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Amazon Expands Video Conversion As A Service Amazon Elastic Transcoder allows users to use the AWS cloud to convert video into formats for Macs, PCs, iOS and Android devices.
CIO Master Class: Choose Your Public Speaking Style Addressing the troops can be fraught with pitfalls. A psychologist offers tips on how leaders can boost teamwork by using situation-appropriate styles of speaking.
Amazon E-Retail Down For Hour On Thursday Amazon offers no explanation. Amazon Web Services continued functioning, with all services apparently available.
Celebrity 'Advisers': Tech's Most Entertaining Ticket BlackBerry names Alicia Keys "global creative director." I can't wait to see who hires Honey Boo Boo.
IBM Showcases Bunchball Social Gamification Partnership To get users to discover the business value of enterprise social networking, first give them a fun experience, IBM says.
Apple Wants You To Dispense Cash Apple's filed a patent application to coordinate the physical transfer of cash between two individuals.
PC Makers, Learn From Car Makers: Use Model Years PC vendors, are you tired of losing sales to the cool new tablets? Take a page from the auto industry's playbook and introduce model years.
United Healthcare's Humedica Buy Signals Analytics' Clout Humedica would give Optum, United's health services arm, new power in the growing health data mining market.
Apple iOS 6.1 Sees Quick Adoption Apple's iOS update was installed on 22% of devices within 36 hours, says website developer.
BlackBerry's New Enterprise Candy Won't Tempt CIOs The company formerly known as RIM can't just copy the same things Apple and Google did to steal the top spot.
HIMSS Goal: Show Value Of Health IT Convincing national policy makers that health IT is worth the investment and promoting interoperability tops health IT organization's Washington agenda.
Bill Gates Touts Analytics To Solve Global Problems In his foundation's annual letter, Microsoft co-founder says analytics are helping developing countries tackle health and education problems, urges setting clear goals.
Apple's Tablet Rivals Gaining Share Apple sold more tablets than any other company during the fourth quarter, but its competitors are starting to catch up.
IBM Sees Progress On Social Software Standards Support for OpenSocial makes it easier to adapt and embed new and legacy applications for use with enterprise social networks.
EHR Accuracy Remains Problem, CHIME Says College of Healthcare Information Management Executives warn technology and workflow burdens make EHR reporting nearly impossible.
Microsoft Surface Pro Storage Snafu: Does It Matter? Windows 8 takes up about 70% of the 64-GB Surface Pro's storage. Will this factor into the tablet's BYOD potential?
OVF 2.0 Takes On Cloud Lock-In Worries DMTF standards body updates its vendor-neutral virtual machine file format. The goal: Make it easier to leap from cloud to cloud.
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subset: commoncrawl


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This is Little Quentin, just your run-of-the-mill wordless animated short about a giant rabbit, a clown, and a hardened Sam Spade archetype out on the town in a hardboiled metropolis. As any good Twilight Zone fan knows, all is not what it seems when massive cottontails hang out with astronauts. This short comes to us from Dutch animators Albert 't Hooft & Paco Vink. In this 10-minute cartoon, there are some clever, subtle cues to a character (or two) you may recognize — we mean you, Grim Reaper.
[Via Animatie]


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Marylyn Ritchie Honored as an Invited Kavli Fellow for the Third Year in a Row
Main Content
Marylyn Ritchie, an associate professor of biochemistry and molecular biology, and the director of the Center for Systems Genomics at Penn State University, has been selected as a 2013 Kavli fellow and has been invited to serve as a member of the organizing committee for the Kavli Frontiers of Science symposium. This is the third time Ritchie has received Kavli honors. In 2011 she was selected as a Kavli fellow and as a general participant for the Kavli Frontiers of Science Indonesian-American symposium. In 2012 and in 2013, she was selected as a Kavli fellow and was invited as a member of the organizing committee of the Indonesian-American symposium. The Kavli Frontiers of Science symposium is jointly sponsored by the U.S. National Academy of Sciences and The Kavli Foundation. It brings together young scientists "to discuss exciting advances and opportunities in their fields in a format that encourages informal collective, as well as one-on-one, discussions among participants."
Ritchie's research focuses on identifying and analyzing genes that may increase susceptibility to common diseases such as cancer, diabetes, hypertension, and cardiovascular disease. To determine how such genes might influence disease susceptibility, Ritchie uses a variety of approaches that span the fields of biology, genetics, and statistics. One of her primary approaches is to develop studies to detect interactions between genes, and to design and apply new statistical and computational methods to analyze data associated with such interactions. In addition, she explores possible interactions between genes and the environment, and studies how these interactions might increase disease susceptibility.
Before joining Penn State's Eberly College of Science, Ritchie was an associate professor in the Department of Molecular Physiology and Biophysics and the Department of Biomedical Informatics at Vanderbilt University. While at Vanderbilt, she also served as an investigator in the Center for Human Genetics Research, where she directed the Computational Genomics Core and the Program in Computational Genomics. In addition, she has served as a consultant for Boehringer-Ingelheim, one of the world's leading pharmaceutical companies.
Ritchie has received many honors throughout her career. In 2010, she was awarded an Alfred P. Sloan Foundation fellowship, and in 2006, she received a Rising Young Investigator Award from the journal Genome Technology. In addition, she won a Best Paper Award at the Genetic and Evolutionary Computation Conference in 2004. She has published numerous papers in peer-reviewed journals such as American Journal of Human Genetics, the Journal of Biological Chemistry, Human Molecular Genetics, Bioinformatics, and Plos Genetics. She is a member of several professional organizations including the American Society of Human Genetics and the American Statistical Association.
Ritchie received a doctoral degree in statistical genetics and a master's degree in applied statistics from Vanderbilt University in 2004 and 2002, respectively. She received a bachelor's degree from the University of Pittsburgh in 1999.


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A Cornucopia of New Drugs
It is painfully evident that new antiretrovirals are needed to treat resistant virus when people are forced to construct a therapeutic regimen by recycling six, or worse yet, eight old drugs. And if there were enough new agents far enough along in clinical development, people would not have to resort to strategic treatment interruptions (STIs). The situation for many is truly desperate.
It is not enough for a drug to be "new," however. To outwit HIV, we need molecules that are significantly different from what has been used before. All too often, new drugs cause undue excitement. Pharmaceutical companies publish posters at these conferences that make claims on the basis of minor test tube experiments that rarely ever translate into clinical success. Next thing they know, activists are demanding expanded access.
In fact, very few of the antivirals in development show promise as rescue agents. Clearly those must be prioritized. The compounds that offer the most promise for patients with multidrug-resistant virus are those that attack entirely new targets in the viral replication cycle. There are chemokine receptor antagonists, integrase inhibitors, transcription blockers and other new classes of drugs in preclinical development, but these will be discussed in an upcoming issue. Nevertheless, even if an antiviral is not active against multidrug resistant virus, we still welcome its development if it leads to HAART regimens that are less cumbersome, simpler to adhere to or easier to tolerate.
Research on several of the drugs in development was presented at the 39th ICAAC conference in San Francisco and the Lisbon meeting. Unless otherwise noted the citations are to the ICAAC abstracts. Because this editor's special area of interest is drug discovery and development, we thought we would expand our coverage to tell you some of the story behind the posters. Treatment newsletter writers and activists interact very closely with the pharmaceutical industry, and we learn things about the companies -- their economic situation, corporate philosophies, history, goals and personalities -- that rarely get reported, but bear upon how a drug gets developed. For example, if Abbott decides it is in its best interest, the company has the experience and might to develop a new drug and get it into expanded access much faster than a baby biotech company with an employee force of 20 bench scientists and an executive director. It is not uncommon for an inexperienced company to conduct poorly designed studies that make its drug look worse than it is because the company is not familiar with clinical practice in HIV disease. In contrast, some (and we emphasize some) of the larger companies know how to conduct a study in such a way to put their drugs in the best possible light. But if any company has a useful drug, it is in everyone's best interest that its venture is a success.
It is important that each company's data are reviewed fairly and that a compound's potential is neither exaggerated (because hype will not suppress your viral load) nor dismissed prematurely. Both are crucial to the survival of people with AIDS who need all of the "true" salvage agents they can get.
Protease Inhibitors
Data from two phase II trials of ABT-378/r, a new protease inhibitor from Abbott that is combined with ritonavir (hence, the small "r"), were presented at a late breaker session at ICAAC. The studies evaluated ABT-378/r in both treatment naive and experienced populations.
In the naive study, patients were randomized into two blinded groups. The first group (n=32) received either 200/100 mg or 400/100 mg of ABT-378/r twice a day, while the second group (n=68) received either 400/100 mg or 400/200 mg ABT-378/r twice a day. Both groups also took d4T/3TC. The median baseline viral loads were 100,000 and 79,000 copies/ml, respectively. At week 36, an on-treatment analysis of both groups showed that slightly more than 95% of patients had HIV RNA <400 copies/ml and 89% had <50 copies/ml. On an intent-to-treat analysis, 81% of those in the first group and 87% of those in the second group had HIV RNA <400 copies/ml. CD4 counts increased by 201 cells in the first group and by 170 cells in the second.
In the treatment experienced study, 70 patients currently failing treatment were randomly assigned to receive 400/100 mg ABT-378/r or 400/200 mg ABT-378/r twice a day, plus nevirapine and two nucleoside analogs (NRTIs), at least one of which was new. Subjects had been receiving a protease inhibitor and two NRTIs for at least three months but no previous NNRTI therapy or previous dual protease inhibitor therapy. The median baseline viral load was 10,000 copies/ml.
By week 36, an on-treatment analysis found that 78% of all patients had HIV RNA <400 copies/ml (67% on an intent-to-treat analysis), and there was a mean CD4 cell count increase of 104 cells. In both groups, the most common adverse events were diarrhea, nausea, asthenia (weakness) and headache, but only two patients out of 170 (which includes both studies) discontinued due to adverse events.
Given the choices available to treatment-naive populations, the primary interest in ABT-378, like most new drugs, is what it offers people who are treatment experienced. Yet, the design of this study makes it difficult to tell what ABT-378 contributed to the treatment outcomes. Note that study participants were receiving a five-drug regimen that included at least three new drugs -- ABT-378, an NNRTI (nevirapine) and at least one new NRTI -- and they had never had dual protease inhibitor therapy before, which means that have never used a protease inhibitor with plasma concentrations enhanced by ritonavir. Thus, it is not clear that the ABT-378-based regimen was any more effective for these patients than a new protease inhibitor plus ritonavir, their first NNRTI, and at least one new NRTI. Even the same regimen except without ABT-378 might have performed equally well. Without head-to-head studies of such regimens, it is impossible to tease out the relative contribution of ABT-378/r. The addition of a member of an entirely different class of agents (an NNRTI), in particular, makes it impossible to say how effective ABT-378/r is in protease inhibitor-resistant patients. After all, it only takes a 1.4 log reduction in viral load to go from 10,000 to 400 copies/ml, which an NNRTI can do on its own.
Moreover, the study provides little information for those who have failed three or more HAART regimens -- precisely the situation facing most people who qualify for Abbott's limited early access program (see ABT-378/r Compassionate Use Program in this issue). Once again, there is no evidence that the ABT-378/r-based regimen would be more effective than any other five drug regimen based on another new protease inhibitor plus ritonavir. Given that the mechanisms of protease inhibitor cross-resistance remain unclear, people with established protease inhibitor resistance face other uncertainties. If they are constructing a rescue regimen with one or two other new drugs and adding ABT-378/r to it, they may be in for a major disappointment. Not only might their regimens fail, but they may become resistant to their remaining therapeutic options because the regimen was not potent enough. Such patients need proof that ABT-378/r is effective against multiply protease inhibitor-resistant virus.
Abbott hopes to answer some of these concerns in future trials. One study, recently filled, will test an ABT-378/r and efavirenz based regimen in multiple protease inhibitor experienced but again in NNRTI-naive patients. Another, planned for early next year, will test higher doses of ABT-378 in patients who have NNRTI and multiple protease inhibitor experience. Abbott will also be collecting data from the early access program. However, results from these trials are not expected until the World AIDS Conference next July.
New pharmacokinetic data on tipranavir, a much-awaited protease inhibitor from Pharmacia & Upjohn, were presented at ICAAC. In contrast to ABT-378, which is promising for protease inhibitor-experienced patients primarily by virtue of its high plasma concentrations which may overwhelm low-level resistance, tipranavir appears to be dramatically different in terms of its resistance profile. Some have described the compound, which is non-peptidic, as being more "flexible," or even "stickier," than the current crop of protease inhibitors, although it is not really clear whether this nomenclature is scientifically accurate. Nonetheless, in vitro and in a number of clinical case studies, this non-peptidic protease inhibitor has demonstrated activity against HIV isolates that show high level resistance to all of the available protease inhibitors.
Unfortunately, the drug's development has been plagued by formulation problems. The first clinical trial of the compound used doses up to 2000 mg tid (ten "horse" pills three times a day). Subsequent studies have used a better formulation, but pill counts remain high nonetheless.
Yet even though this compound is chemically unrelated to the other protease inhibitors on the market, it is metabolized via the same P450 CYP3A4 hepatic enzyme systems as ritonavir, and coadministration may substantially reduce pill burden with tipranavir. However, unlike the other protease inhibitors, it tends to induce rather than inhibit this system. Therefore, it reduces drug levels of most other drugs metabolized this way. For example, in one poster at ICAAC(1), tipranavir reduced plasma concentrations of ritonavir by 80% to 88% (AUC) and there was a 20-fold decrease in ritonavir trough levels. The poster described two pharmacokinetic studies on the coadministration of the two agents. In the first study, tipranavir 1350 mg bid was coadministered to patients taking ritonavir 500 mg bid. This may have been overkill, as ritonavir 500 mg bid caused a 12-fold increase in the AUC of tipranavir and a 45-fold increase in trough levels. In the second study, two different doses of tipranavir, 600 and 900 mg bid, were administered with either 100 or 500 mg ritonavir. The effect of ritonavir upon tipranavir was determined to be dose-related with the low dose boosting tipranavir trough levels by 7- to 9-fold.
Clearly, this is moving in the right direction -- from 30 horse pills down to 8 or 10 per day. But since P & U sold Agouron the rights to delavirdine last October, there is some question as to whether it plans to continue developing tipranavir. A company representative told us that P & U will continue to press forward but acknowledged the company is looking into a partnership or even selling the rights to the drug. If P & U decides to leave the HIV market, who would buy it? Of the remaining major pharmaceutical companies in the field, only DuPont has not produced a protease inhibitor -- yet.
In cooperation with Vertex, Glaxo-Wellcome presented data on VX-175/GW433908, a lower pill count, water-soluble phosphate prodrug of the protease inhibitor amprenavir. Because amprenavir has poor aqueous solubility, it is formulated with a substantial amount of water-soluble Vitamin E to aid in its absorption. Together, it all adds up to eight sizable pills that must be taken twice a day.
This is amprenavir's Achilles' heel. While there is no clear evidence that the formulation contributes to amprenavir's gastrointestinal toxicity (the nausea, vomiting and bloating), the volume of drug can't help. Furthermore, one of the drug's chief selling points was meant to be convenient dosing: twice daily, with or without food. But the pill count can make adherence more difficult for some patients. A number find it easier to spread the pills out over the course of an hour, but so much for convenience.
There are studies that suggest that pill count is not that important to adherence. All things being equal, this might be true, but if the medication is also making you nauseous (the most frequently reported toxicity on amprenavir), each successive pill can grow harder to swallow. This could have been the case for some of the patients in the PROAB 3006 study, amprenavir's head-to-head competition with indinavir, presented in Lisbon (see A Cornucopia of New Drugs in this issue). As noted in the study's executive summary, adherence was better on indinavir, which must be taken three times a day and on a mostly empty stomach. While the rates of virologic failure were not very different between amprenavir and indinavir, poor adherence and a high drop out rate due to toxicity hurt amprenavir in the intent-to-treat analysis. (To both companies' credit, at least they dared to go head-to-head with the gold standard protease inhibitor -- Agouron never did.) Even so, amprenavir worked well in those patients who could tolerate and adhere to it, and much of the toxicity abated after the first month. Nevertheless, initial tolerability and ease of adherence are factors that must be weighed when choosing a first-line or first protease inhibitor regimen. Clearly, the formulation has been hindering the drug's performance.
The solution could be VX-175/GW433908. The amprenavir prodrug is more soluble which makes the Vitamin E unnecessary. The improved formulation should allow for a significant reduction of both the size and number of pills.(2) Studies in rats and dogs showed that toxicology is similar to that of amprenavir.(3) A 24-hour multidose phase I study in healthy men, given with and without food, showed bioequivalence and dose proportionality to amprenavir. Cmax was about 27% lower (but Cmax is more often associated with toxicity than antiviral effect). A high-fat meal reduced AUC by 20% and Cmax by 41%. However, the most important parameter, the trough level of drug, was unchanged.
The next step in bringing VX-175/GW433908 to market will be to conduct a larger study in people with HIV demonstrating bioequivalency of this formulation with amprenavir. Depending upon their final size, this formulation could cut the pill burden down to three or four moderately sized tablets twice a day. Given the long halflife of amprenavir (about 10 hours), it may even be possible to administer the drug once-a-day without a ridiculously high pill count, either with low dose ritonavir or perhaps even without it.
Other Protease Inhibitors
We will have to wait until the Retrovirus Conference to hear news on BMS 232632, which may be cross-resistant with indinavir and ritonavir, but might be administered once a day; AG 1776, which promises activity against protease inhibitor-resistant strains; and Merck's second generation drug L-756,423.
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Emivirine (Coactinon, MKC 442)
The NNRTI furthest along in clinical development is Triangle's MKC 442, now known as emivirine (EMV). This compound is chemically similar to a nucleoside analog, but it functions as an NNRTI. Emivirine is not very well known in this country because, aside from data from a small dose-ranging study, little clinical information has been available on it, and its key clinical trials have been conducted abroad. Yet, emivirine will be the next new anti-HIV drug up for FDA review after adefovir. Preliminary data from one of the pivotal studies that will support this application were presented at ICAAC, and a second was ready for the Lisbon meeting.
The first study, conducted in South Africa, was open-label and divided 197 HIV-positive patients into four arms: (1) 500 mg EMV twice a day, (2) 750 mg EMV twice a day, (3) 250 mg twice a day for 3 days and then 750 mg twice a day and (4) 375 mg twice a day for three days and then 750 mg twice a day.(4) The rationale for arms (3) and (4) was that, like ritonavir, blood levels of emivirine are higher when it is first administered, and it was hoped that a lower lead-in dose might be better tolerated. In all four arms, patients also received d4T and ddI. Patients were NNRTI- and protease inhibitor-naive and had fewer than 28 days of prior NRTI exposure. Thirty-eight percent were women, the median baseline HIV RNA was 4.5 log (about 32,000 copies/ml) and the median baseline CD4 count was over 300 cells.
At week two, 89% of patients in all four arms demonstrated a one-log reduction in HIV RNA from baseline. Seventy-five percent of the individuals who reached week 12 experienced a viral load drop to below 400 copies/ml. On an intent-to-treat analysis at week 24, 64%, 57%, 43% and 52% of patients had HIV RNA <400 copies/ml in arms (1)-(4), respectively (54%, 51%, 30% and 38% were <50 copies/ml, respectively). However, not all subjects in arms (3) and (4) had reached week 24.
Seventy-two percent experienced mild adverse events, the most common of which were nausea, headache, transient dizziness and diarrhea. There were no life threatening (grade IV) adverse events, and grade III events were seen in two to four percent of the patients. Twenty-three percent experienced rash but most (83%) remained on study. The lead-in arms did not improve tolerability, so the company is going to evaluate longer lead-ins.
Given the design of the study, its locale and the preliminary nature of the data, one should not rush to compare these results to those from studies of other NNRTI-based regimens. For instance, here there is no control -- one can only evaluate which emivirine dose or dose-escalation regimen is better. Also, since a sizable proportion of the patients have not yet reached week 24, an intent-to-treat analysis is unfair. Finally, cross study comparisons are never valid, but particularly when comparing studies conducted in the US and Europe to a study conducted in a developing nation, where the standard of care, even in clinical trials, may be much different.
In Lisbon, results were presented from a second pivotal study(5) that compared emivirine plus d4T/3TC to d4T/3TC. The randomized, double blind 24-week study enrolled 162 treatment-naive volunteers, 45% female and 55% male, with median baseline viral loads of 4.3 log (just under 20,000 copies/ml) and median baseline CD4 counts of 418 cells. At Week 24, 40% of the patients on dual nucleoside therapy versus 83% on triple therapy had viral loads below 400 copies/ml (84% of the latter were also undetectable using the ultrasensitive assay).
The side effect profile was very similar to that of the emivirine/d4T/ddI trial. The most common adverse events on triple therapy were nausea (36%), headache (22%), dizziness (17%) and rash (22%). Most of the rash was mild to moderate. Close to 8% of the emivirine-treated patients experienced grade III laboratory abnormalities. Most adverse events were early onset, observed during the first month on therapy. Again, this is part of the rationale for a lead-in dose.
The genotypic and phenotypic resistance patterns in patients who failed on an emivirine regimen in both of these studies were discussed in a poster at ICAAC.(6) Twenty-four out of 138 patients experienced virological failure. Resistance analysis revealed that the most common mutations in these patients were at reverse transcriptase positions K103N (56%), Y181C (9%) and G190A (9%). The K103N mutation causes resistance to all of the marketed NNRTIs, but the company was quick to point out that nine of 24 (37.5%) were still sensitive to at least one other NNRTI. However, such in vitro findings do not mean that an emivirine-failing patient without detectable K103N-mutant virus is likely to experience a durable response to subsequent efavirenz treatment. Genotypic tests are notoriously insensitive, and the K103N mutation is so common that there is a danger that it may be present in all patients failing emivirine but at levels just below the sensitivity of the test. Before banking too much on these findings, Triangle should conduct a sequencing study to show that patients with this resistance pattern can indeed be salvaged by subsequent NNRTI therapy.
In a context where there are several marketed NNRTIs, and where people are cynical about the ability to sequence these agents, the company has to find a clear way to distinguish this product from its competitors. Those who are prone to use NNRTIs for first-line therapy are already used to, and generally comfortable with, the agents they are using. Furthermore, Triangle has decided to run its major studies overseas, so clinicians here have had little experience with the drug. When emivirine hits the market, it may prove a challenge to convince clinicians to choose a less-well characterized compound over one that they have often used.
But Triangle will have the marketing might of Abbott on its side. Several months back, the two companies entered into a pact to codevelop and comarket the antivirals in their portfolios. These include ritonavir, ABT-378/r, emivirine, FTC or emtricitabine, dADP and LFMAU (for HBV). Abbott's sales force is substantial, but it will be interesting to see whether they will expend much energy on marketing a protease inhibitor-sparing regimen when they have one protease inhibitor already on the market and ABT-378/r waiting in the wings.
DPC 961, 963, 082 and 083
DuPont is currently looking at four new "second generation" NNRTIs, DPC 961, 963, 082 and 083, for possible development. Data on their in vitro resistance and potency were presented in a poster session.(7) Researchers examined their potency against resistant strains of HIV as well as the availability of free drug levels. In terms of resistant virus, all four new compounds showed high activity against the K103N mutant (which is associated with resistance to approved NNRTIs) and maintained potency against virus with single mutations and common double mutations such as the K103N/Y181C. In addition, the four compounds show increased levels of free drug in human serum compared to efavirenz. Tests on non-human primates suggest that all four compounds could be used once a day in human trials. While the in vitro results look promising, the real test will come when one of these is tested in patients with NNRTI-resistant virus.
Glaxo-Wellcome is continuing its effort to cover all the antiretroviral bases with an NNRTI of its own, GW420876X, as it appears unlikely that abacavir will be able to compete for efavirenz' and nevirapine's growing market niche. GW420876X is a molecule related to HBY097, which was discontinued by Bayer a couple years ago. Introduced last year at the Fourth International Congress on Drug Therapy in HIV Infection meeting in Glasgow, thus far the drug appears to have a number of interesting properties. It has a very long half life (about 50 hours) so it can be given once a day -- with or without food or even with a high fat meal, according to one study presented at ICAAC.(8) In contrast to the other available NNRTIs, the compound is not metabolized by cytochrome P450 isoenzymes, so it may be free of the drug interactions seen with the other NNRTIs.
The first data on GW420876X in HIV-positive patients were presented at ICAAC.(9) The ongoing double blind trial randomized 60 patients into four arms that received a placebo or 50, 100 or 200 mg of GW420876X once a day. Participants were antiretroviral-naive, had viral loads between 10,000 and 1,000,000 and CD4 cell counts over 200. Baseline characteristics between the groups were similar, with the median viral loads for each study arm ranging between 4.4 to 4.9 log (approximately 25,000-79,500 copies/ml), and median CD4 counts were above 300 cells. More than a third of the patients were women, and 48% were non-Caucasian.
On the first day, subjects received a "loading dose" double their randomized dose. During the first week, the drug's potency as monotherapy was evaluated; for the following three weeks, it was given in combination with AZT/3TC. At day seven, the median drop in viral load in the arms receiving GW420876X was 1.5 log copies/ml; there was no significant difference between the treatment arms. At day 28, 70-86% of patients on treatment had HIV RNA <400 copies/ml. The most common adverse events (in order of frequency) were headache, fatigue, nausea, flatulence and sleep disorders. (GW420876X readily crosses the blood brain barrier in animals, so one question about the compound is whether it will cause neurological side effects.) Most adverse events were mild to moderate, although one person had a serious elevation in ALT, a possible sign of liver toxicity, which resolved when therapy was discontinued. The two higher dose groups showed a trend toward increased adverse events, while there was no difference between the placebo and 50 mg groups.
Samjin Pharmaceuticals presented a couple of posters on a new NNRTI that also has activity by blocking viral attachment to the cell.(10) While mutations that cause resistance to the other NNRTIs also inactivate this molecule's anti-reverse transcriptase activity, it still exerts an antiviral effect in vitro via its anti-attachment mode of action. Yet, compounds that were "attachment" inhibitors in the test tube were some of the first ever be studied in people with HIV -- and not one made it to market.
And The Rest ...
At least a handful of other NNRTIs that promise to have activity again K103N mutant virus are in development. Agouron's AG-1549 is active against virus with single mutations in the reverse transcriptase enzyme, but two or more common mutations may defeat it. The drug is in phase II studies, but no new data were reported at either conference. Bristol Myers Squibb has purchased the development rights to UC781, a compound that shows activity at unusually low doses in the test tube, from Uniroyal. Now that Pharmacia & Upjohn has sold delavirdine to Agouron, it is not clear what the company will do with its second generation NNRTI, PNU-142721. And Sarawak MediChem Pharmaceuticals is still in the running with its rainforest tree derivative, Calanolide A.
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Lodenosine (FddA)
Lodenosine is a nucleoside analog much like ddI, with at least one significant advantage: It does not need to be formulated with an antacid buffer. In order to be absorbed into the bloodstream, ddI needs a buffer to help it survive transit though the stomach's acidic environment, and that buffer's ability to protect ddI is so tenuous that one has to be careful what else is in the stomach with it. Lodenosine, however, is impervious to stomach acid and can therefore be taken without dietary restrictions. Also in its favor, and frankly much more critical for people in need of salvage agents, it has demonstrated activity against nucleoside analog resistant virus, both in vitro and in clinical trials at the National Cancer Institute (NCI). Despite its promise, lodenosine's development at the NCI has been slow, though now it is in the hands of US Bioscience, a small company that developed trimetrexate for PCP. This company licensed the drug from the NCI and launched a moderate sized phase II randomized dose-comparative study about a year ago, but the company has nowhere near the resources of a larger pharmaceutical company.
Much to the surprise of the study's Data Safety and Monitoring Board (DSMB) the company released preliminary results from this on-going study at ICAAC. The members of the DSMB were not advised of this unscheduled analysis (which is highly irregular) and resigned, but the company's action can probably be chalked up more to lack of experience than anything else.
Initially, the data presented looked promising. The study was comparing three different doses (100, 200 or 300 mg twice a day) of lodenosine plus d4T/IDV to 3TC/d4T/IDV. Of 206 patients enrolled, 12 week data were available for 66, who had a mean baseline HIV RNA of 4.6 log (a little under 40,000 copies/ml) and a mean baseline CD4 count of 421 cells. At week 12, there was a 2.6 log decrease in HIV RNA for the lodenosine arms and a 2.3 log decrease in the 3TC arm, a difference that was not statistically significant. Fifty-nine percent of those taking 300 mg of lodenosine had HIV RNA <50 copies/ml, compared to 55% in the 200-mg arm, 50% in the 100-mg arm and 50% in the 3TC arm. CD4 cell counts increased by a mean of 53-117 cells in the lodenosine arms. The highest increase was seen on the lowest dose.
The adverse event rate was similar across all study groups. The most common were nausea, increased bilirubin and vomiting. Most of the toxicity was mild and not dose-related. Thirteen serious adverse events were reported, but at ICAAC, none were linked to lodenosine. Nevertheless, only a week later, US Bioscience announced that it was suspending the trial due to those serious adverse events and the death of a study participant.
Is it curtains for lodenosine? We are not sure. It is hard to say whether events that happen regularly in any trial spooked an inexperienced company or whether lodenosine has toxicity that had heretofore gone unnoticed. Some of the nervousness might stem from the fact that it is a fluorinated nucleoside analog like FIAU, which caused the sudden deaths of several patients in an investigational study for hepatitis. At the time, the deaths on FIAU came as a shock, but it has since become clear that there were many warning signs. One was that FIAU-treated woodchucks, which serve as an animal model for hepatitis B, were dying before the drug was ever put in humans.
But fluorination was not the cause of FIAU's morbidity, severe mitochondrial toxicity was. Since FIAU, the Food & Drug Administration requires evidence on a nucleoside analog's mitochondrial toxicity before it can go into humans. Lodenosine seemed very benign in preclinical trials, and there had been no reports of severe adverse events in the three years that the NCI had been studying the drug (which entered clinical trials as far back as 1996). In fact, the NCI has at least 12-month follow-up data on some patients.
At present, researchers are investigating what role, if any, lodenosine played in these adverse events. It is our hope that it played none and that this interruption in the development of lodenosine is will be brief. While it is important to take all necessary precautions, if lodenosine proves not to be the culprit behind these adverse events, its clinical development must resume.
Triangle Pharmaceuticals is concurrently developing a number of antivirals, led by emivirine (see Emivirine, above) and FTC, now called emtricitabine, a more potent and once a day version of 3TC (the only new data on FTC was in patients with Hepatitis B). Joining these now is dADP, a new guanosine (like abacavir) nucleoside analog. dADP is actually the prodrug of dioxolane guanosine (DXG), a compound with very potent activity against HIV and Hepatitis B virus (HBV). There were two posters on dADP/DXG at ICAAC.
The first presentation reported that DXG remains active against recombinant viruses and clinical isolates of HIV from people who have failed NRTI and NNRTI combination therapies.(11) The second poster further noted that DXG has a synergistic effect in combination with AZT, 3TC and nevirapine.(12)
Preclinical studies demonstrated that DXG had anti-HIV activity (EC50=30-290 nmol) at doses far below those toxic to cell cultures. Furthermore, no significant dose-limiting toxicity was observed in mice, rats and two species of monkeys administered doses up to 1200 mg/kg/day for one month. Of course, animals tend not to complain about pill burden, but the human equivalent of this dose for a 70 kg person (154 lbs.) would be 84 grams a day!
In vitro studies have noted that the development of a L74V mutation, which also occurs with ddI and abacavir, may lead to a four-fold shift in sensitivity to DXG, while a mutation at K65R (also seen with ddI, ddC and abacavir) can lead to an eight-fold shift in sensitivity. Given the drug's potency and wide therapeutic window, such shifts in sensitivity may not amount to much. However, a combination of mutations may lead to greater resistance and should probably be expected. Nevertheless, these mutations do not occur commonly in patients who take ddI or in the very infrequent patient who takes ddC. What happens in patients who take abacavir no one yet knows.
Triangle Pharmaceuticals is now conducting Phase I/II dose escalation studies of dAPD.
Biochem Pharma's dOTC is an NRTI that is similar to 3TC. Researchers assessed the pharmacokinetics, safety and antiretroviral activity in a double-blind, placebo-controlled phase I/II trial of dOTC monotherapy in HIV-positive patients.(13) Six groups of ten patients (eight given active drug, two placebo) were randomized into one of the following arms: 200, 300 or 400 mg of dOTC twice a day, or 400, 600 or 800 mg once a day. At baseline, mean HIV RNA was 4.35-4.93 log (approximately 22,400-85,000 copies/ml) and mean CD4 counts were 295-523 cells. The median change in HIV RNA at day 7 was -1.03 to -1.36 log copies/ml, and 63-100% of the patients had either a 1.0 log decrease in HIV RNA or <400 copies/ml. One grade IV adverse event, CPK elevation, was recorded, but it resolved itself during therapy. The most common adverse events were headache, lethargy and low-grade fever, and they were not dose-related.
While similar to 3TC, the M184V mutation appears to only decrease susceptibility to dOTC slightly (two- to threefold). Nevertheless, earlier studies have reported that some clinical isolates from 3TC-experienced patients are resistant to dOTC. What causes this resistance has yet to be worked out. It is could be that other common mutations, say to AZT or other nucleoside analogs, might render the drug impotent, as occurs with abacavir. Whatever the reason, it is important that the activity of dOTC be determined against virus that is resistant to multiple nucleoside analogs in order to see how useful this drug might be for salvage therapy.
Nucleotide Reverse Transcriptase Inhibitors (NtRTIs)
Gilead's adefovir diprivoxil (ADV), a nucleotide analog reverse transcriptase inhibitor (NtRTI), is presently under review by the FDA. Much of the data in support of adefovir's new drug application (NDA) were presented at ICAAC, only a few weeks before its FDA hearing. As we went to press, the FDA's Antiviral Advisory Committee voted not to recommend approval for adefovir at present, the first time an FDA advisory committee has ever said no to an anti-HIV drug's NDA. Will adefovir be relegated to the pharmaceutical dustbin? A misadventure on the road to tenofovir? More next month.
Tenofovir (Formerly PMPA)
With adefovir's fate in limbo, the success of tenofovir disoproxil fumarate (TDF) becomes even more crucial for its maker, Gilead Sciences. Fortunately for the company, not to mention the people awaiting new agents, in the most recent data presented in a late breaker at ICAAC, the drug has yet to evidence any of the problems that plagued its predecessor.
The data were drawn from Gilead 902, an ongoing 24 week, double-blind study in 189 treatment-experienced patients with detectable viral loads on antiretroviral therapy (LB 19). One of three doses of TDF (75, 150 or 300 mg) or a placebo were added to a stable regimen of four or fewer drugs that participants had taken for at least eight weeks. Baseline HIV RNA was approximately 3.7 log (just over 5,000 copies/ml) and baseline CD4 count was 376 cells. Participants were heavily pretreated with a mean antiretroviral experience of 55 months. Genotypic analysis revealed evidence of resistance to NRTIs in 94% of the subjects. Sixty-three percent had isolates with decreased susceptibility to one or more protease inhibitors.
All three treatment arms showed significant HIV RNA reductions when compared to the placebo arm. At week 24, the 300 mg arm achieved a mean reduction of 0.75 log copies/ml in viral load, compared to a 0.40 and 0.45 log drop in the 150 mg and 75 mg arms, respectively.
Safety data were available up to 48 weeks. Serious adverse events were reported in four patients (7%) in the 300 mg arm and for three (11%) on placebo. None of the kidney toxicity (proximal renal tubular dysfunction) seen with adefovir treatment was observed, nor did any patients experience elevations in serum creatinine of 0.5 mg/dl over baseline (a warning sign for severe nephrotoxicity seen on adefovir).
While a 0.75 log drop in viral load in such heavily treatment-experienced patients is impressive, tenofovir may have yet unrealized potential. Given the nephrotoxicity observed on the other nucleotides that Gilead has worked on, it is easy to see why the company may want to proceed more cautiously developing this drug, but the maximum tolerated dose of tenofovir has never been established, and higher doses may be even more active. In studies in macaques with SIV, PMPA injections achieved viral load reductions of greater than 2.0 log in under two weeks.(14)
Perhaps Gilead has compelling preclinical toxicology data suggesting that nephrotoxicity would emerge at higher doses. If not, we need to be certain that we are using the optimal doses in patients who are failing their third or fourth regimens because incompletely suppressing viral load will lead to resistance and eventual treatment failure. Remember that long before 48 weeks (after 24, in fact), there was clear evidence of kidney toxicity on adefovir. Here there is none. Higher doses should be evaluated for patients failing currently available therapy, particularly in light of the fact that a small number can now get the drug on expanded access (see Tenofovir Compassionate Use Program in this issue).
Fusion Inhibitors
T-20 (Pentafuside) and T-1249
T-20 is the first fusion inhibitor, an entirely new class of antiretrovirals, being developed by Trimeris Pharmaceuticals in partnership with Hoffmann-La Roche. The compound mimics one of two coil-like segments of HIV-1's gp41 envelope protein that play a critical role early in the process of infection. After the virus latches onto the CD4 receptor, these two coils become exposed and twist around each other, pulling the gp41 protein taut and erect so that it can penetrate the cell membrane. Acting as a decoy, T-20 interferes with this intertwining, and the flaccid gp41 protein is unable to inject the viral core into the target cell. The synthesized drug is a large protein, composed of 36 amino acids. While potent at low doses, it must be administered as a subcutaneous injection.
With such a distinct mechanism of action, the drug is active against virus that has developed high level resistance to each of the other classes of antiretrovirals currently available. Thus its development is a life and death issue for people who need salvage agents. To the credit of Trimeris, the company has made salvage therapy the focus of the drug's development; but T-20 is costly to make and until the recent collaboration with Roche, resources for the young company have been limited. Still, Trimeris has been able to mount a few studies.
Sixteen-week results from the most recent of these studies were presented during a late breaker session at ICAAC.(15) This is an ongoing single-arm, phase II study of T-20 (pentafuside), self-administered as a subcutaneous injection. The study enrolled 71 HIV-positive adults who were heavily pretreated: patients had a median of 11 previous antiretrovirals, 93% had exposure to the three available drug classes, 93% showed genotypic evidence of protease inhibitor resistance and 87% had mutations related to reverse transcriptase inhibitors. The median number of NRTI and protease inhibitor relevant mutations was four and five per patient, respectively. To top it off, all participants had previously been briefly exposed to T-20 therapy as well, in earlier phase I/II studies. In fact, access to T-20 in this study was in a sense a reward for participation in the shorter trials.
At baseline, the median HIV RNA was 4.9 log (about 79,500 copies/ml) and the median CD4 count was 70 cells. Subjects took 50 mg of T-20 twice a day in addition to an individualized regimen consisting of a median of four oral drugs chosen on the basis of each patient's history and genotypic results. At week 16, data were available for 55 of 71 patients. In an as-treated analysis, 60% (33 of 55) had a sustained decrease in viral load of >1.0 log or were below 400 copies/ml, 36% (20 of 55) were below 400 copies/ml and 20% were below 50 copies/ml. In an intent-to-treat analysis, 55% had a 1.0 log reduction in viral load, and 33% were below 400 copies/ml. The average decrease in viral load was greater than 90% over 16 weeks. Most adverse events were mild to moderate, and they included irritation at the site of injection (67%), fever and headache. This study will continue to 48 weeks. A phase III trial is expected to begin in 2000.
Without a control arm, it is impossible to measure the relative contribution of T-20 to the antiviral suppression in these patients. It is possible, though, that T-20 furnished the lion's share of antiviral effect, bearing in mind the extent of these patients' pretreatment. But are these responses sufficient? While 30% to 40% below 400 copies/ml might be what we have come to expect from "mega-HAART" regimens in salvage populations, this regimen included a very potent drug from a new class of agents. As prior therapy included T-20, either given as a monotherapy or added to stable failing HAART regimens, it is reasonable to assume that at least some patients had developed some resistance to T-20. Further study of this cohort should demonstrate the frequency of resistance.
Yet, much of the resistance might have been preventable with a different T-20 dose. In the earlier dose-ranging studies of T-20, there was a clear dose-response to the drug, which peaked at the highest dose tested, 100 mg bid -- twice the dose currently under evaluation. Why did Trimeris not proceed with the 100 mg bid dosage? For one, this is a costly agent to synthesize and will likely be quite expensive when it is marketed. Consider the cost of other recombinant proteins such as IL-2 or EPO, which cost tens of thousands per year. Aside from the issue of cost, there is a limit to how many injections a person can take. But, at the risk of sounding monotonous, there is a danger that the doses being used are suboptimal. In fact, even 100 mg bid may be inadequate. There is no way of telling since that was the highest dose ever tested.
Given Roche's experience with the suboptimal Invirase dosage and formulation of saquinavir, one would expect them to think twice before moving forward with another antiretroviral without determining the maximum tolerable dose, but this is exactly what the companies are doing. As it is presently formulated, each shot can only deliver 50 mg of T-20, so a 100 mg bid dose would require four shots a day. This may indeed be too much for a patient to tolerate. Still, no study has addressed the question. And if it is the cost of therapy that is indeed the dose-limiting factor, how much is cost-prohibitive? Is $15,000 too expensive? $30,000? Just how expensive are we talking? At present, neither company is anxious to say.
Regardless of the cost, according to Roche's International HIV Medical Director, Dr. Neil Buss, a higher "induction" dose trial is being considered. The question is, when? Right now, the plan is to wait until post-marketing.
Trimeris and Roche may be betting that T-20 will not be the last "shot" for failing patients in this study. The companies are developing a second fusion inhibitor, T-1249, that is active against T-20 resistant virus in vitro. A poster in Lisbon described preclinical studies with this slightly larger peptide.(16) Preliminary dosing studies in monkeys demonstrate a longer half-life for this compound, suggesting that a once-a-day subcutaneous regimen might be possible. A phase I dose-ranging study is now enrolling.
- Abstract 657.
- Abstract 916.
- Abstract 917.
- Abstract 502.
- Abstract 201.
- Abstract 1173.
- Abstract 1172.
- Abstract 332.
- Abstract 504.
- Abstracts 925 and 926.
- Abstract 924.
- Abstract 932.
- Abstract 503.
- Bischofberger N et al. 9th ICAR, Japan 30:A42, 1996.
- Abstract LB-18.
- Abstract 319.
Back to the GMHC Treatment Issues September/October 1999 contents page.


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Posted on Aug 27, 2013
Homework for Seniors and Projects to Do at Home with In Home Care for the Elderly
School days have started for many communities around the country. Routine of getting up in the morning and preparing for a day of learning has returned. Autumn is fast approaching and crisp weather will soon be upon us. You may feel a little reminiscent about the days when you were in school. Just because you are no longer school age does not mean you can't continue to learn and participate in educational activities. This is also especially important to remind an elderly loved one who may feel like their days are running into each other that they could really benefit from the joys of learning something new each new day.
The dog ate my homework. Nearly everyone has heard of this expression. You may even remember that feeling of being in class and creating an excuse for why your work wasn't complete on time. We thought it would be fun to create homework ideas for your elderly loved one. These ideas will help your loved one feel more engaged and may even spark new interest in subjects they may have forgotten how much they love!
One example of homework for your elderly loved one is journaling. Give your aging loved one a journal and ask them to write an entry every day of the week. They can write about anything they desire. I remember in school when my teacher would ask us to free write. We basically would allow a stream of consciousness to flow out on paper. This helped us to find creative ideas to write about. At the end of the week, give your loved a special treat, and read their entries out loud with them, if this is okay with them. If they would prefer that their entries be kept private, that is okay too.
Another homework assignment to give to your senior loved one is an art project. Take your senior to a local park or cityscape downtown and have them sketch or paint what they see. Remind them that art is in the eye of the creator so it does not have to be perfect. An abstract painting would work just as well serving as art.
Another fun homework assignment could involve reading. You and your loved one could even form a mini book club between the two of you and can meet up to discuss the book together. Pick out a book together, read a chapter a day, and sit down to discuss over tea or coffee. You may find your loved one's perspective on the same book to be rather fascinating. This may even inspire your elderly loved one to recite old stories of their past. You may learn something about your senior loved one that you may not have otherwise discovered.
This time of year, when cooler weather is approaching and children return to school, remind your elderly loved one that you don't have to be school age to continue learning. You don't even have to be in school to discover something new and exciting. These simple homework assignments will help your loved one to stay mentally active and may even maintain a more positive outlook on life.
If you would like to learn more about in home senior care and in home dementia and Alzheimer's care, call Senior Helpers of Fountain Valley to speak to a senior care specialist today 714-593-1177! Senior Helpers of Fountain Valley provides a wide range of services including Alzheimer's and dementia care, personal assistance, companionship, and so much more to all areas of Orange County, Huntington Beach, Fountain Valley, Costa Mesa, Laguna Hills, and Laguna Woods, California.


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A few friends have asked about financially supporting our move to Peru. I will be honest. It is very hard for me to ask people to support us financially and then live on others' financial support of us. When we left full time ministry 3 years ago, I actually swore that we would never ever raise support again. We did not have a good experience.
Thankfully, I have grown a lot in the past 3 years. I have also come to realize, personally, what a JOY it is to give money away. Riley's decision to raise money for clean water profoundly changed me. From my past fundraising experience, I thought we would have a hard time raising $2,500, so that is all we asked Riley to raise. And then, something beautiful happened, our friends gave $15,000. It was the first time that I saw people giving joyfully and freely. It changed me and prepared me to say "yes" to our current adventure. I realized that there is never any harm in asking. I love being told of new organizations or movements that are helping people and I love giving to them. I also realized that by NOT asking we could be missing an opportunity to be blessed and to be joined in our journey. Because we can't do this alone.
So, here we stand asking for financial help. I have said it before, but we would never ask for financial support of an organization that we did not believe in wholeheartedly. We believe in this program enough to move our family of 6 to a foreign country! We need to raise $60,000 for seed money to start the Krochet Kids program in Peru. By 2014, this program will be completely self-sustaining and we will not need to raise any more money.
Want to know more about what you are giving to? Krochet Kids offers 3 year programs to women living in poverty. In this program, the women learn to krochet hats to earn an income and be able to fully support themselves for the first time in their lives. In fact, the 87 women in the Ugandan program are supporting over 400 dependents! This program literally changes lives. The women are also taken through a specific program with training in personal budgeting, saving, loaning practices and business skills. After the 3 years, the women will have enough knowledge, training, and education to start a small business or get a sustainable job in the work force. The aspect of the program that I am most excited about is walking alongside these women and doing life with them. Women living in poverty have been sold a lie their whole lives- they have been told that they are worthless. I cannot wait to shatter that lie and let these women know how beautiful and loved they are! They will come to see the power that they have inside of themselves to change the course of their lives. They just need someone to give them their first opportunity.
You can visit Krochet Kids' website here to meet the women in Uganda and learn more about the program. I can't wait until there are women from Peru on there! We will start with 10 women the first year and we dream of eventually reaching hundreds of women.
You can also watch this video we made if you're more of a visual person.
And if you want to give to Krochet Kids to start the program in Peru, you can go here. Please indicate under "Purpose" that your giving is for the Goodfellows/Peru. If you want to give through check or any other offline method, please email me at bsgoodfellow (at) gmail (dot) com. You can also email me if you want any more information on Krochet Kids or to discuss anything.
As soon as we get this money raised, we will be moving to Peru! Thank you for reading our blog, following our journey, and letting me ask you for money.


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Double disk ripper Harley Ellington, product manager for Wil-Rich, says farmer input was the primary impetus for the design of the company's new V957 DDR Double Disk Ripper. "Too much trash was being left on top," he says. "We've got the solution."
The V957 combines the cutting action of a disk with the deep penetrating work of a ripper. Hydraulically controlled disc gangs allow for individual depth adjustment on the go. Walking tandem axles maintain an even depth penetration. The disc gangs have 28-in. notched blades mounted on 15-in. spacings. The gangs are offset, allowing for more uniform cutting, mixing and incorporation of crop residue.
Behind the discs, the ripper is equipped with auto-reset, 11/4-in., high-strength, abrasion-resistant steel shanks with a chromium carbide shin. The "smooth action" shanks have 5,000-lb. trip pressure with 16 in. of trip clearance. Contact Wil-Rich, Dept. FIN, Box 1030, Wahpeton, ND 58074, 800/688-3300, www.wil-rich.com or circle 200.


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freakingidiot wrote:When is the estimated shipping date?
Production is expected to be finished in early May. For more details check out the latest post on the homepage.
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Blunder122 wrote:I just found out about this and was wondering if there is going to be another printing or if any books are still avalible because this is something i want to buy.
Turkeyman wrote:Hi, I sent an email to email@example.com requesting an address change, but haven't gotten a response yet. Just want to make sure that the email got through. It was sent on March 20th.
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A Treasured Nintendo Classic Arrives on the Wii System.
The second game in the fan-favorite Pikmin franchise originally launched for the Nintendo GameCube console in 2004. Now Wii users can enjoy the imaginative fun of this classic and colorful mass action strategy game, now available as part of the value-minded, family-friendly Nintendo Selects series. The brave Captain Olimar has returned to marshal new types of Pikmin in a wild, open-ended adventure. On a mission to pay back his employer's debt, Olimar and his sidekick Louie must command squads of tiny Pikmin to help locate valuable treasures, exploring mysterious environments and battling pesky enemies along the way. Players of any experience level can use the Wii Remote and Nunchuk controllers to command these curious creatures and complete their mission. The game also invites friends to deviously pit their Pikmin squads against one another in a rough and ruthless two-player mode*.
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Max Recycle is one of the North's biggest private waste and recycling specialist and we are now in the Lakes too. We have been operating in the area for some time and are delighted that we are expanding our business waste management services further into Southern Lakeland. Small, medium and large business, hotels, caravan sites and rental property owners can all benefit from using Max Recycle for their regular business waste. Our company offers you the opportunity to save money and help make recycling easy.
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Business Waste Collection in Brigsteer
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The history of Christmas should make us ponder. Christians had no Christmas for more than 200 years after Jesus was born. The origin of the feast had nothing to do with the birth of Jesus because no one knew when he was born.
Bible scholars inform us of contradictions and impossibilities in the biblical accounts contributing to the myth, the Gospels of Matthew and Luke (the authors actually are unknown, but that's another story). Rev. E. J. Niles, a scholar quoted in Unity magazine, says,
I love how Joseph was said to take his pregnant wife Mary 94 miles to Bethlehem to fulfill a type of civic duty (a census) that most women would never have even participated in during those times.Also factual nonsense are the genealogies in Matthew and Luke, which disagree with each other, as do their implied dates of Jesus' birth. Quirinius was governor after Herod died, not before.
But we don't need Bible scholars to tell us that the manger myth lacks facts; any intelligent reader can infer its disagreements with science and history. Myths are not about facts; they're about meaning.
Not until the third century, at the earliest, did Christmas begin. It developed in competition with Pagan feasts observing the birthday of the sun on the winter solstice, when the sun "dies" as daylight reaches its shortest point and then is reborn or resurrected as daylight increases. The Romans celebrated Sol Invictus, the Unconquered Sun, "whose annual journey across our sky can be celebrated worldwide as a truly unifying expression of our global family." This last lovely sentiment comes from Acharya S., an atheist writer. I note this to banish Christian notions that we own Christmas exclusively.
The earliest written record of Christmas appeared in 336 CE, and in 354, a calendar entry for December 25 listed the births of both Sol Invictus and of Christ in Bethlehem of Judea. This double notice provides an example of syncretism, the melding of religious ideas, which, contrary to Christian claims, occurred often in our tradition.
Before the earth was known to be a revolving sphere, the sun mysteriously disappeared in the west every evening, followed some unknown course below earth during the night, then reappeared in the east every morning. Naturally this cycle of nature inspired mythmaking. The Goddess enveloped the sun in her body in the evening and sent it forth in the morning. The Greek sun god Helios crossed the heavens from east to west in a shiny chariot, descended to the underworld, and was "born anew every morning," sang the poet Horace.
The sun's daily descent and ascent also provided rich Christian symbolism. Surrounded by and steeped in Greek myth, Christians of the early centuries imagined Christ journeying to the underworld and rising in the east. "As the sun rises daily for all, so the mystical Sun of Righteousness rises for all," sang a Christian verse. In ancient records Christ was listed as one sun deity among several.
Pagans called their birthday feast of the sun god "Epiphany," meaning "appearance." The Pagan Epiphany happened on January 6, which also became the date of the rival Christian feast celebrating Christ's appearance in the flesh, showing Christmas to be one solar celebration among several.
Calendar adjustments moved the winter solstice to December 25 and later to December 21. Some quarreling between Christians in East and West broke out when the East continued to observe the birth of Christ on January 6 after the West switched to December 25. Today Eastern Orthodox Christians still celebrate Christmas on January 6.
Because of its Pagan origin, the Puritans did not celebrate Christmas at all, and a few other Christian groups have discredited Christmas for the same reason. But that would also disqualify Easter, All Souls Day (Halloween), and other Christian feasts related to Pagan holidays.
For thousands of years before Christians took over solstice celebrations, human cultures developed myth and ritual to mark it. Huge bonfires were an important part of such events. We can easily imagine that before artificial light existed, the annual shrinking of light down to the shortest day of the year, followed by the steady growth of light foretelling spring, would have had a huge impact on human life.
Today we see the human impulse to light up the darkness in the riot of artificial lighting from November to January. The lights are not necessarily related to the Christian festival, as few people in the West believe the manger story literally anymore.
But for good reasons we continue singing songs that repeat and embellish the myth. There must be something besides commercial value that makes Christmas precious to more than believing Christians. The birth of the Child represents the birth of the precious Self inside each of us, the Christ consciousness in every person—the urge to give generously, the warm feelings of unity with all. This, I believe, is the enduring value of Christmas.
Christmas message, December 26, 2008
Here's my Christmas message along with my consoling philosophy/faith. I learned 28 years ago that I could reconcile my knowledge of Christian myth with my need for spiritual solace by trusting in a Higher Power. It shows Its face in interesting ways when I give myself over to Its guidance.
I was planning to drive somewhere on Christmas Day, having spent Christmas Eve with my son and daughter. In various ways I was prompted to change my mind, sure that it was best to stay home. I prepared to enjoy music and reading. But a friend in emotional need called and we spent much of the day together. I could not have been there for her, had I insisted on my original plan instead of being attuned to the subtle prompts diverting me from that plan.
This sort of thing happens to me often—an inner thread pulling me through the little and big decisions of life. Others attuned to a Higher Power, whether they respond to Jesus or another name, will not scoff at this.
I don't consider this a late Christmas message. When I was growing up we started the Christmas season on December 25, and it lasted through January. The Advent period before that really did await the day when celebrations would start. On Christmas morning we woke up to the miracle performed by Christ Kindchen the night before. He brought our presents, trimmed the tree, made Christmas cookies—everything. When a school classmate told me slyly that Santa Claus was fake, I was surprised that he'd ever believed in silly Santa Claus. It did start the wheels in my little brain turning with regard to belief in the miracle.
I resent consumerism for stealing Christmas. On this day after December 25, radio stations refuse to play Christmas music anymore, the inspirational, meditative music appropriate to this dark and wintry transitional time between the old and the new. Professional musicians and singers who perform the music know its text is based on myth but appreciate our spiritual heritage. But the commercial world has convinced Americans that material stuff makes up the whole purpose of life. No more buying presents after the 25th, so no reason to play Christmas music. Despicable reasoning.
I wonder what the purveyors of consumerism think "The Twelve Days of Christmas" are about. The twelfth day was Epiphany on January 6, which was the Roman Empire's winter solstice until a calendar adjustment moved it to December 25. Pagan religions celebrated the birth of the sun on this day and Christians established a rival feast to celebrate the birthday of their "true sun." When the solstice moved to the 21st in another adjustment, Christmas stayed on the 25th in the West, but Eastern Orthodox still celebrate Christmas on January 6.
Dates and names are less important than the theme of death and renewal—Easter's theme. For this reason it was a more important Christian feast than Christmas, before consumerism stepped in. Enough of that.
May the economic downturn direct us away from material things during the following year and toward healthy, loving relationships. This is my Christmas wish for all.


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Evening classes canceled Feb. 7, 2018. Learn more.
Home | Academics | Our Schools | Conservatory of Performing Arts | Conservatory News & Features
Nelson Chipman, graduate program director and associate professor, gave a presentation titled "Production Companies, Entertainment and Transmedia Studios in Academic Programs: Models, Experiences, Outcomes," at the annual Broadcast Education Association conference, held April 5-9 in Las Vegas, Nev.
Chipman addressed the group of industry professionals to talk about Point Park's involvement on "The Chair," a documentary series that follows two up-and-coming directors as they compete to make the best feature film. The series will air on the Starz network this fall.
"My key message was expressing the student and alumni benefits of Point Park partnering with an outside group to produce a documentary series and two feature films. When you look at the scope of these productions, they provided a spectrum of opportunities for students to engage in real-world production environments and for alumni to find professional work," said Chipman.
"The Chair" is being produced by veteran Hollywood producer Chris Moore, and Pittsburgh native and renowned actor Zachary Quinto. More than 100 students and alumni supported the project as interns, employees and through class projects.
"The positive feedback that I received about our students that worked on this project emphasizes that they are going to be creative, active members in the film production industry after they graduate," added Chipman.
The BEA is an international academic and professional organization dedicated to multimedia enterprises and electronic media.
Explore the cinema arts program at Point Park University.
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Want more for the Pirates of Drinax? Stand by for the 'missing' Patrons expansion, Lions of Thebus which you can grab right here: http://www.drivethrurpg.com/product/222 ... te_id=7242
The Travellers are engaged by an Aslan lord to rescue his missing son Ftahteas from the world of Thebus. Ftahteas has fallen victim to local conditions and is in grave distress, not least since he is being hunted by Aslan-hating humans who intend to claim they mistook Ftahteas and his followers for local wildlife. The rescue attempt leads the Travellers to one of the old cities of Thebus, bombed but not quite destroyed in the last days of the Sindalian Empire. The biggest obstacle to the rescue, however, is Ftahteas himself.
Lions of Thebus expands one of the Patron encounters in the Pirates of Drinax campaign into a full adventure, though it can be used in any Traveller campaign.
Mongoose News - Lions of Thebus
General chat about Mongoose Publishing and its releases
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Mongoose News - Lions of Thebus
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Mongoose Publishing
Re: Mongoose News - Lions of Thebus
This looks good. Give good and honest opinions and, if allowed, reviews and I may even decide to get this instead of Liberty Pot with the money I've saved, but I'll still have both by mid May at the very latest
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Good nutrition is key for a fit pregnancy and healthy baby development. A well-balanced, healthy and eco-friendly pregnancy diet includes USDA certified organic foods and beverages and/or locally grown food that's been minimally processed. Avoid artificial colors and flavors. Also try to avoid canned foods and processed foods; eating fresh when possible. At the very least avoid processed foods that contain ingredients you can't pronounce. Your first trimester is an excellent time to jump on board with healthy eating. Your baby makes some important developmental leaps during the first trimester, plus, the sooner you get into the habit of eating right, the better, for both you and your baby. Keep reading to see some organic power foods for the first trimester.
Organic Sweet Potatoes
Organic sweet potatoes, in my opinion, are one of the world's most perfect foods. Babies love pureed and mashed sweet potatoes, toddlers love sweet potatoes as finger food and yes, adults adore them as well. Sweet potatoes are ultra healthy and almost entirely fat-free. Just one cup of sweet potato has as much vitamin A as 16 cups of broccoli and is a great source of iron, vitamin E and dietary fiber.
Sweet potatoes are also perfect for pregnant women. Potatoes and related veggies are known to ease morning sickness symptoms. Additionally, sweet potatoes are chock full of potassium; an important mineral for pregnant women. Potassium helps your body maintain correct fluid and electrolyte balance. It also helps your muscles contract, keeps your blood pressure stable and allows your body to release the right amount of energy from protein, fat and carbs. In addition, potassium also helps reduce swelling and leg cramps – both typical problems for many pregnant women.
- How to Prepare Sweet Potatoes
- Difference Between Sweet Potatoes and Yams (for the hyper curious).
Remember Organic Red Produce
Pregnant women should have at least 85mg of vitamin C daily. Vitamin C helps to strengthen your body's membranes, including the amniotic membranes. Later on, having strong amniotic membranes means you're more likely to avoid preterm labor. You don't have to OD on oranges to get vitamin C either. Vitamin C is found in all sorts of foods, but if you need an easy way to remember which foods in particular are vitamin C-rich, go with red produce. Most red produce contains higher than average amounts of vitamin C, so stock up on delicious red strawberries, red bell peppers, ruby red and dark red citrus fruits, tomatoes and other red produce delights.
Organic Whole Grains
Pregnancy is not the time for white, flavorless bread, especially if you're experiencing morning sickness. Women with morning sickness should concentrate on the least offensive, most nutritious foods possible. Basically, if you can't keep much food down, it makes sense to make every bite count, and white processed grains don't count for much. An added benefit of eating whole grains is folic acid. Folic acid helps prevent birth defects and is available in whole grain food sources like fortified grains, pastas and breakfast cereals. The following whole grains aren't too offensive if you have morning sickness, and pack a healthy punch, even in small amounts.
- Organic whole grain crackers – try with a wee bit of organic peanut butter, organic hummus or organic jam.
- Organic whole wheat toast slices or a small whole grain bagel.
- Steamed organic brown rice.
- Organic oatmeal.
Organic Spinach
Iron is vital for a healthy pregnancy but it's hard for most women to get enough. In fact, iron-deficiency anemia affects about 20% of all pregnant women. Luckily, fresh organic spinach makes it easy to sneak in extra iron. Spinach is jam-packed with iron, but is also rich in calcium, folate, magnesium, vitamin C and vitamin A. You can add spinach to spaghetti sauce, smoothies, homemade soup, salad or any casserole you choose. Spinach goes with so many things. My favorite spinach dish is Black Bean Chilaquile – everyone I've ever met loves it and you can add extra spinach to it, plus make it vegan or low-fat if you choose. You can also try a spinach frittata, quick spinach and tomato pasta, or easy sauteed spinach. That said, even though spinach is a top source of iron your body can't absorb all of the iron it provides. So you'll still need iron from other sources like beans, and when paired with a vitamin C source such as tomatoes, you'll be able to get even more of the iron benefits.
Organic Milk
Studies show that mamas who get lots of calcium during pregnancy have significantly higher bone density than mamas who miss out on their daily calcium requirements. Pregnant women need about 2,000 mg of calcium per day. A glass of 1% or fat free organic milk has around 300 mg of calcium – just make sure you're drinking real organic milk. A report by The Cornucopia Institute, the Dairy Report and Scorecard, shows that some organic milk companies have inadequate organic policies in place. Check out the dairy rating report to find out which organic dairy companies have the best (and worst) organic practices. For example, Organic Valley milk (shown above) gets an excellent score while Horizon Organic Dairy gets a terrible score for using factory farm-like practices.
Milk offers a super easy calcium fix, but if you hate the taste of milk or if you're lactose intolerant or vegan there are plenty of other calcium rich food options to choose from.
Six + Organic Veggies & Fruits Per Day!
When you're pregnant, you need lots of veggies and fruits each day. Aim for six + servings, but more won't hurt you. Fresh organic produce offers untold nutrients for you and your growing baby, can ward off upper respiratory tract infections, plus produce fills you up, without packing on too many excess calories (you only need about 300 extra calories a day while pregnant). If you're having trouble fitting in veggie and fruit servings, try adding extra produce to the foods you already eat. Some ideas:
- Salsa with whole grain crackers.
- Baked potatoes covered with other steamed veggies and some shredded cheese.
- Fun new creations, like rainbow salad.
- Make veggie or fruit ice pops.
- Add more veggies to soups or sauces, like a tomato-based spaghetti sauce.
- Keep tempting produce washed, cut and ready to munch, in small bowls in the fridge, for example, cold sweet peas, tangerine slices, raspberries or fresh green beans.
- Make veggie burritos on whole grain tortillas packed with beans, brown rice and lots of veggies – sliced bell peppers, carrots, mushrooms and salsa.


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Home > News & Events > Wayland Press Release Archives > 2001 Press Releases > October 2001 > Loudat to present senior recital at Wayland
Loudat to present senior recital at Wayland
Wayland Baptist University senior Mary Loudat will present her senior music recital at 7:30 p.m. on Saturday, October 27, in Harral Memorial Auditorium.
A native of Albuquerque, NM, Loudat is a music education major with voice emphasis. Jennie Lynn Hodges, associate professor of music at Wayland, serves as her private voice instructor.
During her recital, Loudat will sing a variety of selections. Her program will include "Intorno all idol mio," "Muss es eine trennung," "O Liebliche Wangen," "Casta Diva," "Flower Duet (Lakme')," "Mon Coeur S'ouvre a ta voix," "Mary is a Grand Old Name," "I Could Have Danced," "Dido's Lament." Mezzo soprano Miriam Wilcox will be featured in two numbers and guest artist Bobbie Mann will appear for one.
The recital is free and open to the public.


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(YouTube link for mobile viewing)
Since the beginning of this year, we've been working with The 99 Percent – a group of very dedicated New Yorkers who are passionate about helping creative workers execute better. At the helm is Scott Belsky, author of "Making Ideas Happen" – a great read for ANYONE with ideas!
Recently, The 99 Percent's Jocelyn Glei wrote On Keeping it Simple – explaining three different practices that can help simplify everyday tasks, distractions and as Jocelyn writes "brain clutter".
With all the brain clutter around mobile solutions, we thought we'd simplify things a little bit by creating two new videos explaining how the BlackBerry® solution can help you and your business communicate better. "Start Your Business" and "Grow Your Business" are each tailored to talk you through the different mobile tools that can help you get more done, and simplify your communications.
(YouTube link for mobile viewing)
Hope you'll check them out and let us know what you think!


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Employee in Massachusetts Gas Explosion Did Right Thing
SPRINGFIELD, Mass. (AP) - The president of the gas company behind an explosion in Springfield, Massachusetts that injured 21 people says the employee blamed for piercing a gas line followed proper procedure and protocol.
The blast Friday that leveled an adult entertainment club and damaged 42 buildings was blamed on "human error." Investigators say the employee was following incorrect markings on a sidewalk that indicated the location of the gas line.
Columbia Gas of Massachusetts President Steven Bryant says the unnamed employee was following standard company procedure when he responded to the smell of gas.
Bryant said the employee had the presence of mind to order an "appropriate" evacuation of the building.
Columbia plans to open a claims center at City Hall on Monday for residents and businesses affected by the explosion.
Copyright 2012 by The Associated Press. All rights reserved. Material may not be redistributed.


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Rep Steve King Announces Hearing on English as Official Language
Known for his hard-line stance on immigration, Rep. Steve King, R-Iowa, resurfaced Wednesday the debate over whether English should be the official language of the United States.
King announced that a Judiciary Committee hearing on the Official English Act, legislation that King has championed since 2003 when he was sworn into Congress, will be held next week.
"The Judiciary Committee hearing next week reflects the need to get a vote on the floor of the House of Representatives on this popular issue- 87 percent of Americans say that English should be the official language of the United States," King said in a press release.
The Official English Act, H.R. 997, would make English the official language of the United States – something that the U.S. currently does not have – requires the federal government to encourage individuals to learn English, requires all functions of the government be conducted in English and establishes a language requirement for people to become naturalized citizens.
"A common language is the most powerful source of unifying force for any nation," King said. "Over the course of history, common languages have created cohesive cultures and have helped prevent division."
English as the country's official language has been a hotly debated issue since the 1980s and has come up during many of the last presidential elections. King and other supporters of the claim that an official language would advance political unity based on linguistic commonality, while critics argue it is a ploy based on people's irrational fear of immigrants.
A common language is the most powerful source of unifying force for any nation...Over the course of history, common languages have created cohesive cultures and have helped prevent division.
"'English Only' laws, which declare English to be the country's official language and bar government employees from providing non-English language assistance and services, are inconsistent with both the First Amendment right to communicate with or petition the government, and the right to equality," wrote the American Civil Liberties Union. "They are also unnecessary and sometimes even dangerous to both individuals and the public."
King – who is running for reelection against Democrat Christine Vilsack – previously enacted legislation that established English as Iowa's official language when he was a member of Iowa's Senate
As the vice chairman of the House immigration subcommittee, recently made waves again when he drew parallels between attracting the best from around the world to emigrate here, and picking the best dog of a litter. His critics said King was again showing what they say are his denigrating views of immigrants.
"In my house, we have raised really good, high-quality Labrador Pointers, we've received the pick of the litter from all over the planet. You pick the vigor, the most perky. It was the utilization of the pick of the litter. What is the pick – the alert, the frisky, that's the one you want," King said during an interview with Fox News Latino. "If someone is insulted by that, I don't know that they belong in this country."
The Judiciary Committee hearing will take place next Thursday and is a continued effort on the part of King to get this legislation passed.
"I've introduced the Official English Act every session I've been in Congress because I know that an official language will keep this nation bound together and I look forward to next week's hearing," King said. " Now we need to get Official English passed into law."
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