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Dual Protease Inhibitors Gain Ground
- Adding Ritonavir to Boost Saquinavir
- Once-Daily and Twice-Daily Regimens with Indinavir Plus Ritonavir
- Kaletra: Abbott Joins the Bandwagon
- Bringing Amprenavir Back from the Edge
- What Is the Real Benefit?
- Selected Sources
The past couple of years have seen a marked increase in the use of combinations of highly active antiretroviral therapy (HAART) that contain two protease inhibitors (PIs), usually ritonavir (Norvir) plus another PI. Ritonavir's function is not primarily to further contain HIV but rather to increase the blood levels of the second PI, decrease pill burden, simplify dosing schedules, and thereby improve drug adherence.
Back in the early 1990s, PI developers at Abbott Laboratories faced a major problem. Their initial molecule, A77003, potently blocked HIV in the test tube but broke down rapidly in the body. Its half-life was only 30 minutes (the half-life is the time required for half of the amount of an agent to be eliminated from the body). Even 24-hour infusions could not maintain adequate blood levels, and they caused severe vein irritation at the infusion site. In response, Abbott's scientists altered the structure of their molecule. (Among other things, they changed the hexagonal carbon-nitrogen rings at each end to pentagonal rings that also included a sulfur atom.) The change yielded a molecule that was more than a potent inhibitor of the HIV protease enzyme. It also strongly inhibited the CYP3A4 liver enzyme that breaks down A77003 as well as many other drugs.
The U.S. Food and Drug Administration (FDA) approved Abbott's revised PI, ritonavir, on March 1, 1996, two weeks before it approved indinavir (Crixivan) and less than three months after saquinavir (first marketed as Invirase and later, in a revised formulation, as Fortovase). Even though the recommended dose was 600mg twice daily, ritonavir found few customers due to its wide range of disturbing side effects at that dose. These included numbness around the lips and on patches of skin, increases in blood lipids (fats), high blood levels of liver enzymes (a sign of liver damage), diarrhea, and stomach upset (including regurgitation of the extraordinarily bitter ritonavir).
Indinavir and saquinavir both had their own problems. One was familiar to ritonavir's developers at Abbott: relatively low blood levels. Saquinavir performed very well in lab tests, but in the Invirase formulation, it was absorbed inadequately in the body (only 4% of each dose was absorbed) and almost totally metabolized by the liver immediately after digestion. Invirase was therefore weakly effective in humans, performing about the same as ddC (Hivid) monotherapy. The newer Fortovase formulation, which came on the market two years later, was absorbed to a greater extent than Invirase, but this required ingesting six large capsules three times a day.
The dosage of indinavir (800mg every eight hours in two or four capsules) was limited by indinavir's penchant to concentrate and precipitate, or collect in solid form, in the kidneys during excretion, causing a painful condition known as nephrolithiasis, or kidney stones. Meanwhile, the liver as well as the kidneys efficiently remove indinavir from the body such that blood levels subside by 98% before the next dose is scheduled to be taken. Indinavir's minimum blood levels therefore are so low in some people that the drug's effectiveness can be markedly impaired; for this reason the drug must be taken every eight hours around the clock. While monitoring drug levels (also known as therapeutic drug monitoring, or TDM) may be potentially beneficial, no therapeutic window -- the precise range of drug levels that are effective without being toxic -- has yet been determined for PIs or any of the other anti-HIV drug classes. And if intracellular drug levels of PIs (i.e., drug levels within cells) turn out to be more important than blood levels of the drugs, monitoring blood levels will not be useful. (For more information on TDM, see "Therapeutic Drug Monitoring" in the Autumn 2000 BETA.)
Indinavir levels also vary greatly from person to person and even in the same person from day to day. A recent study of the AZT (Retrovir)/3TC (Epivir)/indinavir combination in Thailand found that indinavir blood levels were of marginal efficacy in a quarter of the trial participants. In a one-year Dutch study of persons taking AZT/3TC/indinavir, virologic relapse (increases in viral load) was more frequent in those with lower indinavir levels in the blood (33%) compared with those with higher indinavir levels (15%). Viral breakthrough also has been especially common in those with pre-HAART treatment histories that triggered the formation of drug-resistant HIV and limited the effectiveness of supporting nucleoside analogs (NRTIs) in indinavir-containing regimens.
Adding Ritonavir to Boost Saquinavir
As early as the spring of 1996, it was clear that because of their drawbacks, both saquinavir (as Invirase) and ritonavir (as a single PI therapy) were likely to be very unpopular compared with indinavir. Yet their complementary strengths -- comparative tolerability and inhibition of hepatic (liver) metabolism -- made combining the two drugs at lower doses an attractive idea. Ritonavir could enhance saquinavir through its inhibiting effect on hepatic metabolism, which raises saquinavir blood levels 20-fold and more. This allowed for a significant dose reduction of saquinavir from 600mg three times a day to 400mg twice a day, resulting in fewer side effects. By April 1996, a ritonavir/saquinavir trial was enrolling volunteers under the supervision of University of Ottawa AIDS specialist William Cameron, M.D.
This trial enrolled 141 HIV-positive persons with CD4 cell counts between 100 and 500 cells/mm3 and no prior exposure to PIs. The trial cohort initially received one of four regimens: 400mg ritonavir/400mg saquinavir twice daily; 600mg ritonavir/400mg saquinavir twice daily; 600mg ritonavir/600mg saquinavir twice daily; or 400mg ritonavir/400mg saquinavir three times daily. No supporting NRTIs were used at first, but the trial participants could receive these extra drugs if their viral loads were not below 200 copies/mL at week 12 or if they later rebounded above this threshold. (After week 48, supporting drugs could be added at the physician's discretion.) Ritonavir and/or saquinavir dosages could be reduced in case of intolerance.
At week 48, about 90% of volunteers remaining in the trial had viral loads below 200 copies/mL regardless of their initial regimen. A quarter of the original cohort had dropped out of the trial. Of those remaining, almost half (52 of 106 persons) were on the twice-daily 400mg/400mg regimen by the end of the first year, and 26 were receiving supplemental NRTIs, mostly d4T(Zerit) plus 3TC. These figures remained stable thereafter. At week 144, 88% of the remaining participants had viral loads under 200 copies/mL. (By an intent-to-treat analysis that considers dropouts to be participants with viral breakthroughs, this percentage goes down to 69%.) Sixty percent of the continuing cohort was on the twice-daily 400mg/400mg regimen, and another 21 had added NRTIs. The 600mg/600mg and three-times-daily regimens had very high rates of intolerability.
But why stop at the combination of 400mg ritonavir/400mg saquinavir? Wouldn't further reducing the ritonavir while increasing the saquinavir to compensate result in a more tolerable regimen that is at least as effective? Abbott scientists have been opposing such suggestions since 1996. At a community meeting held that year during the XI International Conference on AIDS in Vancouver, Canada, and elsewhere, they argued that the dual PI combination needed some antiviral effect from ritonavir. Drug levels of saquinavir were still marginal for some people even when combined with ritonavir. Also, the combined PIs might show some anti-HIV synergy (enhanced effects) because somewhat different mutational patterns are required to reduce HIV susceptibility to each of these drugs. The genetic barrier to drug resistance and treatment failure may therefore be greater at the 400mg/400mg doses used in the study. However, Hoffmann-La Roche, saquinavir's developer, has more recently taken up the argument and advocated reduced ritonavir dosages. Since the introduction of Fortovase, Roche has tried to reduce this formulation's pill burden and thrice-daily schedule through the use of several "mini" doses of ritonavir. Roche researchers are currently testing a twice-daily combination of 1,000mg saquinavir plus 100mg ritonavir and a once-daily combination of 1,600mg saquinavir plus 100mg ritonavir.
One recent trial with available data tried saquinavir/ritonavir at the twice-daily dose of 1,000mg/100mg plus efavirenz (Sustiva) and two NRTIs in 32 persons. On enrollment, the volunteers were all unable to suppress HIV while taking their first PI-containing regimen, with baseline viral loads over 5,000 copies/mL. None of them had ever taken saquinavir or any non-nucleoside reverse transcriptase inhibitor (NNRTI). At week 48, 56% had viral loads below 50 copies/mL.
Roche is sponsoring an ongoing 300-person, one-year trial comparing 1,000mg saquinavir/100mg ritonavir, Roche's preferred dosing of the combination, with 800mg indinavir/100mg ritonavir, both twice daily, in treatment-naive (without prior treatment) and treatment-experienced volunteers. A similar trial testing the same saquinavir/ritonavir regimen against the standard twice-daily dose of Kaletra (400mg lopinavir/100mg ritonavir) is in the planning stages.
Antiretroviral Drugs: Dietary Restrictions
No dietary restrictions
Taken on an empty stomach
Taken with a light snack
Taken with a full meal
Although medications in the "No dietary restrictions" column do not have specific dietary requirements, taking them with food may help reduce gastrointestinal side effect.
*avoid taking with a high-fat meal
**can also be taken with a low-fat snack
Once-Daily and Twice-Daily Regimens with Indinavir Plus Ritonavir
Combining ritonavir with indinavir has been shown to stabilize indinavir blood levels, resulting in less variability. In general, lower doses of indinavir (combined with ritonavir) could result in less kidney toxicity and greater efficacy. Since changes in liver activity (i.e., metabolic processes) are a main source of intra- and inter-personal variability in indinavir levels, adding ritonavir might also make those levels at least somewhat more uniform from day to day and from person to person (although there are many other unidentified reasons for pharmacokinetic variability within and among persons). Merck & Co., indinavir's developer, initially was reluctant to endorse the indinavir/ritonavir combination. Instead, Merck advocated the use of 1,200mg twice daily as a simplified indinavir schedule. It embarked on a highly publicized trial endeavoring to demonstrate the efficacy of this regimen compared with the standard dose of 800mg three times daily. However, early results from the trial showed a significantly higher rate of viral breakthrough in those taking twice-daily indinavir. Merck halted the trial in September 1997, and the company warned the public against twice-daily indinavir, which had become increasingly popular. Only after this unfortunate situation did Merck begin to approach the idea of combining indinavir and ritonavir.
Abbott, meanwhile, hoped to repeat its success with ritonavir-enhanced saquinavir. In the spring of 1998, the company's scientists formally reported their initial findings on indinavir/ritonavir, both dosed at 400mg twice daily. The combination resulted in an average exposure to indinavir that was nearly the same as with the standard indinavir-alone dosing schedule. Peak indinavir levels were reduced while the minimum (trough) levels between doses were increased about ten-fold, minimizing the window of opportunity for HIV to replicate (at least, if the HIV contained no drug resistance-conferring mutations, and assuming perfect adherence and drug absorption). Further, taking the drugs with meals made no difference in indinavir levels. Indinavir without ritonavir cannot be taken at mealtimes because full (high-caloric) meals interfere with its absorption.
Note that this interaction study was conducted in HIV-negative volunteers. Later, a German study followed 92 HIV-positive, treatment-naive volunteers who all took 400mg indinavir and 400mg ritonavir twice daily along with two NRTIs. The average baseline viral load was 401,000 copies/mL. Forty-eight weeks worth of data were available for 88 of the participants, including 24 who dropped out. About 90% of the continuing trial participants, or 70% of the entire 88, had viral loads below 80 copies/mL at this 48-week point. Development of ritonavir-enhanced indinavir was delayed when production difficulties in June 1998 caused Abbott to take the capsule form of ritonavir off the market for a year. This meant that consumers were forced to take the vile-tasting liquid form of ritonavir until a new capsule version became available in the summer of 1999.
This past year has seen an abundance of new data on various dosage combinations of these two PIs, particularly at the 8th Conference on Retroviruses and Opportunistic Infections (CROI), held February 4-8 in Chicago. That conference featured reports on two Abbott-sponsored studies that evaluated switching persons on combinations containing three-times-daily indinavir to combinations containing twice-daily indinavir/ritonavir.
The first was conducted in subjects with treatment-suppressed HIV. It found that viral suppression continued at least through week 24, whether or not the participants were switched from indinavir alone to indinavir/ritonavir at 400mg/400mg twice daily. Of the 332 persons assigned to this dual PI combination, 35% dropped out of the study compared with 31% of 83 who remained on indinavir alone. The second trial enrolled 37 persons with detectable viral loads, ranging from 50 to 50,000 copies/mL. Their PI was changed from standard indinavir to 400mg indinavir plus 400mg ritonavir. More than half of the volunteers dropped out. Of the 16 who remained for the full 48 weeks, 38% had viral loads below 50 copies/mL. In both these studies, high blood lipid levels were the only commonly observed serious toxicity and contributed greatly to the drop-out rates, especially in those receiving ritonavir. Indinavir-associated kidney problems (nephrolithiasis) or elevated bilirubin were rare, but note that both trials enrolled only volunteers who already had some previous history on indinavir. People susceptible to such side effects (e.g., persons who had developed nephrolithiasis while previously on the drug) presumably were excluded from the studies.
The high discontinuation rates among those taking indinavir/ritonavir in these two trials were mostly due to drug-related side effects. Analogous with saquinavir/ritonavir, patient discontent may be moderated by lowering the ritonavir dose while increasing that of indinavir. This is a strategy advanced by many recent Merck-sponsored studies.
In one such study, all 72 trial participants had previously received indinavir and had not been able to adequately suppress HIV on at least one PI-containing regimen. In the trial, they received indinavir/ritonavir twice daily at doses of 800mg/200mg (47 volunteers) or 400mg/400mg (25 volunteers). They also received supporting NRTIs and, in two-thirds of the subjects, NNRTIs. In preliminary 12-week results, 24 of the 44 volunteers (55%) on the 800mg/200mg regimen with results available had viral loads under 400 copies/mL compared with 8 of 24 (33%) on the 400mg/400mg combination.
The Thai study alluded to above recruited 106 volunteers whose only previous therapy was AZT plus either ddI (Videx) or ddC. The volunteers received AZT, 3TC, and indinavir with or without ritonavir for 48 weeks. The indinavir/ritonavir combination consisted of 800mg indinavir plus 100mg ritonavir, both twice daily. Median baseline viral load was 10,000 copies/mL while the median CD4 cell count at study entry was 168 cells/mm3.
No advantage in viral suppression rates over indinavir alone was apparent in the indinavir/ritonavir combination, even though it enabled participants to forego the midday dosing and empty stomach requirements required by indinavir alone. After 48 weeks, virologic results in the standard indinavir and the indinavir/ritonavir arms were equivalent: about 60% had fewer than 50 copies/mL of HIV RNA. Adverse event rates were also nearly the same, with the indinavir/ritonavir arm having a slightly higher incidence of such indinavir-related side effects as nephrolithiasis and high bilirubin levels. (Note that high bilirubin alone due to indinavir almost never causes symptoms.) Sixteen percent of the indinavir arm and 18% of the indinavir/ritonavir arm dropped out of the trial while adverse events required dose reductions or treatment interruptions in 36% of those in the indinavir arm and 44% of those on indinavir/ritonavir. An ongoing German study of NRTIs plus the same indinavir/ritonavir combination is also observing a high rate of nephrolithiasis (19.3% of 54 volunteers at 24 weeks).
One of the potential benefits of adding ritonavir to indinavir is that it may enable people to take their PIs only once a day. One Dutch study examined this possibility in 11 persons who had a history of not adhering to regimens with more complicated dosing schedules. The study also enrolled five treatment-naive individuals who strongly preferred a once-daily regimen. The study participants were prescribed 1,200mg indinavir plus 400mg ritonavir once a day (a total of seven capsules). They also took at least one other once-daily drug (some combination of 3TC, d4T, nevirapine [Viramune], and/or efavirenz; note that once-daily dosing of nevirapine and NRTIs except ddI is considered experimental). In preliminary results out to six months, no serious PI-related toxicities were observed. Starting with a median viral load of 280,000 copies/mL, eight of the first nine volunteers had viral loads below 500 copies/mL at six months.
But the daily ten-fold swings in indinavir levels observed in this study meant that those levels frequently exceeded the indinavir toxicity thresholds observed in the Thai study. Early results from a similar U.S. study in ten persons indicated that lipid levels were rising in most study participants. Among the six who had continued beyond six months, one had developed evidence of nephrolithiasis.
One Merck study tested a once-daily 1,200mg indinavir/200mg ritonavir combination in 40 treatment-naive volunteers. It obtained indinavir blood levels that were only slightly lower than the 1,200mg/400mg studies. Eight persons dropped out of the study, and at week 24, 28 of the remaining 32 had viral loads below 400 copies/mL (21 also were below 50 copies/mL). One volunteer had evidence of nephrolithiasis, and lipid levels (especially cholesterol) were generally rising by the end of six months.
Finally, a French study has pushed the indinavir/ritonavir combination to new extremes in an attempt to find a nontoxic, convenient formulation. This retrospective, multicenter study examined the records of 431 persons taking indinavir/ritonavir in various twice-daily combinations: 400mg/100mg (103 persons); 400mg/400mg (83 persons); 600mg/100mg (76 persons); and 800mg/100mg (169 persons). (According to the researchers, some physicians had lowered indinavir doses in some of their patients due to adverse events.) The researchers also measured blood levels of indinavir in each of these persons; blood levels varied widely in each regimen but usually were above the threshold of efficacy. Notably, they seemed to depend on the indinavir dose, but not on the ritonavir dose. There was no significant overall difference between the 400mg/100mg and 400mg/400mg indinavir/ritonavir combinations. Compared with three-times-daily 800mg of indinavir by itself, the 400mg/100mg twice-daily combination achieved two times higher minimum indinavir blood levels and 2.5-fold lower maximum levels, thus potentially leading to improved efficacy and reduced toxicity.
In the French study, 71 subjects with drug-related toxicities and high indinavir levels had their indinavir dosages reduced. As indinavir dosages decreased, so did the frequency of side effects and the possibility of viral breakthrough. Among the 29 subjects with documented virologic results, 22 had viral loads that either remained below 200 copies/mL or newly attained that level. Viral loads in two persons decreased one log (90%) but remained above 200 copies/mL, and in another five, viral load did not change appreciably.
A prospective study is now in the planning stages. (In the U.S., the government-sponsored ACTG 5055 trial is comparing an 800mg/200mg combination twice daily with 400mg/400mg in 50 persons not achieving viral suppression with saquinavir, nelfinavir [Viracept], or amprenavir [Agenerase] as mono-PI therapy.) To the extent that it is successful, and given the data from the French study mentioned earlier, a 400mg/100mg indinavir/ritonavir combination would be revolutionary in terms of convenience (two capsules twice daily) as well as tolerability, which would presumably improve adherence. It would also be relatively inexpensive -- half the price (in U.S. dollars) of the standard 800mg three-times-daily indinavir-alone regimen, or about the same as a single NRTI.
One recurrent theme about the 400mg/400mg twice-daily regimen of indinavir/ritonavir is the near-zero rate of kidney stones, unlike all the other combination doses. And this appears to be the case even without fluid supplementation that is standard for all the other twice-daily indinavir/ritonavir doses and the FDA-approved three-times-daily dosing of indinavir without ritonavir.
Kaletra: Abbott Joins the Bandwagon
This past September 15, the FDA announced approval of a new anti-HIV drug, Abbott Laboratories' new PI formulation, Kaletra. Each Kaletra capsule contains a combination of 133mg of the new PI lopinavir (formerly known as ABT-378) plus 33mg of Abbott's ritonavir. Lopinavir is a highly potent PI that is active against some PI-resistant HIV. But without the added ritonavir, lopinavir blood levels -- never very high to begin with -- decline to negligible levels in four or five hours. Yet these levels are very sensitive to the presence of ritonavir.
Normally, three Kaletra capsules (a total of 400mg lopinavir plus 100mg ritonavir) are taken twice daily. Abbott itself has thus bought into the ritonavir "mini-dose" strategy, abandoning its former insistence on the need to enhance other PIs with 400mg of ritonavir.
Abbott says that the ritonavir in the twice-daily regimen also leads to plasma levels of lopinavir that are at least 75-fold higher than those needed to suppress normal, wild-type (nonmutated) HIV by 50% (the IC50 level, after correcting for protein binding). At those levels, lopinavir may be able to suppress HIV that contains mutations conferring some resistance to the drug. These claims are based on testing in laboratory cell cultures; the ultimate proof is how well Kaletra performs in humans.
In persons without prior treatment, a 653-subject Phase III trial compared d4T/3TC/Kaletra with d4T/3TC/nelfinavir. At 48 weeks, 67% of those starting in the Kaletra arm had viral loads under 50 copies/mL compared with 52% in the nelfinavir arm. (These figures come from an intent-to-treat analysis that counted as treatment "failures" those who altered their initial therapy.)
Toxicity-related dropouts were low in both trial arms: by week 40, 2% of those taking Kaletra and 3% of those taking nelfinavir had discontinued for this reason. The most common serious side effects were diarrhea (about 15% in each arm) and nausea (7% for Kaletra and 4% for nelfinavir). Blood lipid levels increased in both trial arms. The Kaletra arm had significantly more cases of serious triglyceride elevations compared with the nelfinavir arm (9% vs 1%); serious elevations were defined as being at least 750mg/dL, based on nonfasting blood samples. The overall dropout rates for any reason were 17% on Kaletra and 24% on nelfinavir.
The results were almost as favorable in volunteers whose treatment histories included multiple PIs, provided they had not received any NNRTIs. One Kaletra salvage therapy trial enrolled 57 such persons with current viral loads over 1,000 copies/mL. The trial participants had to have a history of more than three months on at least two different PIs and yet still be naive to NNRTIs such as efavirenz. They received efavirenz and Kaletra plus two individually selected NRTIs. All started on a Kaletra dosage of three capsules twice daily (400mg lopinavir/100mg ritonavir). After the first two weeks, half of them added an extra Kaletra capsule (for a total twice-daily dosage of 533mg lopinavir and 133mg ritonavir), while the other half did so at week 24. (Adding the extra capsule overrides the effect of efavirenz, which stimulates the liver's degradation of lopinavir and other drugs.)
At the end of 48 weeks, 56% of the trial participants had viral loads below 50 copies/mL (this result was arrived at through the same sort of intent-to-treat analysis as the one above). The most common side effects were diarrhea and asthenia (lack of energy). Blood lipid levels (both triglycerides and cholesterol) increased by about one quarter during the 48 weeks. Among the ten drop-outs (a rate of 17.5%), three left the study due to drug-related toxicities.
Abbott took this trial's outcome to show that Kaletra is a highly effective drug even in situations where PI drug resistance is common. Sixty-eight percent of the volunteers had HIV with cross-resistance to three or more PIs. This past September, Abbott presented further data indicating that the response rate to the combination formulation (Kaletra) depended on the blood levels of lopinavir relative to the lopinavir resistance present in individual trial participants.
Lopinavir resistance in turn was not associated with any definite set of HIV mutations, but with a number of the standard HIV mutations that confer resistance to other PIs. The company analysis indicated that the risk of lopinavir failure increases as more and more of these mutations are present in the HIV protease gene. The chance of lopinavir "failure" reaches 50% when the number of baseline protease mutations is about six. Another risk factor was the inability to include effective NRTIs that would give lopinavir support in suppressing HIV replication.
At this past February's CROI, however, it became clear that even the high blood levels achieved by ritonavir-enhanced lopinavir cannot overcome all the effects of multiple resistance-conferring HIV mutations acquired during past PI therapy. In an Abbott pediatric trial, only 54% of 22 PI-experienced children achieved week 60 viral loads below 400 copies/mL compared with 79% of 76 children without prior PI experience. (Note that viral suppression is much harder to achieve in children.)
The record of the Kaletra expanded access program, which enrolled 8,733 persons needing Kaletra to construct a new treatment regimen, indicates lopinavir's potential. At some point, 70% of the enrollees achieved a viral load below 500 copies/mL or at least one log (ten-fold) below pre-Kaletra levels. (Using a stricter standard, only about 40% of total enrollees ever dropped below 500 copies/mL on the viral load assay.) Such success depended on baseline viral load and baseline CD4 cell count -- as well as number of prior NRTIs, NNRTIs, and PIs, which reflected baseline drug resistance. The influence of treatment history is in line with the observations in the Abbott salvage therapy trial.
Resistance to prior PIs is demonstrably detrimental to Kaletra's effectiveness, but how detrimental it is varies according to the PI: Abbott has found a high degree of cross-resistance to lopinavir in trial participants whose HIV had developed resistance to ritonavir and/or indinavir. The correlation between amprenavir or saquinavir resistance and reduced susceptibility to lopinavir is much weaker. One trial participant achieved viral suppression with a ritonavir-enhanced amprenavir regimen after disappointing results with Kaletra.
Bringing Amprenavir Back from the Edge
Amprenavir, co-developed and co-marketed by GlaxoSmithKline and Vertex Pharmaceuticals, is the latest agent to partake of ritonavir's advantages. Without ritonavir, the amprenavir dosage (1,200mg, eight capsules, twice daily) is limited by the individual's physical inability to ingest many of the hefty 150-mg capsules, which frequently cause gagging and nausea. In CNA2007, a salvage therapy trial conducted at the National Institutes of Health (NIH), PI-experienced volunteers with viral loads above 500 copies/mL were given standard abacavir (Ziagen), efavirenz, and amprenavir. In contrast with Kaletra, it reportedly was not possible to increase the amprenavir pill burden to make up for the efavirenz-induced acceleration of amprenavir's elimination (efavirenz decreased the peak level of amprenavir by 46% and the minimum level by 59% in a pilot study done in preparation for CNA2007). The loss of amprenavir potency is one reason for the trial's poor outcome, with only a quarter of the participants achieving viral loads below 500 copies/mL at week 16.
The NIH researchers have since conducted a 22-person study that combined efavirenz and amprenavir at their standard doses along with 200mg or 500mg of ritonavir twice per day. Both of these doses had the same effect: with or without efavirenz, they increased the minimum amprenavir blood levels by more than four-fold. Maximum levels were about the same as those achieved with the standard dose of amprenavir without any concomitant drugs.
Raising the minimum amprenavir levels is of vital importance: in one Glaxo study, 11 out of 22 individuals on standard-dose amprenavir had minimum drug levels below the threshold (220 nanograms/mL) for triggering development of amprenavir resistance via a mutation that also confers moderate cross-resistance to most other PIs (this mutation is located on codon 54 of the protease gene).
Another new Glaxo study compared the standard 1,200mg twice-daily amprenavir regimen with ritonavir-enhanced amprenavir at doses of 600mg amprenavir/100mg ritonavir twice daily and 1,200mg amprenavir/200mg ritonavir once daily. These are the two most common amprenavir/ritonavir combinations being studied. The 54 volunteers also received abacavir and 3TC, two of Glaxo's NRTIs. Due to a previous regimen, nearly all subjects started with viral loads below 400 copies/mL, and they maintained that suppression for the 12-week observation period. Once again, about half of the 15 persons in the amprenavir-alone arm had minimum blood levels of amprenavir that were below 220 nanograms/mL. Both the ritonavir-enhanced doses raised this minimum amprenavir level nearly six-fold, whereas the maximum level -- achieved soon after a new dose was taken -- increased less than 50%. Either of these regimens has a significantly lower pill burden compared with amprenavir alone.
The notable feature of the once-a-day ritonavir-enhanced regimen is that the amprenavir levels fall to their minimum only one time in a 24-hour cycle rather than twice. For that reason, the average amprenavir level in the blood over the course of a day is more than two-fold higher than the 600mg/100mg twice-daily combination (and nearly four-fold greater than that of amprenavir without ritonavir enhancement). Whether this higher average blood level leads to better efficacy or worse side effects remains to be determined. The once-daily regimen is less forgiving, however, with a longer period of low amprenavir levels if one dose is missed, when compared with the twice-daily regimen.
One potential problem with the 600mg/100mg combination arises when amprenavir/ritonavir is taken together with efavirenz or the NNRTI nevirapine, which also accelerates amprenavir's metabolism. In that case, amprenavir levels again become marginal according to a German study of five volunteers. In contrast with the German study, French investigators monitoring 20 volunteers found that the 600mg/100mg combination mostly curbed the influence of efavirenz or nevirapine.
The German study also tried a different twice-daily dose combination, 450mg amprenavir and 200mg ritonavir, which is much easier to take than the NIH combination described above. The 450mg/200mg combination reversed the efavirenz/nevirapine effect in 12 volunteers, resulting in amprenavir levels on the order of those achieved in five persons not on NNRTIs. They also approximated the amprenavir levels achieved in the Glaxo study of the twice-daily 600mg/100mg and once-daily 1,200mg/200mg combinations without efavirenz or nevirapine.
What Is the Real Benefit?
One of the problems encountered by people taking PIs and researchers trying to understand their action in the body is that PIs often do not reach their target cells in large amounts. Countering this difficulty by raising the recommended dose is not always possible because of the limits imposed by drug toxicities and the individual's capacity to ingest more capsules. It is therefore no wonder that successfully suppressing HIV depends on at least 95% adherence to dosing schedules and that even in adherent persons -- to the extent that PI levels have been studied -- PI levels may be suboptimal.
Manufacturers have now embraced adding ritonavir as one strategy for overcoming these restrictions. DuPont, Boehringer Ingelheim, and Bristol-Myers are all testing ritonavir enhancement as part of the development program for their experimental PIs.
Glaxo has even included a 600-person, ritonavir-enhancement trial for the new amprenavir prodrug, GW433908. The prodrug is a more easily absorbed version of amprenavir that should presumably increase drug levels on its own. As it turns out, GW433908 produces the same drug levels in the blood as standard amprenavir with just three compact capsules and less digestive upset. Increasing the dose does not raise these blood levels, perhaps because an upper limit to the digestive system's ability to absorb the drug has been reached.
In this glut of different combinations and different doses, it is difficult to say which is more effective or safer. There have been few trials that compare ritonavir-enhanced regimens with single PI combinations. With the possible exception of Kaletra, there is no demonstration that adding ritonavir to another PI results in a substantial clinical advance in controlling HIV.
Clearly, the field is fraught with commercial implications, and each company is struggling to produce data that support higher doses of its own drug and less ritonavir. With little clinical data, the basis for devising and ranking ritonavir-enhanced PIs falls on an evaluation of the difference between the minimum blood levels and the concentration of drug necessary to suppress HIV. Both these measurements are derived in a variety of ways and are open to a variety of interpretations.
Abbott bases its comparative data on the inhibitory quotient (IQ), or the minimum blood levels obtained in vivo (in the body) divided by the IC50, a lab measure of the concentration of drug that reduces HIV replication by 50%. The IQ for lopinavir in the Kaletra combination is about 75. In the case of indinavir/ritonavir, Abbott claims that minimum levels of indinavir are raised to about 25 times the IC50 for wild-type HIV for the 800mg/100mg indinavir/ritonavir combination. Merck measured the IC95, a much higher level of viral inhibition (95%). It found that the indinavir trough (minimum) level is 29 times the drug's IC95 for the 800mg/100mg combination and 69 times for the 800mg/200mg combination.
Meanwhile, Glaxo has created the so-called forgiveness quotient, or FQ. The FQ is defined as the IQ after missing one PI dose and just before taking the next scheduled one -- i.e., using blood levels 24 hours after the last dose for a twice-a-day regimen and at 48 hours for a once-a-day regimen. By this measure, amprenavir/ritonavir turns out to be the best combination, according to their calculations. Amprenavir's longer half-life in the body makes for somewhat less dependence on absolute adherence.
Depending upon which measurement (IQ or FQ) is used, saquinavir/ritonavir may be inferior in terms of drug concentrations achieved. So it is not surprising that Roche's scientists are questioning the validity of the other companies' techniques. They point out that different methodologies can lead to wide differences in the estimate of minimum blood levels, inhibitory concentrations, and binding to blood proteins (which locks up most of the ingested PI). These researchers suggest de-emphasizing laboratory estimates as much as possible and measuring real activity and real drug concentrations in average persons going about their daily lives.
Yet none of these approaches would account for the amount of drug reaching cells. In the final analysis, intracellular drug levels appear to be of paramount importance, and estimates of intracellular drug concentrations take the evaluation of ritonavir-enhancement a giant step further into the realm of speculation. Intracellular concentration depends on the activity of P-glycoprotein, which exists on cell membranes to expel PIs as well as other "undesirable" drugs. PIs are affected by this cellular pump to varying extents, both in the target white blood cells and in the digestive system, where P-glycoprotein on cell walls reduces the absorption of PIs.
There is evidence that ritonavir blocks P-glycoprotein activity parallel to its blocking of the CYP3A4 liver enzyme that breaks down PIs. The extent of that P-glycoprotein inhibition in various cell types has not been well characterized. And there is as yet no clinical proof that blocking P-glycoprotein will increase the PIs' anti-HIV activity. There is in fact some concern that an opposing effect will negate any possible benefit -- in the laboratory, cells with high levels of P-glycoprotein better resist entry and infection by HIV.
Further study in humans is also needed to account for the overall risks of ritonavir enhancement. PIs have become associated with a number of long-term metabolic side effects, especially fat accumulation, or lipodystrophy, and impaired sugar processing (though only rare cases of diabetes). Combinations of ritonavir with other PIs usually lead to reduced maximum blood levels of the boosted PIs, which are traditionally held accountable for most side effects. At the same time, ritonavir increases the overall exposure and minimum concentration of the boosted PIs, while the effect on long-term toxicities has yet to be determined. Some experts are also concerned that low-dose ritonavir exposure may lead to resistance against ritonavir, hence to other PIs.
One might well wonder what the long-term effects of ritonavir are on the liver, which may be central to lipodystrophy due to its lipid and sugar regulatory functions. Ritonavir is noted specifically for increasing blood lipids, which raises the risk of cardiovascular disease. In addition to increased lipid levels, the incidence of liver inflammation, as measured by blood levels of liver enzymes, is also elevated in trials of ritonavir-enhancement.
More immediately, ritonavir raises levels of many drugs, not just PIs. The extent of these changes is not well-defined: the official ritonavir package insert contains a long list of interactions between ritonavir and other medications, a good number of which are poorly characterized even for the standard 600mg twice-daily ritonavir dose. Among the problematic drugs are some of the common lipid-lowering agents that ritonavir use might necessitate. Such drug-drug interactions can create life-threatening situations, as in the case of sildenafil (Viagra), whose total exposure, or area-under-the-curve (AUC), is boosted 11-fold by full-dose ritonavir. (According to Cristina Gruta, Pharm.D., of San Francisco General Hospital, the sildenafil dosage is limited to 25mg every 48 hours in persons taking a ritonavir-containing regimen to minimize the risk of serious, potentially life-threatening toxicity. Persons taking sildenafil with any ritonavir-containing regimen are encouraged to talk with their providers about drug interactions.)
Still less is known about P-glycoprotein inhibition. Inhibiting P-glycoprotein might allow more drugs and undesirable substances into the body and into cells. It would also circumvent blood-brain and maternal-fetal (womb) barriers that provide special protection in these vital areas.
The bottom line is that low-dose ritonavir often improves blood levels of the boosted PI, yet may also complicate the medical management of persons with HIV, who may be taking a variety of medications for other physical and psychological conditions both related and unrelated to their HIV infection. This medical juggling often increases as people with HIV age, since more medications are often necessary due to other, non-HIV-related chronic conditions.
One last issue is what might happen if a ritonavir-enhanced regimen should fail. The addition of ritonavir in the regimen may create evolutionary pressure that selects for HIV that is resistant to ritonavir as well as to the boosted PI, particularly if viral suppression is not achieved. Such ritonavir-associated mutations were frequently observed in one small study of persons taking 600mg saquinavir three times daily (in the old, less absorbable Invirase formulation) plus 100mg ritonavir twice daily. Selection of resistant mutants might become a greater concern with the passage of time: last year, Dutch researchers published findings that saquinavir levels declined substantially in six persons on 400mg saquinavir/400mg ritonavir for more than a year. The median change in minimum saquinavir level was 30%, and the maximum levels were still more strongly affected. Only one subject had a detectable viral load over the course of the study, suggesting an increase in metabolic resistance to saquinavir among the six participants rather than problems with adherence.
PI drugs as a class have a serious flaw: not enough drug gets into the blood and reaches cells. Adding ritonavir is one obvious way to get around this problem and allow the boosted PI to reach its antiretroviral potential. But with the exception of Kaletra, little is established concerning the proper doses or dosing schedule for a ritonavir-enhanced combination. Still less is known about each combination's comparative value, and even less about its long-term effects. Ritonavir enhancement is now popular, especially for second-line therapies, but it has become so as a result of word-of-mouth rather than rigorously designed studies.
Nevertheless, it should be noted that the expert panel of physicians advising the Department of Health and Human Services (DHHS) has included ritonavir plus either saquinavir or indinavir among the "strongly recommended" first-line agents in the U.S. treatment guidelines for adults and adolescents updated this past February (see www.hivatis.org, Table 12).
Most of the ritonavir plus second PI dosing combinations discussed in this report should be considered experimental. Not all changes in side effects or drug concentrations (minimum, maximum, and AUC) were listed for each dosing combination, particularly in combination therapy with an NNRTI. Always consult with a physician about medication dosing before changing any drug regimen.
Dave Gilden is Director of Treatment Information Services at amfAR.
Selected Sources
Bangsberg, D.R. and others. Adherence to HAART predicts progression to AIDS. 8th Conference on Retroviruses and Opportunistic Infections. Chicago. February 4-8, 2001. Poster 483.
Bernstein, B. and others. Absence of resistance to Kaletra (ABT-378/r) observed through 48 weeks of therapy in antiretroviral-naive subjects. 8th CROI. Poster 453.
Brun, S. and others. Patterns of protease inhibitor cross-resistance in viral isolates with reduced susceptibility to ABT-378. 8th CROI. Poster 452.
Burger, D. and others. Both short-term virological efficacy and drug-associated nephrotoxicity are related to indinavir (IDV) pharmacokinetics (PK) in HIV-1-infected Thai patients. 8th CROI. Poster 730.
Burger, D. and others. Indinavir pharmacokinetics are related to efficacy and toxicity. 7th European Conference on Clinical Aspects and Treatment of HIV-Infection. Lisbon. October 23-27, 1999. Poster 826.
Cadman, J. The great salvage therapy drug juggle. GMHC Treatment Issues 12(4): 1-6. April 1998.
Back to the SFAF BETA Spring 2001 contents page.


text:
In case you missed it, I was in Las Vegas last week for PubCon 2009. It was my first PubCon and as you can imagine, lots of fun! As far as presentations, every presentation was great but I do have a few favorites. Here they are in order of appearance…
- One of my favorite presentations at PubCon was Rob Snell's "Ecommerce and Shopping Cart Optimization." Rob always impresses me with his creativity and common sense approach to increasing conversions with things like original content creation. Rob stressed liberating manufacturer content in addition to creating original product descriptions and content. Maybe it's a "southern thing" but is for certain, Rob is no "Dummy" when it comes to ideas for developing great content to increase ROI.
- Another great presentation was Ted Ulle's "SEO Design & Organic Site Structure." Ted's FRANKENSITE analogy was really great! He focused on the importance of keeping things simple and setting goals early. Ted offered some other really great advice about documenting decisions, graphic design being placed lower down the priority list and why "code geeks" shouldn't write copy. Splitting a cab with Ted was also a big thrill, it's not every day I get to ride with celebrities.
- Vanessa Fox's "Multivariate Testing and Conversion Tweaking" presentation was really interesting. In addition to providing recent data about the average number of keywords per query, Vanessa dove into the topic of personas and the role they play in conversions. According to Vanessa, focusing only on ranking reports can cause you to miss important information. That said, I've already pre-ordered Vanessa's new book and strongly suggest you do too.
- As always, Matt Cutts was truly entertaining during the "Interactive Site Review: Organic Focus" session at PubCon. (Tip, if your site is obviously spamming don't sign it up for review! ) I know Barry has been giving Matt a hard time about not attending conferences lately but, Matt really went above and beyond even shaving a spammy head or two at PubCon 2009 :).
- Greg Hartnett, Michael McDonald, Barry Schwartz, Lee Odden and Loren Baker teamed up for "Search Bloggers: What's Hot and Trending?". This session was a jam packed PowerPoint free dialogue between the best in the industry.
- Saving the best for last, my favorite session was "Super Session : Search Engines and Webmasters." Shawn from Microsoft was up first and talked about Bing's recent changes. He demonstrated Bing's hover preview feature and talked about the new and improved MSNBOT 2.0b According to Shawn, Steve Blamer expects to win search and acquire 51% market share with Bing. After Shawn, Matt Cutts presented Google's "State of the Index." Matt talked a lot about the importance of site speed and Google's new social search experiment. He suggests digging deeper into Google Webmaster Tools as well as subscribing to the blog and YouTube channel.
PubCon was a great conference and I strongly suggest it to anyone interested in interactive marketing. Thanks again to Neil Marshall and the PubCon staff, Barry Schwartz and Search Discovery Inc..

subset: commoncrawl


text:
Browsing Divinity (School of) by Subject "A.J. Scott"
Now showing items 1-1 of 1
Rooted in all its story, more is meant than meets the ear : a study of the relational and revelational nature of George MacDonald's mythopoeic art (University of St Andrews, 2011-06-21) - ThesisScholars and storytellers alike have deemed George MacDonald a great mythopoeic writer, an exemplar of the art. Examination of this accolade by those who first applied it to him proves it profoundly theological: for them ...


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From MeritBadgeDotOrg
(standardize Otheruses text)
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*Citizen is preparing you for [[Family Life]], [[Citizenship in the Community]], [[Citizenship in the Nation]], and [[Citizenship in the World]] Merit Badges
*Citizen is preparing you for [[Family Life]], [[Citizenship in the Community]], [[Citizenship in the Nation]], and [[Citizenship in the World]] Merit Badges
*Citizen Requirement 5 can help prepare you for [[Scout Badge]] Requirement 4
*Citizen Requirement 5 can help prepare you for [[Scout Badge]] Requirement 4
*Citizen Requirement 4 can help prepare you for [[Tenderfoot
*Citizen Requirement 4 can help prepare you for [[Tenderfoot ]] Requirement 6
*Citizen Requirement 7 can help prepare you for [[First Class
*Citizen Requirement 7 can help prepare you for [[First Class ]] Requirement 5.
Revision as of 15:37, October 14, 2012
and cross-references for related Cub Scout belt loops & pins and Cub Scout awards.
Citizen is the most popular Webelos Activity Badge and is required for the Webelos Badge. ◄ Prev - Next ►
| This is the Citizen activity badge for Webelos Scouts.
Cub Scouts and Webelos Scouts can also earn the Cub Scout Citizenship belt loop and pin.
|The Webelos Citizen activity badge helps prepare Webelos Scouts for the Boy Scout Citizenship in the Community, Citizenship in the Nation, and Citizenship in the World merit badge(s).
|The Webelos Citizen activity badge options include earning the Citizenship belt loop.
|This Activity Badge is required for the Webelos Badge.
| Webelos
Activity Badge
The Webelos Citizen Activity Badge is one of 20 different Activity Badges that can be earned in the Webelos Scout Program. The requirements are typically worked on during den meetings or den activities while the skills are practiced at home, with the help of the Webelos Scout's family. The requirements are either completed with the den or at home with the den leader's approval. Projects are brought to meetings to share with the den and for Webelos Den Leader or Activity Badge Counselor approval.
Citizen requirements
Do this:
Do all of these:
And do two of these:
View the change list (history) of these requirements. The text of these requirements may be locked. In that case, they can only be edited by an administrator.
Please note any errors found in the above requirements on this article's Talk Page.
|A FREE workbook for Citizen is available here! (PDF or Word) with the maps, charts, links, diagrams, and checklists you need! Or click here to print just the Citizen requirements.
|usscouts.org has PDF and Word versions of workbooks for Scouts BSA ranks and merit badges, Cub Scouting ranks and adventures, and STEM Nova awards.
- The Webelos Program uses the Fast Tracks Den Meeting plans to the Webelos Adventures in as little as 12 months.
Requirement resources
1. Citizenship - Rights - pp. 146
2. Your President, Vice President, etc. - State Websites - Information about your state's government - pp.147
3. See Flag Ceremonies for these topics and much more: Flag Description and much more - History of the flag - How to Display the Flag - pp.148-9
4. Flag Etiquette - Days to display the flag - pp.149-53
5. Pledge of Allegiance: - pp. 153
- ""I pledge allegiance to the flag
- of the United States of America
- and to the republic for which it stands,
- one nation under God,
- indivisible, with liberty and justice for all.""
6. Library of Congress: Star-Spangled Banner - pp.154
7. Rights - Duties - Jury Duty - Obligations (Responsibilities) - pp.155-6
8. See the Cub Scout Citizenship Belt Loop.
9. See the BSA Home Security Checklist is included in the Citizen Worksheet - The National Crime Prevention Council - Call 911 only when you need to - What to do if you see a crime Nat. Sheriffs' Association - Nat. McGruff House Network - Youth Crime Watch - Nat. School Safety Center - pp.157
10. Find Information about your county's government - pp.158-9
11. Whitehopuse.gov: US Presidents - Wikipedia:US Presidents - pp.155-6
14. Why we have laws - pp.160-1
15.Local Government Services - pp.163
16. United Nations Official page - International Court of Justice (World Court) - : World Health Organization - pp.162
17. IRS online search for charities - GuideStar Directory of Non-profit Organizations - BBB list of charities - pp.162
- General Resources
- CubRoundtable: Citizen 38 page reference guide
- KISMIF: Citizen Links
- Bill Smith's Webelos Leader Resources: Citizen
- Webelos Roundtable Packet: Citizen
Related awards
- Cub Scout Citizenship Belt Loop and Pin
- Citizen is preparing you for Family Life, Citizenship in the Community, Citizenship in the Nation, and Citizenship in the World Merit Badges
- Citizen Requirement 5 can help prepare you for Scout Badge Requirement 4
- Citizen Requirement 4 can help prepare you for Tenderfoot rank Requirement 6
- Citizen Requirement 7 can help prepare you for First Class rank Requirement 5.
Personal Development Awards
|Personal development-related awards
See also
|Webelos Den Leader portal
External links
- Nations Trails United States Heritage Award
- U.S. House of Representatives
- U.S. Senate
- The U. S. Constitution Online
- The White House
- FirstGov, U.S. General Services Administration
- GovSpot
- National Constitution Center
- The National Crime Prevention Council
These Activity Badges were replaced with Adventure Pins in 2015.
Physical Skills group: Aquanaut | Athlete | Fitness | Sportsman
Mental Skills group: Artist | Scholar | Showman | Traveler
Community group: Citizen | Communicator | Family Member | Readyman
Technology group: Craftsman | Engineer | Handyman | Scientist
Outdoor group: Forester | Geologist | Naturalist | Outdoorsman


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Top 5 with Lisa Foiles: Top 5 Robots
Pages PREV 1 2 3 4 5 6 7 8 9 10 11 12 13 14 NEXT
mine too.
Lisa, you're too good for that blender. Come live with MEEEEEEEE! D:
OMG, I've got it all figured out!
He said he would do it, but we just wouldn't listen.
I was watching Malcolm in the Middle yesterday and I swear my mum looked at me as if she could hear the penny dropping in my head... Holy time travelling monkeys Batman. Shame about the lack of a top five this week. D; Also your twitter background amuses me, though it kind of lays to rest any hope of a topless five... Also you were the second person I followed on there when I made it earlier - Right after Yahtzee. ;)
The blender is easily the funniest thing in that whole video.
No cake for you, Lisa.
Holy SHIT i had one of those "emilio" robots! I swear he had a different name though...he had a newspaper slot on his back, ONE arm that would move up and down in a phalic motion, and a head that would swivel if you forced it...which may or may not have been a feature.
Now he spends his days in my loft :(
Should do a Top 5 Videogame Deaths with Blendy as host. Not even a single mention of Lisa. Would be the best show yet. >.>
Btw, shes very late. Redheads are so unreliable. XD
GLaDOS is a computer rather than a robot, surely?
I'm just a sucker for Monkey Island references, any chance of a Top Five - Weirdest Solutions to Puzzles in Point & Click Adventure Games?
Rubber chicken with a pulley has got to feature somewhere...
Claptrap is the shit I mean how can you resist that dance not to mention the whole interplanetary ninja assassin thing.
1. Claptrap
'nuff said.
So whats up here guys? 2 weeks and still no Lisa? Any word?
perhapes she went overboard with the Smirnoffs from two weeks ago, lol
I just realized something: Two episodes after ENN changed its format to the (terrible and lame) newsroom, the show was canceled. Lisa changed her hair color to red, released two videos, and now there's a hiatus.
If this means what I think it means, then we'd better hope that Yahtzee doesn't decide to try out a new background color for Zero Punctuation.
i too have come to complain about the 2 week hiatus. RARGH
I'm telling you, Blendy killed her !
The day of reckoning is finally upon us, skynet has gained self-awareness, the robots are starting to take over
Damn you Blendy! Damn you! How will I know what the top 5 (whatever) in gaming is?! How?! D:
Did they replace the beautiful Lisa with some fat guy yelling into a mic? I think I may lose faith in the escapist, if not humanity all together.
Actually, just a thought, but she might have been spending these two weeks playing the arch villainess with the Anthony Saves The World gang.
Is there actually a reliable place to find out if escapist shows are just taking a break, or the creator's on vacation or something as opposed to the show being cancelled? It seems like there isn't an announcement visible when shows are cancelled so we are just left wondering. I too am wondering if Lisa is on vacation for two weeks or something or if the show is actually cancelled. And this has happened before.
Can Blendy take responsibility and do the next top 5 show?
Where are you Lisa :(?
We miss you Lisa and we hope to see you again soon.
Bring back Lisa!
-Edit- Removed one éntendre.
Lisa, come back!
I swear, if that blender's damaged a single red hair on that head of yours... well, let's just say you'll have some new "modern art" in your kitchen.
The lack of Top 5 is tearing us apart,Lisa!
Don't worry about that. Lisa loves you as a human bean. Oh, hai, Twitter.
Anthony Saves The World hasn't been updated either, sadly :(
Well, good. At least we know; me and my friends already proclaimed her dead. Shame there wasn't any announcement. Not for her death, for the break.
Just on holiday then. I was wondering.
you forgot about ED-E off fallout new vegas he is awesome
I love the background on her Twitter. Anyone else? :P
Waaaah! Where is Lisaaaaa! :C
Lisaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa... nevermind, I've read the "need a break" post :P we need you to come back asap tho' ;)
Please stop with so much make up, you really do not need it
|Pages PREV 1 2 3 4 5 6 7 8 9 10 11 12 13 14 NEXT


text:
Built at the Internet Archive
Type of Collecting Organization
Sort By:
Sort By:
Items in the archive are listed below. Narrow your results at left, or enter a search query below to find a collecting organization, collection, site, specific URL or to search the text of archived webpages.
The following results were found for the term(s): virginia tech
Page 1 of 1 (1 Total Results)
Collected by: Virginia Tech: Crisis, Tragedy, and Recovery Network
Archived since: Oct, 2011
More than 400 people, mainly children, have died in an outbreak of viral encephalitis in northern India, health officials say. Nearly 6,000 children have died of encephalitis in the hospital since the first case was detected in 1978.
Subject: Spontaneous Events, encephalitis , india, epedemic
Creator: kiran
Date: October 12th 2011
Page 1 of 1 (1 Total Results)


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The recent title update to Halo: Reach has rendered unplayable the free disc version of the game given to Xbox Live dashboard beta participants earlier this year. Rather than say tough luck, Microsoft is giving all of them a free digital copy of the game.
An email to dashboard beta participants today advised them of the title update's problem and the solution. All save files from the previous version of the game is portable to the digital one.
Of course, this means one needs a hard drive with 6.6 gigabytes free, whether that's on the console or a USB drive.
If this situation affects you and you have the hard drive space, just download the digital version of the game and chuck the disc in the trash.
[h/t reader progame13]


text:
Gary and Betty Hasenbank of Goessel announce the engagement of their daughter, Laura M. Hasenbank, to Douglas L. Schmidt, son of Karen Sklenar of Hillsboro and Eddie and Anita Schmidt of Durham.
Hasenbank, a graduate of Drury University and Butler County Community College, is a licensed substitute teacher and co-owner of Eagle Eye Art, where she practices graphic design and photography. Schmidt is a truck driver for Sequoyah Trading and Transportation, LLC in Hillsboro. The couple resides in Hillsboro and plan to marry at Marion County Park and Lake in October.


text:
Cisco Service Provider Strategy: Complete Lifecycle Approach
Cisco follows four main tenets to promote your business success: deploy services, build networks, accelerate demand, and optimize business.
Find the Solution that Works for You
Escalating customer expectations and increasingly competitive markets are leading service providers toward several all-encompassing fundamentals. You may need to:
Cisco experts can help you:
Deploy Services: A Cisco IP NGN enables you to layer existing and new services to develop revenue growth and reduce time to market.
Build Networks: With the addition of Scientific-Atlanta, Cisco now helps you build intelligent IP infrastructures for more services and greater efficiencies.
Accelerate Demand: Through the Cisco Powered Network program, Cisco connects organizations of all sizes to service provider services to help expand your customer base.
Optimize Business: Cisco provides expertise to support business and network transitions, improve operational efficiencies, and address fundamental business challenges.
Cisco Powered Networked partners have access to important resources.
Cisco and T-Systems
This content requires the latest version of Adobe Flash Player.
Scripting must be enabled to view the video.
Cisco and T-Systems
T-Systems Adapts to Market Needs, Delivers Next-Generation IP Services, and Transforms Business Experiences. (2:40 min)
Service Provider SP360 Blog
Join the conversation and discuss service provider technology and trends.
> Go Now
OPEX Reduction and Flexible Bandwidth
Mobile Transport over Pseudowires extends IP-MPLS capabilities into the radio network.> Learn More
IP NGN Solutions for Service Provider Success
Cisco helps you deploy services, build networks, accelerate demand, and optimize business.View Flash Video
Programs and Communities


text:
Wednesday, March 7, 2012
Nikki Reed, Paul McDonald Music VIDEO!
Directed by Nikki and Whitney Dean, the clip offers a small peek into the twosome's year-long relationship, as the newlyweds walk hand-in-hand through a leaf-strewn field and duet atop a rusted-out Volkswagen Beetle. In anticipation of the release, we put a call into the couple (who were driving down to Santa Monica for the weekend) to talk about their labor of love.
"I'm always walking around the house with a guitar, and I'm always writing songs and stuff like that," Paul said. "Nikki's a great writer and she always kind of sings along with me. I'm like, 'Dude, you have a great voice. Why don't we do something?' When we were on the way back from France, this song kind of happened on the plane. We just got together and wrote it."
"Basically, what Paul and I are learning about each other, which is so awesome, is I'm a completer. I like to complete things and Paul likes to start things. It's really great," Nikki continued.
And so it was that Paul handed Nikki the beginnings of "Now That I've Found You," which she put the finishing touches on in about 20 minutes. Coming up with the video concept, however, wasn't quite so easy. Nikki originally had a June Carter/Johnny Cash-esque performance treatment in mind, but scrapped it for something a bit more stripped down.
"I wanted it to be simple and sweet and tell the story of two people and have it be more about the atmosphere," she said. "I don't know if you notice, but there's a very specific choice in there with cuts and specific shots that are partial and you can only see parts of our mouths and hands. I don't want to dwell on the shots of us for too long."
With Nikki at the helm, Paul said the filming process felt like any other day together. "It was easy. It was kind of weird because at the same time we're shooting the video, and I'm wondering if Nikki's going to be acting," he said with a laugh. "She's really good to work with. It all just kind of fell into place. She didn't boss me around too much."
Via @MTV
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text:
WEST HARTFORD, Conn. (AP) Tyreek Duren netted 15 points to lead four La Salle players in double figures as the Explorers took down Hartford for a 64-51, nonconference victory on Tuesday night.
La Salle (2-1) got a double-double from Rohan Brown, who had 10 points and 12 rebounds. Jerrell Wright had 14 points and nine rebounds, while Ramon Galloway hit 3 of 4 3-point tries en route to 13 points.
The Explorers opened with a 16-4 lead, capped by a 3-pointer from Galloway exactly six minutes in. Hartford (1-3) came back with an 8-0 run to cut the lead to 16-12, but was outscored 24-10 before halftime and trailed 40-22 at the break.
La Salle was 60.9 percent (14 of 23) from the field in the first half, including 5-of-8 shooting from beyond the arc.
Mark Nwakamma hit a game-high 16 points for the Hawks.


text:
Decision : CONF 208 X.A
Derwent Valley Mills (United Kingdom)
Property: Derwent Valley Mills
Id. N°: 1030
State Party: United Kingdom
Criteria: C (ii) (iv)
The Committee inscribed the Derwent Valley Mills on the World Heritage List under criteria (ii) and (iv):
Criterion (ii): The Derwent Valley saw the birth of the factory system, when new types of building were erected to house the new technology for spinning cotton developed by Richard Arkwright in the early 19th century.
Criterion (iv): In the Derwent Valley for the first time there was large-scale industrial production in a hitherto rural landscape. The need to provide housing and other facilities for workers and managers resulted in the creation of the first modern industrial towns.
DocumentsDecisions Report
Decision Code: CONF 208 X.A
Themes: Inscriptions on the World Heritage List
States Parties (1): United Kingdom of Great Britain and Northern Ireland
Properties (1): Derwent Valley Mills
Year: 2001


text:
Defiant Raw HolesFavorites [+]
Pay-Per-Minute Viewing
You can now enjoy this movie on your iPhone®, iPad®, or compatible Smart TV & Android devices.
Purchase Options
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Running Time: 110 minutes
Released: 11/2016
Studio Name: Raw Strokes
Director: Marco Paris
Categories: Amateur Interracial Bareback Anal High Definition
Description: Hung daddy Tex spoils his boy Armond in this sizzling scene. Deep Dicc pumps his seed in our sexy newcomer Augusto Acosta. Massive black cocks at work here, all bareback!
5 Scenes from Defiant Raw Holes
Defiant Raw Holes: Scene 1 Free Preview
Starring: Mr. Cali Julius Caesar ... More Details
Stars: Mr. Cali, Julius Caesar
Sex Acts: Oral Sex, Nipple Play, Masturbation, Anal Sex, Rim Job
Positions: Doggy Style, Kneeling, Missionary, Side Saddle, Sitting, Spoons position, Standing
Defiant Raw Holes: Scene 2 Free Preview
Starring: Armond Rizzo Tex Davidson ... More Details
Stars: Armond Rizzo, Tex Davidson
Sex Acts: Oral Sex, Creampie, Male On Male Action, Nipple Play, Masturbation, Anal Sex, Rim Job
Positions: Cowgirl, Doggy Style, Laying, Missionary, Reverse Cowgirl, Standing
Defiant Raw Holes: Scene 3 Free Preview
Starring: Esteban Orive Matie (Raw Strokes) ... More Details
Stars: Esteban Orive, Matie (Raw Strokes)
Positions: Cowgirl, Doggy Style, Missionary, Side Saddle, Standing
Settings: Kitchen, Living Room
Defiant Raw Holes: Scene 4 Free Preview
Starring: Deep Dicc Augusto Acosta ... More Details
Stars: Deep Dicc, Augusto Acosta
Positions: Doggy Style, Laying, Missionary, Sitting
Settings: Bedroom, Living Room
Defiant Raw Holes: Scene 5 Free Preview
Starring: Mr. Marky Matie (Raw Strokes) ... More Details
Stars: Mr. Marky, Matie (Raw Strokes)
Positions: Doggy Style, Kneeling, Missionary, Standing
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New 2019 HondaCivic LX Sedan
- Stock: H544735
- Fuel Economy
- 30.0/38.0 mpg City/Hwy
- Exterior Color
- Rallye Red
- Interior Color
- Blk Clth
- Body/Seating
- Sedan/5 seats
- Transmission
- continuously variable automatic
- Drivetrain
- front-wheel
- Engine
- 2.0L I-4 cyl
Highlighted Features
- Lane departure
- Distance pacing cruise control
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- Auto high-beam headlights
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Detailed Specifications
Dealer Notes
Recent Arrival! 30/38 City/Highway MPG
KBB.com Consumer Reviews
- 5.0
Best car in its class for 2016
By 2016 Civic Driver on Friday, April 27, 2018Really a great value. Two minor complaints: the CVT can be jerk-y when going uphill at a low speed, i.e. 10 mph. Also, they could have included more/larger cup holders in the interior. Other than that, the car is very reliable, and for a baseline model it has lots of features that usually are only found on more expensive versions of other makes. The car is rated for 41 mpg freeway, but I have achieved up to 49 mpg using Eco mode and cruise control while driving 65 mph on the freeway in flat terrain. Driving around town, I get about 30-33 mpg. The car has plenty of room and is comfortable, and the new 2016 body style is a major improvement compared to previous models. I would definitely recommend this car!
- 1.0
Don't Buy Honda
By Integrity on Tuesday, July 09, 2019Don't Buy Honda! They can't even make a car with reliable A/C! How has Honda not NOT RECALLED this Car! I am a Veteran and cannot stand behind such a poor product! Toyota and Subaru smoke this car, it's not even close. My 16yr old is going to have to sweat it out until we find some other fool to buy it from us!
- 5.0
Small sedan is really a sports car.
By TBK on Friday, February 01, 2019Quickest 0-60 mph in class. CVT is great. Factory tires not as grippy as I would have liked, put Michelin's on it and it sticks the corners now, really carves up the pavement. Technology is great. More passenger space than meets the eye, easy for four 6+ ft. humans to relax with plenty of leg room. Best sedan I have ever owned.
Prices shown are manufacturer suggested retail prices only and do not include taxes, license, or doc fee. Manufacturer vehicle accessory costs, labor and installation vary. Please contact us with any questions.
**Based on 2014 EPA mileage ratings. Use for comparison purposes only. Your mileage will vary depending on driving conditions, how you drive and maintain your vehicle, battery-pack age/condition and other factors.
For 2014 Honda Accord Plug-In Hybrid, 115 combined miles per gallon of gasoline-equivalent (MPGe) electric rating; 47 city/46 highway/46 combined MPG gasoline only rating. 13 mile maximum EV mode driving range rating. 570 mile combined gas-electric driving range rating. Based on 2014 EPA mileage and driving range ratings. Use for comparison purposes only. Your MPGe/MPG and driving range will vary depending on driving conditions, how you drive and maintain your vehicle, lithium-ion battery age/condition, and other factors. For additional information about EPA ratings, visit http://www.fueleconomy.gov/feg/label/learn-more-PHEV-label.shtml.


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On this day — Serious questions are raised about the accuracy and veracity of Rick O'Donnell's TPPF white paper that supports Jeff Sandefer's plan for university overhaul; the Willingham hearing drags into day two; several SBOE members continue to express frustration over social studies standards; the House passes its ideas for SBOE redistricting onto the Senate as the fight begins over how to redraw district lines for the lower body; critics slam the House for "raiding" the public school trust fund; the Senate Finance Committee sends their budget bill to the printers; Perry attempts to allay concerns about the deep budget cuts; and it's day two in Texas for a visiting delegation from California.
***Significant Questions Raised About O'Donnell's Paper
An exhaustive review of a white paper authored by controversial UT System Special Advisor Rick O'Donnell entitled "Is Academic Research A Good Investment For Texas" by the Houston Chronicle and San Antonio Express-News raises significant questions about the accuracy and citations of claims made in the paper. The review, spearheaded by the Express-News' Melissa Ludwig, found more than two-dozen problems with the paper. Chairman of the UT Board of Regents Gene Powell has promised an investigation.
A provocative paper authored by a special research assistant to the University of Texas regents contains about two dozen errors, including quotes attributed to the wrong people, inaccurate citations and fuzzy data, according to an analysis by the San Antonio Express-News.
Written by Rick O'Donnell, a Colorado transplant and advocate of higher education reform, the paper's premise that the bulk of academic research in Texas produces "few tangible benefits" whipped up a firestorm of controversy over the past month as did his hiring at $200,000 a year.
O'Donnell wrote the paper, "Is Academic Research a Good Investment for Texas?" in 2008 for the Texas Public Policy Foundation, a conservative Austin think tank where he was an unpaid fellow.
David Guenthner, a foundation spokesman, claimed responsibility for the errors, saying staff merged several drafts of the document, jumbling the footnotes and leaving some out entirely.
It's worth noting that what appears to be Rick O'Donnell's former page at the Texas Public Policy Foundation (TPPF) has been stripped of its content.
***RELATED: See It Now
Below is an embedded PDF, which is made up of several PDF's provided by the Houston Chronicle and the San Antonio Express-News as part of our analysis of Rick O'Donnell's controversial white paper entitled "Is Academic Research a Good Investment for Texas?"
The PDF below has been compiled from three different documents.
– Pages 1-3 are a sample of errors found by the Chronicle/Express-News by our examination.
– The white paper that we examined can be found on pages 4-19
– A letter from O'Donnell to one of UT's Regents can be found on the remaining pages.
The Scribd documents embedded below has been configured to allow for easy printing and sharing. If you have problems, please shoot me an e-mail.
***Lads, Man The Printers
The Chronicle/Express-News Austin Bureau Chief (and budget guru extraordinaire) Peggy Fikac reported late last night that the Senate Finance Committee has sent its budget to the printers. The Senate budget spends billions more than the budget proposed by the House and they have identified where they're going to get the extra revenue from yet.
*** "Raiding" Schools' Trust Fund
The House voted to pull $200 million out of the Permanent School Fund on Thursday, which led to a volley of criticism from a great many quarters. The move, once again, highlights the struggles of the Legislature to pass a budget that slashes 13 percent of total spending without gutting the state's already stingy social welfare programs, public education and university funding. The Chron/E-N's Peggy Fikac reports:
Backers noted the Permanent School Fund exceeds $25 billion and said it makes sense to require that one-half of the net revenue from part of its portfolio be used to meet direct education expenses in these tough times.
Land Commissioner Jerry Patterson, who oversees the portfolio affected by the proposal, is among those who disagreed. He said those who oversee the trust fund should maintain the discretion to manage it.
"They're going to raid the fund that was established in 1854, and put in the constitution as a permanent endowment in 1876, instead of having the cojones to look at the rainy day fund," Patterson said after the House Appropriations Committee voted 24-1 for the proposed constitutional amendment and accompanying bill by Rep. Rob Orr, R-Burleson.
***Attempt to Allay
The Houston Chronicle's Patti Hart reports that during Perry's press conference this morning, which was ostensibly to talk about higher education, Perry attempted to allay fears that massive cuts to state spending could permanently harm important programs like public education.
Perry said Thursday he was not particularly concerned in finding new ways to sustain state government.
"I'm not spending a lot of time looking for new revenue in the state of Texas. I think we need to look at the expenditure side first," he said. "We had an election in 2010, and I don't think anybody got confused about what the lieutenant governor, the (House) speaker and myself and most members of the Legislature said, and that is, we are going to balance our budget without raising taxes."
***Willingham: Day Two
After a day spent arguing over grammar points, the commission investigating whether or not bad science was used to convict and then execute Cameron Todd Willingham for an arson that killed three of his children — the commission returns today to continue its work on it's final report. The Houston Chronicle's Allan Turner reports:
Death penalty opponents have argued that the case of Cameron Todd Willingham could be the first instance of a person wrongly executed in the U.S. since capital punishment resumed more than three decades ago. The New York-based Innocence Project first raised questions about the case in 2006, two years after Willingham was executed for the deadly home fire.
The Texas Forensic Science Commission noted that 20 years have passed and insisted that nothing in its report "constitutes a comment upon the guilt or innocence of any individual." The panel determines whether forensic science in such cases was sound, though it doesn't have the power to exonerate Willingham or reopen his case.
But the commission won't issue a finding on the arson determination until the state attorney general's office determines whether it has jurisdiction to do so, said the panel's chairman, John Bradley. Several experts have concluded that the fire was an accident or its cause should have been undetermined, not arson.
***Social Studies Standards — ROUND 234567
The Chronicle/Express-News' Gary Scharrer reports that the State Board of Education has found itself embroiled in a debate over the controversial social studies standards they passed last year. After passing the standards, the composition of the board was significantly altered as more moderate candidates beat several of the staunch conservatives.
Board member Mavis Knight, D-Dallas, revived discussions Thursday about the social studies standards.
She and other minority members complained they were getting considerable pushback from social studies teachers and coordinators from school districts they represent about the new curriculum standards. But other members defended the standards, which garnered national attention last spring.
Various civil rights and minority advocacy organizations have opposed the standards, and the Thomas B. Fordham Institute, a conservative-leaning education think tank, gave the standards a harsh review, saying they offered "misrepresentations at every turn."
***Redistricting in Two Parts
Much like a Harry Potter movie — coverage of redistricting is so awesome, so intense and so exciting that it must be divided into two for double the price of admission. The Houston Chronicle's Joe Holley reports on the House's passage of their version (Chron) of what SBOE districts should look like; and he reports on efforts by Hispanic legislators to push back (Express-News) against a map that would reduce the number of Hispanic minority/majority districts.
***They Came from California…
And they didn't even bother to bring the weather. And they didn't bother to bring me a Giants cap for that matter. What brought them to Texas then? Well, I'd like to think it was the possibility of getting a witty blog post written about them in our Texas Politics blog.


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In May 2017, OVH Group, a global hyper-scale cloud provider, acquired the vCloud Air business from VMware.
VMware has evolved its business strategy to focus on providing hybrid and cross-cloud software and services. Given this evolution, VMware is transitioning vCloud Air U.S. and European data centers, customer operations, and customer success teams to OVH. After the close of the acquisition, OVH will operate the service as vCloud Air Powered by OVH, will continue to leverage VMware's hybrid cloud technology, and will closely partner with VMware on go-to-market and customer support around the three proven vCloud Air use cases: data center extension, data center consolidation, and data center recovery.
OVH is one of the largest cloud service providers in the world with more than one million customers and 260,000 servers deployed. OVH has been a long-time VMware vCloud® Air Network™ partner with more than 200,000 VMs from thousands of customers running VMware vSphere® Private Cloud. Both companies collaborated to bring Software-defined Data Center (SDDC) as a Service to market in 2016. vCloud Air customers will benefit from greater choice as they select from OVH's global data centers across four continents and experience faster performance and workload mobility through the company's thousands of miles of dark fiber and 32 points of presence worldwide.


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HARTFORD — Midway through his postgame press conference at the XL Center Tuesday, UConn Coach Geno Auriemma was handed a cellphone by his administrative assistant Sarah Darras.
This had to be important. It was. The President of the United States was on the phone.
Auriemma has taken the last two women's basketball national champions to the White House for recognition. And after the Huskies defeated Florida State, 93-62, for their record-setting 89th straight win, Obama wanted to extend his congratulations.
"If I was calling you and you had all of these reporters in front of you, you'd be dying to take my call," Auriemma told the President.
The talked for about five minutes, a conversation that was recorded by all of the television cameras.
"Mr. President, I appreciate your call very much. It's an incredible thing that these kids have done," Auriemma said. "And I sure some credit goes to that lesson you gave them [the 2008-09 champions] on the White House basketball court. It really paid off and I appreciate you doing that for him."
Obama obviously knew that the Huskies have not lost since he was elected since his inauguration.
"How about we keep that streak going for a couple more years," Auriemma said.
After he hung up the phone, Auriemma made a joke.
"That was the new President of the University of Connecticut," Auriemma said. "Might as well get off to a great start. . . Things just keep getting more ridiculous by the day as you try to sort it all out, figure what it means."
Other Streaks
The Huskies' victory Sunday in New York actually tied them for the most consecutive wins for a North American women's college team.
The University of Winnipeg won 88 straight from 1992-95. That team competed in many U.S. tournaments in its run and featured point guard Pam Danis, the current coach of the program.
The women's team from Wayland Baptist won 131 straight from 1953-58. That team played in the Amateur Athletic Union, usually based in rural communities featuring semipro teams with business sponsors.
Moment For The Moose
There was a moment of silence for the late Walt Dropo, the former three-sport star at UConn from Moosup and 1950 American League rookie of the year with the Red Sox who died on Friday. … Auriemma was honored before the game by USA Basketball's Carol Callan for being chosen USA Basketball's co-coach of the year .. . .Former Florida State and NFL running back Warrick Dunn sat behind the Seminoles bench. . . Tina Charles, last year's college player of the year and the WNBA's rookie of the year, was also among the many UConn alumni at the game. … Said Big East commissioner John Marinatto: "I would like to congratulate Coach Geno Auriemma and recognize his staff and student-athletes who contributed to the his remarkable accomplishment. This is truly an extraordinary moment for UConn, the Big East and the entire sport. To win 89 consecutive games is a historic achievement and one of the most significant team accomplishments in all of sports."


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Texas House members stood up and applauded Rep. Joe Farias, D-San Antonio, today after he read HR 1694 applauding President Obama, the U.S. intelligence community and the armed forces for killing Osama Bin Laden.
Farias got the idea Sunday night after learning, with the rest of the nation, about Bin Laden's killing. Farias succeeded in suspending all rules to immediately bring the resolution directly to the House floor – bypassing committee hearings and legislative rules governing legislation and resolutions.
Farias choked with emotion as he read from the resolution:
Excerpts from HR 1694:
"Whereas The president's patience, leadership, wisdom and determination have led directly to the demise of the most wanted man in the world, and have hardened this nation's resolve to defeat the forces of malevolent fanaticism, and by destroying the mastermind behind the worst terrorist attack on American soil, he has struck a significant and historic blow against Al Qaeda;
"Whereas, Following the death of the perpetrator of the attacks, the family members and friends of those who lost their lives in the attacks on September 11 are able to achieve a greater sense of closure;
"Whereas, After months of meetings of the National Security Council, led by President Obama who directed intelligence officials to zero in on Bin Laden's whereabouts, intelligence officials devised and carefully carried out a clandestine operation which had frequently been rehearsed in an effort to minimize casualties, both civilian and military.;
"Whereas, As Commander-in-Chief of our great nation, he boldly gave the final authorization to commence the operation to brave and highly trained members of our nation's armed services;
"Whereas, Upon hearing the news of Bin Laden's elimination, in an impressive show of unity and in defiance of the fanatics who still today seek to destroy our free way of life, jubilant citizens expressed pride in our nation and our president by spontaneously celebrating the news in cities across the country, singing "The Star Spangled Banner" and loudly chanting, "U-S-A," and former presidents Bill Clinton and George W. Bush have offered him their congratulations;
"Whereas, President George W. Bush had the near universal support of the freedom-loving peoples and countries of the world after the attacks on September 11, 2001 when he famously pledged to defend freedom against fear, saying, 'We will not tire, we will not falter, and we will not fail,' and President Obama had the strength and wherewithal to see that pledge through to fulfillment;"
"Resolved, That the 82nd Legislature of the State of Texas hereby congratulate President Obama on his proven and successful policies in the war on terrorism and in homeland security;"
The resolution also commends the intelligence personnel and the armed forces of "heroically carried out an incredibly sensitive mission with no military losses and with a minimal loss of civilian lives."
Copies of the resolution will go to the president, speaker of the U.S. House, governor of Texas, members of the Texas congressional delegation and entered into the Congressional Record.
Farias got emotional as he read the resolution, telling colleagues that he fought in Vietnam as a member of the U.S. Army.;
Rep. Jim Keffer, R-Eastland, said he hopes every state join Texas in passing such a resolution.
Democrats and Republicans stood shoulder-to-shoulder "on that terrible day" nearly 10 years ago when Bin Laden's Al Qaeda took down the Twin Towers, Keffer noted, adding it's appropriate that Republicans and Democrats "stand shoulder-to-shoulder in the celebration."
House GOP Chairman Larry Taylor, R-Friendswood, asked that all members' names be added to Farias' resolution.
And then they paused for a moment of silence after the resolution passed without objection.


text: Lucky Brand made its mark on the fashion world by designing some of the most coveted denim jeans there are. They quickly transcended their expert skills into other areas such as accessories. All of that expertise is easily recognizable when you're looking at a pair of Lucky Brand earrings. From dangling gemstones and cascading jewels to whimsical charms and playful buttons, the label has a wide variety of earrings you can accessorize with. One of the most appealing aspects though is that for this upscale look you will not be paying upscale prices.


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May, 2008
Q: Your research lab is focused on mostly rare genetic mutations that cause autism, epilepsy, mental retardation, and learning disabilities in children. What drives your interest in these genetic anomalies?
A: My interest is both scientific and medical. Human disorders of brain development, which these all are, highlight what I consider to be some of the great unanswered questions in the basic biology of the brain—what makes us human? What is the biological basis of language, intelligence, and social behavior? In my mind, we can only solve these basic biological problems by understanding this critical set of medical problems. As a neurologist I also happen to be excited by the possibility of contributing in some small way to understanding these medical conditions, since they represent a major burden of illness.
Q: What are the most common ways in which cortex development goes awry in humans? What are the therapeutic implications?
A: There are many rare disorders in which the human brain is obviously abnormal in its shape, size, or pattern of widespread connections. therapeutically, these conditions would appear to be the biggest challenge, since it seems that definitive treatment requires impossible amounts of change to the tissue of the brain.
On the other hand, the most common way in which development of the cortex goes awry is a brain that looks outwardly normal but does not function normally, resulting in mental retardation or autism. We had assumed for a long time that these latter disorders were also untreatable, since perhaps the "microstructure" of the brain was still impossibly abnormal, and even if we corrected the genetic defect, the brain would be permanently impaired. Much to everyone's surprise and delight, recent work on animal models (from labs other than our own) has suggested that some mental retardation and autism syndromes (notably Rett syndrome and Fragile X syndrome) can be substantially reversed—even in a fully grown mouse brain—with the proper therapy, which might include replacing a [dysfunctioning] gene or otherwise compensating for it. As a neurologist, the prospect that genetic disorders may be subject to successful therapies guided by gene identification is tremendously hopeful, even if it only works for one or two genes.
Q: You've investigated how gene expression patterns differ between the left and right hemispheres, with an eye toward understanding whether such differences explain left-right specializations of the brain. What have you found so far?
A: The short answer is that we do not know for sure at this point [if left-right specializations are a result of differential gene expression]. We hope that this might be the case, and it is a reasonable hypothesis, but at this point it remains a hypothesis that needs to be rigorously tested. One of the genes that we found to be expressed more highly in the right hemisphere than the left hemisphere, called LMO4, appears to regulate the size of the sensory cortex in mice. This might suggest that left-right differences in the brain originate by slightly asymmetric "maps" of sensation or motor function in the two cerebral hemispheres.
We have also more recently identified a series of families in which several people share a malformation of the right cerebral hemisphere, but the left hemisphere looks normal.
Perisylvian PolymicrogyriaMisfold: Polymicrogyria describes a condition in which at least one region of the brain's cerebral cortex has too many folds (gyri) and the folds are smaller than normal. Polymicrogyria can occur focally or all over the brain. Walsh's lab is trying to identify the genes that may be responsible for genetic forms of the condition to better understand the types of proteins that are important in brain development. (Image courtesy of Christopher Walsh, HHMI, Beth Israel Deaconess Medical Center)
We hope that understanding the gene that causes this condition will help us understand mechanisms of hemisphere-specific development.
Q: You have suggested that some genes that cause developmental brain disorders when mutated have likely been important to the evolutionary specializations of the human brain. What are some examples?
A: Several genes that cause developmental brain disorders appear to have been targets of evolution in the lineage leading from nonhuman primates to humans over the last two million or so years. And in some cases, the function of the gene—as elucidated by the details of the genetic disease—offers hypotheses about how the gene might have acted evolutionarily.
For example, Abnormal spindle microcephaly (ASPM) is a gene that is mutated in a human disease called microcephaly, in which the brain is greatly reduced in size and intelligence is low. ASPM seems to have undergone evolutionary changes in structure in parallel to the evolution of the large brain that distinguishes us from other primates (our brain is about twice as large as the chimp, our nearest relative). On the other hand, the evolutionary changes in ASPM seemed to stop about the time our brain became fixed at its present size, and so far there is no data that differences in ASPM between different humans account for any present-day differences between people.
We identified another gene, AHI1, that is mutated in Joubert syndrome, in which children have abnormal coordination, mental retardation, and other symptoms due to abnormal patterns of axon fiber connectivity in the brain. AHI1, like ASPM, shows evolutionary changes in gene structure in the lineage leading up to humans. We speculate that this evolutionary change in the gene accompanied changes in brain wiring, perhaps including those necessary for optimal motor coordination. But we do not yet know exactly how the evolutionary changes in gene structure map onto changes in gene function, and thence to changes in brain structure. That is for future work.
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