning chambers, spectrophotometers and calorimeters. Another important type of laboratory equipment is laboratory glassware such as the beaker or reagent bottle, or even a thermometer.
Laboratory equipment is generally used to either perform an experiment or to take measurements and gather data. Larger or more sophisticated equipment is generally called a scientific instrument.
The title of laboratory is also used for certain other facilities where the processes or equipment used are similar to those in scientific laboratories. These notably include:
In recent years government and private centers for innovation in learning, leadership and organization have adopted "lab" in their name to emphasize the experimental and research-oriented nature of their work.
In some laboratories, the conditions are no more dangerous than in any other room. In many labs, though, hazards are present. Laboratory hazards are as varied as the subjects of study in laboratories, and might include poisons; infectious agents; flammable, explosive, or radioactive materials; moving machinery; extreme temperatures; lasers, strong magnetic fields or high voltage. In laboratories where dangerous conditions might exist, safety precautions are important. Rules exist to minimize the individual's risk, and safety equipment is used to protect the lab user from injury or to assist in responding to an emergency.
The Occupational Safety and Health Administration (OSHA) in the United States, recognizing the unique characteristics of the laboratory workplace, has tailored a standard for occupational exposure to hazardous chemicals in laboratories. This standard is often referred to as the "Laboratory Standard". Under this standard, a laboratory is required to produce a Chemical Hygiene Plan (CHP) which addresses the specific hazards found in its location, and its approach to them.
In determining the proper Chemical Hygiene Plan for a particular business or laboratory, it is necessary to understand the requirements of the standard, evaluation of the current safety, health and environmental practices and assessment of the hazards. The CHP must be reviewed annually. Many schools and businesses employ safety, health, and environmental specialists, such as a Chemical Hygiene Officer (CHO) to develop, manage, and evaluate their CHP. Additionally, third party review is also used to provide an objective "outside view" which provides a fresh look at areas and problems that may be taken for granted or overlooked due to habit.
Inspections and audits like also be conducted on a regular basis to assess hazards due to chemical handling and storage, electrical equipment, biohazards, hazardous waste management, chemical waste, housekeeping and emergency preparedness, radiation safety, ventilation as well as respiratory testing and indoor air quality. An important element of such audits is the review of regulatory compliance and the training of individuals who have access to and/or work in the laboratory. Training is critical to the ongoing safe operation of the laboratory facility. Educators, staff and management must be engaged in working to reduce the likelihood of accidents, injuries and potential litigation. Efforts are made to ensure laboratory safety videos are both relevant and engaging.[3]
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The services offered by Marinaz Agraria E Giardinaggio are the result of long experience. We have always been convinced that in order to earn customers' trust, you must go further than offering the best products and keen prices. Key aspects of our philosophy are advising, suggesting, proposing projects and solutions, making ourselves available professionally and with courteously to remove a doubt or resolve a problem. This is particularly true because our experts take care of this and they are people whose feet are firmly on the ground.
Ettevõtte veebileht
www e-kaubanduse veebileht


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Explore window materials or choose the style of window for your home.
Make a grand entrance with a new Hazlemere Door.
Keeping you safe. Reducing your energy bills. Giving you choice.
Explore our orangery range - chosen just for you.
Choose from our range of solid tiled roofs from the products below.
© 2018 Hazlemere Window Company Ltd.
Authorised and regulated by the Financial Conduct Authority.


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What is El Niño anyway?
El Niño is a condition that sometimes occurs in the Pacific Ocean, but it is so big that it affects weather all over the world.
Weather depends a lot on ocean temperatures. Where the ocean is warm, more clouds form, and more rain falls in that part of the world. In the Pacific Ocean, near the equator, the Sun makes the water especially warm on the surface.
Normally, strong winds along the equator push the warm surface water near South America westward toward Indonesia. When this happens, the cooler water underneath rises up toward the surface of the ocean near South America.
However, in the fall and winter of some years, these winds are much weaker than usual. They actually blow the other way (toward South America instead of Indonesia) in October. So the warm surface water along the equator piles up along the coast of South America and then moves north towards California and south toward Chile.
Many fish that live in the normally cooler waters off the coast of South America move away or die. The fishermen call this condition of warm coastal waters and poor fishing "El Niño" meaning "the Christ Child," because in the occasional years it comes, it comes at Christmas time.
In El Niño years, lots of rain clouds forms over this warm part of the ocean. These clouds move inland and dump much more rain than usual in South and Central America and in the United States. Meanwhile, other parts of the world can suffer drought. Weather patterns all over the world may be unusual, making lakes out of deserts and charcoal heaps out of rain forests.
How do we know what is happening to the ocean temperatures around the Earth? The best way is to go up into space!
How do you take the ocean's temperature from space?
Where the ocean is warmer, sea level is slightly higher. In 2008, the Jason-2 satellite (also called the Ocean Surface Topography Mission) was launched into orbit around Earth. It continued the measurements being made by Jason-1, launched in 2001. Both satellites have a sensitive altimeter onboard. An altimeter measures height from itself down to the Earth's surface (land or water).
Using information from Jason-1 and Jason-2, scientists make topographical maps of the hills and valleys on the ocean's surface. The different heights of the ocean are shown on flat maps using different colors.
In these maps, purple, blue, and green are the colder parts of the ocean where the sea level is a little lower. Red, pink, and white are the warmer parts where the surface of the ocean bulges upward a bit. The surface of the water where the ocean is warmest is only about 2 meters (a bit less than 7 feet) higher than in the coldest areas.
Whip up some El Niño pudding!
You have probably heard people blame "El Niño" for everything from bad weather to lost homework. Now we are going to "blame El Niño" for inspiring a delicious and colorful dessert!
Here's the recipe for El Niño pudding.
As you make your El Niño pudding, think about the Jason-1 and Jason-2 satellites. They are like minivans full of instruments up in space. They each go around the world 4,700 times a year making maps of the sea surface height. Jason-1 and Jason-2 are two of several satellites that keep an eye on our oceans and add to the information we get from ships and buoys.


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Aydin was an Iranian mountaineer who had climbed 572 steps to the top of the Cascade — a towering architectural feat in the heart of Yerevan that now houses the Cafesjian Center for the Arts — with his wife.
On a South Caucasus road trip, Armenia was their last stop after having visited Azerbaijan and Georgia. They raved about the beauty of that country's capital, Tbilisi.
With a foggy Mount Ararat in view, we spoke of Nietzsche, Dostoevsky and E.E. Cummings. Aydin wondered what Americans thought of contemporary Iran. I wondered what life was like in the country I was born in, beyond the headlines of protests and occasional bans on everything from Western hairstyles to the press.
He casually mentioned the Nagorno-Karabakh conflict, calling it a "tough situation;" and I told him about the Blue Mosque, the one and only mosque operating in Yerevan.
Extending beyond the burgeoning trend of vacationing in Armenia during Nowruz, the Iranian New Year, Aydin and his wife are among thousands of Iranian tourists who arrive in Armenia to spend their summer holidays in the country, where they can openly drink alcohol, eat pork and engage in other forms of debauchery banned by the Islamic Republic.
In the city center or around Lake Sevan, one of the largest high-altitude lakes in the world, families and singletons are soaking up the nightlife and flexing their freedom muscles on a cheap excursion to Armenia, which is no doubt adding fuel to the country's economy via tourism.
In the first four months of 2011, more than 31,000 Iranians visited Armenia, according to local media. The head of tourism at the Ministry of Economy recently revealed that a poll of 101 Iranian tourists showed that around $1,600 is spent by the average Iranian tourist during a 10-day holiday, according to News.am.
Whether Iranians are pumping life into the Armenian tourism market or not, their presence has given rise to ambivalent reactions from locals who cite their loud, obnoxious behavior and alleged penchant for sex tourism as reasons they're unhappy with the influx. The country's mono-ethnic makeup, with about 98% of the population ethnically Armenian, also adds to some unfamiliarity when dealing with diversity.
With non-existent American-Iranian relations and the dangers of practicing journalism in Iran (the country is considered one of the world's worst jailers of journalists and has forced at least 18 native journalists to flee their homes in the past year, according to the Committee to Protect Journalists), the mass of Iranian tourists is a personal blessing in disguise because I can mix and mingle with a people I consider as much my own as Armenians.
Through the Iranian men and women — many of them with their long, thick hair flowing free from the confines of their rusaris, or headscarves — I see glimpses of a country I was born in, a country my parents grew up in, studied in, worked in, laughed and loved in until the dire circumstances of the 1978 Revolution forced them to flee their home.
When I hear Farsi being spoken on the streets and in the supermarket, I almost want to close my eyes and pretend that I'm in Tehran, which is how I felt when I ran into Aydin, overlooking downtown Yerevan on a sweltering day.
We took a photo together, exchanged email addresses and spoke some more about philosophy and literature. For that half hour, I felt like I was reclaiming a part of my heritage, rings in the tree trunk of my identity that can never be erased — even if egged on by fear, I can't seem to cross the border to see it myself.


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Some "Charlotte Russe "cakes decorated with chocolate, strawberries and cream. Two slightly different cakes. Hope you like it. Available in my Etsy store.
Love this photo. It just happened when I took the photos. My cat is curious and jumped up on the table to have a look. Wonder what she thinks.."crazy woman I can't eat this";)


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The Repeating Pattern in Vedanta Limited That Triggers Right After an Earnings Beat and The Option Trade That Follows
Vedanta Limited (NYSE:VEDL) : The Repeating Pattern in Vedanta Limited That Triggers Right After an Earnings Beat and The Option Trade That Follows
Date Published: 2018-11-7
DisclaimerThe results here are provided for general informational purposes, as a convenience to the readers. The materials are not a substitute for obtaining professional advice from a qualified person, firm or corporation.
LEDEThere is a bullish momentum pattern in Vedanta Limited (NYSE:VEDL) stock 1 trading day after earnings, if and only if the stock showed a large gap up after the actual earnings announcement.
This is a conditional entry -- the company reports earnings and if the stock move off of that report is a 3% gain or larger, then a bullish position is back-tested looking for continuing momentum in a short window to follow. The event is rare, but when it has occurred, the back-test results are noteworthy.
Vedanta Limited (NYSE:VEDL) EarningsIn Vedanta Limited, if the stock move immediately following an earnings result was large (3% or more to the upside), if we test waiting one-day after that earnings announcement and then bought a three-week at the money (50 delta) call, the results were quite strong.
This back-test opens one-day after earnings were announced to try to find a stock that continues an upward trajectory after an earnings rally.
Simply owning options after earnings, blindly, is likely not a good trade, but hand-picking the times and the stocks to do it in can be useful. We can test this approach without bias with a custom option back-test. Here is the timing set-up around earnings:
Rules* Condition: Wait for the one-day stock move off of earnings, and if it shows a 3% gain or more in the underlying, then, follow these rules:
* Open the long at-the-money call one-trading day after earnings.
* Close the long call 14 calendar days after earnings.
* Use the options closest to 21 days from expiration (but more than 14 days).
This is a straight down the middle direction trade -- this trade wins if the stock is continues on an upward trajectory after a large earnings move the two-weeks following earnings and it will stand to lose if the stock does not rise. This is not a silver bullet -- it's a trade that needs to be carefully examined.
But, this is a conditional back-test, which is to say, it only Triggers if an event before it occurs.
RISK CONTROLSince blindly owning calls can be a quick way to lose in the option market, we will apply a tight risk control to this analysis as well. We will add a 40% stop loss and a 40% limit gain.
In English, at the close of every trading day, if the call is up 40% from the price at the start of the trade, it gets sold for a profit. If it is down 40%, it gets sold for a loss. This also has the benefit of taking profits if there is a stock rally early in the two-week period rather than waiting to close 14-days later.
Another risk reducing move we made was to use 21-day options and only hold them for 14-days so the trade doesn't suffer from total premium decay.
RESULTSIf we bought the at-the-money call in Vedanta Limited (NYSE:VEDL) over the last three-years but only held it after earnings and after an earnings pop higher, we get these results:
Long 50 Delta Call
|% Wins:
|Wins: 2
|Losses: 1
|% Return:
Tap Here to See the Back-test
The mechanics of the TradeMachine® are that it uses end of day prices for every back-test entry and exit (every trigger).
Track this trade idea. Get alerted for ticker `VEDL` 1 days after earnings
Looking at AveragesThe overall return was 102.9%; but the trade statistics tell us more with average trade results:
➡ The average return per trade was 35.18% over each 13-day period.
➡ The average return per winning trade was 73.61% over each 13-day period.
➡ The average return per losing trade was -41.67% over each 13-day period.
WHAT HAPPENEDBullish momentum and sentiment after earnings can be quite powerful with the tailwind of an earnings beat.
Please note that the executions and other statistics in this article are hypothetical, and do not reflect the impact, if any, of certain market factors such as liquidity and slippage.


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CHEYENNE, Wyo. (AP) -- An explosion has killed three workers who had been laying a fuel line at a Wyoming oil storage site, an oil company spokesman said.
The blast at about 10 a.m. Monday near Glenrock, in a remote region of eastern Wyoming, sparked a 10-acre fire before it was brought under control, Samson Resources Co. spokesman Dennis Neill said. The fuel line where the blast victims had been working was intended to supply a heater treatment facility that separates oil from water as they're pumped out of the ground.
The workers were employed by a contractor that the Tulsa, Okla.-based Samson had been hired to bring an oil well back into production at the site, Neill said. The well wasn't involved in the explosion and fire, which happened on the Hornbuckle Ranch, about 50 miles northeast of Casper.
Neill declined to name the company that employed the workers. Samson officials were traveling to the area, and state and federal investigators were on the scene, he said.
Neill said local and federal authorities are investigating the explosion, with the cause still unknown Tuesday. Authorities have not named the three workers.
"Obviously we're very concerned about the family and friends in this situation," Neill said.
Tina Wells, spokeswoman for Samson, said Tuesday that the company intended to release a statement on Tuesday. She said no information was available in advance of that.
Wyoming administers its own workplace safety program through the Department of Workforce Services.
J.D. Danni, manager of the Wyoming Occupational Safety & Health Administration program, said Tuesday that his office has two investigators on the scene of the explosion.
Danni said they will prepare a report on the cause of the explosion within 180 days. The report will look at the cause of the explosion as well as whether any workplace safety violations contributed to it, he said.
Danni said he didn't know whether there were any other witnesses to the explosion. He said his office is still confirming the names of the victims and the company they worked for. He said Samson hasn't received any citations from the state in recent years.
In July, a newly built gas pipeline exploded in northeastern Wyoming. No one was hurt, but the blast could be heard 10 miles away and left a 50-foot-long trench in the ground.
In 2006, a gas well blowout near Yellowstone National Park spewed a cloud of explosive natural gas, forced evacuations for miles around and polluted the drinking water. The cause is still unknown.
The Wyoming Department of Workforce Services reported last week that the number of occupational fatalities in the state rose to 34 last year - an increase of nearly 79 percent from the year before. Of those 34 workplace deaths, 10 were in natural resources and mining.
A bill that would have increased employer penalties for workplace safety violations was rejected early last year in the Wyoming State Senate. Then-Gov. Dave Freudenthal had urged passage of the bill, which had been supported by industry groups.
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Having been transplanted from the UK to New Zealand when I was four years old, I knew little of my extended family other than what my parents were able to tell me.
I grew up on stories of my mother's Scottish family. The characters and stories she told me were real and tangible and stimulated my imagination. They gave me a sense of belonging and a feeling of Scottishness. Helped me feel more accepting about having an annoying Gaelic name that no one could pronounce. I always felt very Scottish.
My father's family however, was something of a mystery. I'd met a couple of his relatives, and I'd met my paternal grandfather when I was very young, but knew little about him.
My father also knew very little about his family. His mother died of TB when he was a few months old, and he was brought up with a neighbour's family.
I was living in London, when my father asked me to look up some info at the Family Records Office for him. He'd been writing his life story and trying to piece together info from his older surviving relatives including his older sister.
I did the look up for him - and that was it. I was bitten by the bug and have been obsessed ever since.
The hobby, led to a new career, and the rest as they say is HISTORY (or in this case HERSTORY LOL)
Sunday, January 9, 2011
How I got bit by the (genea-)bug
Posted by Unknown at 9:21 AM
Labels: beginning genealogy, research
4 comments:
So pleased to see you blogging - will look forward to hearing more of your stories than is possible to share in 140 characters on Twitter.ReplyDelete
I started in a very similar fashion. My father was trying to locate where his grandparents were buried and was having no luck, so I decided to help him out and I was hooked. I've been working on my and my husband's family tree ever since.ReplyDelete
Seonaid, you're such a nerd :) But I love it.ReplyDelete
LOL. Thanks Hana - the old saying: "Takes one to know one!" LOLReplyDelete
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