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February 1998
A newly discovered allele, SDF-1, offers twice the protection of other gene variants...
We previously reported that individuals who have inherited a particular genetic mutation, CCR5-Delta32, from both parents seem to remain immune to HIV infection, even after repeated exposures (see "Genetic mutation appears to confer immunity to HIV," Vol. 2, No. 5). Those who inherit the gene from only one parent do develop HIV disease, but in these individuals progression from asymptomatic disease to frank AIDS takes three or four years longer than it does in people who lack the CCR5-Delta32 mutation.
Subsequent research identified variants of two additional cell-surface co-receptors, CCR2 and CXCR4, that appear to play roles in retarding the progression to AIDS. Now the team of investigators at the National Cancer Institute that discovered CCR5 has found another gene variant -- this one named SDF-1, for stromal-derived factor -- that also retards the rate at which HIV infection progresses to AIDS. SDF-1, which is also called pre-B cell growth-stimulating factor, is a powerful chemoattractant. It is the natural ligand for CXCR4, which is one of the surface co-receptors that virulent, late-stage HIV uses to enter cells. When SDF-1 is present, it down-regulates CXCR4 in cells, thereby preventing HIV from entering target cells.
The demonstration that SDF-1 effectively inhibits HIV replication prompted a search for SDF-1 structural gene variants that might influence the transmission or pathogenesis of HIV. In a subgroup of 2,854 patients enrolled in five large national HIV cohorts, Winkler et al. screened 1,354 of the base pairs represented in human SDF-1 transcripts with a series of polymerase-chain-reaction primers and other assays. What they found is that a common mutational variant of SDF-1, SDF-1-3'A -- which occurs in roughly one- third of Caucasians -- affords approximately twice the protection of CCR5 or CCR2 against disease progression and death in HIV-infected patients when it is present in two doses, one from each parent. They also discovered that the protection provided by the two CCR alleles and SDF-1 is additive: patients with both of these protective genotypes avoid AIDS and death longer than those with only one.
Winkler C, Modi W, Smith MW, Nelson GW, Wu X, Carrington M, Dean M, Honjo T, Tashiro K, Yabe D, Buchbinder S, Vittinghoff E, Goedert JJ, et al. Genetic restriction of AIDS pathogenesis by an SDF-1 chemokine gene variant. Science 1998; in press.
Dr. Stephen J. O'Brien, author of "A New Approach to Therapy," the editorial that appears in this issue, and an author of the paper cited above, comments:
Although the frequency of SDF-1 homozygous protected individuals is low -- less than 5% in the five large HIV cohorts that we studied -- the effect of this genetic variant, when it is inherited from both parents, is quite strong. The protective effect of SDF-1 is more apparent during the later stages of HIV infection, when rapidly reproducing, extremely virulent, T-cell-tropic forms of HIV develop, but the principal effect of SDF-1 may actually involve strong protection against rapid disease progression during the early stages of infection. We know, for example, that approximately half of those with HIV who do not carry the double allele for SDF-1 succumb to AIDS within 10 years of infection. By contrast, less than 5% of those with the SDF-1 homozygote genotype develop AIDS in the same period.
The real significance of this discovery is not that certain fortunate individuals, thanks to their genetic endowment, do not develop HIV even if they are repeatedly exposed to the virus, but that we can now add yet another gene variant to the growing list of chemokines that confer protection against HIV infection or retard its progress to full-blown AIDS. The discovery of these genetic variations opens a promising new avenue of research -- into therapies that prevent infection, or dramatically slow the progress of HIV disease, by mimicking the antiretroviral action of these variants.
...and CCR5 slows disease progression in children as well as adults
In the October 1996 issue of HIV Newsline we reported that a team of researchers in the Laboratory of Genomic Diversity at the National Cancer Institute had discovered a gene that appeared to confer protection against HIV infection in persons homozygous for the variant allele and that slowed disease progression in persons heterozygous for the allele.
The N.C.I. team -- which was headed by Dr. Stephen J. O'Brien, author of the editorial in this issue -- announced that this mutant gene, CCR5-Delta32, seemed to provide complete immunity against HIV infection to the one individual in 100 who has inherited the mutation from both parents; for the one individual in every five who has inherited the mutant gene from one parent, it confers resistance to disease progression. The surprisingly high incidence of partial resistance could explain why some individuals survive for many years with active infection.
A team of researchers from the French Pediatric HIV Infection Study Group recently reported the first data on the effects of CCR5-Delta32 on vertical transmission and disease progression in children. Misrahi et al. followed 512 children born to seropositive mothers. Of the 512 children, 276 proved to be infected with the virus. All were tested for the CCR5 mutation. The one infant who had inherited the mutant allele from both parents was persistently HIV-negative. Of the 49 infants who had inherited CCR5-Delta32 from only one parent, half eventually tested seropositive -- evidence that heterozygosity for the gene does not prevent vertical transmission.
However, heterozygosity for CCR5-Delta32 did appear to slow the progression of HIV disease. At 36 months, 28% of the children with a pair of normal CCR5 genes showed stage C symptoms of disease, while only 9% of the children with one mutant gene had progressed that far. By age eight, only 11% of the children with normal genes had not yet developed stage B or C symptoms of HIV disease, whereas fully 49% of the children with one mutant CCR5 gene had no evidence of disease progression. The French team's findings mirror results seen in studies of adults.
Misrahi M, Telgas J-P, N'Go N, Burgard M, Mayaux M-J, et al. CCR5 chemokine receptor variant in HIV-1 mother-to-child transmission and disease progression in children. JAMA 1998; 279: 277-80.
1. New tests for detecting viral RNA and immune response to HIV infection
The 5th Conference on Retroviruses and Opportunistic Infections, which convened in Chicago in the first week of February, offered clinicians new insights and information on the technology used to detect replicating HIV and to measure the immune response to infection. For example, the team of investigators who evaluated the two-drug combination of DMP-266 (efavirenz, Sustiva®) and indinavir were able to demonstrate the potency of this NNRTI-protease inhibitor combination, but more to the point they showed that the study participants who failed this treatment were those who failed to achieve the lowest level of replicating virus.
This finding suggests that "below the limits of detection" is, in fact, a moving target: what was once regarded as an acceptably low level of HIV RNA may not be low enough, given that viral load, even at fairly low levels, seems to correlate with response to therapy. It may be necessary to lower the present limits of detection of most commercial assays. If the level and durability of viral suppression is indeed predictive of a durable virologic response -- and is predictive even at levels that currently fall "below the limits of detection" of these assays -- then we will need a new and considerably more sensitive generation of assays to guide us in managing our patients on suppressive therapy.
Several presentations made at the conference demonstrated that dried-blood-spot specimens can be used to detect HIV RNA and HIV DNA in a large population. This technique is wonderfully stable, and these quantitation methods may be very useful in developing countries, where standard viral-load measurements are impractical. In addition, these methods may prove useful in detecting HIV in very small samples of blood and plasma (such as the stored specimens from neonate heel-sticks), and in detecting the presence of HIV infection among groups in diverse geographic locations.
A study with significant public-health implications demonstrated the utility of the dual-EIA antibody test. This system takes advantage of the time-sensitive development of HIV-specific antibodies. Newly infected individuals who are past the stage of symptomatic acute infection -- or who never manifest symptoms of acute infection -- can be identified as recently infected (that is, infected within the past 180 days) if their serum reacts to standard third-generation antibody tests but does not react to the detuned EIA.
This system of dual testing can be implemented in a variety of clinical settings to identify those with recently acquired infection. Such individuals tend to have high levels of circulating virus, and this makes them highly contagious. Identifying these highly efficient transmitters of HIV, and treating their primary infection in an aggressive manner, may help us to reduce "community viral burden" and thus limit the spread of infection. In addition, this system may be an excellent way to trace people who have been put at risk of HIV through contact with a recently infected individual, since most people are likely to remember their most recent sexual liaisons. These people can then be contacted and encouraged to submit to testing to determine if they have recently been exposed to HIV.
Another important presentation at the conference dealt with rapid HIV testing. There is considerable interest in providing HIV antibody results to clients while they are in the clinic, rather than at a follow-up visit. Providing results to clients immediately, instead of after a one- or two-week delay, may lead to reduced rates of new infections, since the window between testing and notification can be a window of opportunity for transmission.
The additional advantage of rapid HIV testing is that it permits the rapid initiation of maximally suppressive therapy, which reduces viral burden and, with it, the enhanced risk of transmission that occurs during periods of high viremia.
James O. Kahn, M.D.
2. Immune reconstitution
A key theme of the 5th Conference on Retroviruses and Opportunistic Infections was the potential for reconstitution of the immune system after it has been damaged by HIV. One of the highlights of the meeting was a state-of-the-art lecture on this topic delivered by Dr. Bruce D. Walker of Massachusetts General Hospital. In "The Body Fights Back" Dr. Walker presented detailed information on the immunologic responses of so-called long-term non-progressors, people who have maintained low viral loads and high CD4 counts despite up to 20 years of documented infection.
Dr. Walker's data suggest that these fortunate individuals mount vigorous and sustained HIV-1-specific T-helper cell responses to HIV infection. These T-helper cell responses promote and sustain cytotoxic T-lymphocyte reactions, which rapidly clear HIV-infected cells from circulation -- thus controlling viremia even in the absence of antiretroviral therapy. This critical T-helper cell response to HIV infection has been shown to be less emphatic -- or even absent -- in individuals with rapidly progressive disease. In addition, this response has been found to correlate inversely with viral load in all patients studied.
In light of these discoveries, Dr. Walker and his colleagues sought to mimic this vigorous T-helper cell response by using potent antiretroviral therapy to suppress viremia during acute HIV infection. Their intent was to limit virus-mediated destruction of HIV-specific T-helper cell responses. The group was able to demonstrate, in 11 of 11 individuals treated during the acute stage of infection, HIV-specific T-helper cell responses and robust cytotoxic T-lymphocyte responses, both of which were absent prior to therapy.
Within three to seven months of the initiation of therapy, all 11 subjects were found to have strong T-cell and CTL responses, with corresponding reductions in viral load. It remains to be seen if these individuals have in fact developed the ability to control viremia without antiretroviral therapy in the period since these important immune responses were fostered.
As Dr. Walker emphasized, there appears to be a relatively narrow window of opportunity following HIV infection for interventions designed to bolster immune function. Individuals with chronic infection and progressive disease often fail to mount T-cell and CTL responses, even with aggressive antiretroviral therapy and even when viral loads fall to undetectable levels.
Chronic HIV infection is associated with progressive loss of immune system components and immune function, as demonstrated by loss of CD4 cells, particularly those expressing the naïve phenotype. In addition, chronic infection leads to an increased CD8/CD4 ratio, to perturbation of the T-cell receptor repertoire, and to loss of delayed-type hypersensitivity lymphocyte proliferation responses to new and recall antigens.
The potential for reversal of this immune destruction and dysfunction was addressed by a number of participants in this meeting. At last year's conference Dr. Michael Lederman presented preliminary data from ACTG 315 which suggested that patients with advanced disease (CD4 counts less than 300 cell/mm3) experienced partial immune reconstitution after 12 weeks of potent antiretroviral therapy with zidovudine, lamivudine, and ritonavir, as evidenced by increases in absolute CD4 counts, increases in naïve CD4 and CD8 lymphocytes, and improved responses to functional assays such as the delayed-type hypersensitivity skin-test.
These initial findings were confirmed by the 48-week data from ACTG 315, which were presented by Dr. Elizabeth Connick in early February in Chicago. These data demonstrate a two-phase CD4 lymphocyte response to combination therapy. The first phase consists of rapid increases in both naïve and memory CD4 cells and in naïve CD8 cells -- presumably as a result of the redistribution of cells from lymphoid tissues. The second phase consists of more gradual but persistent increases in naïve CD4 cells combined with decreases in memory CD4 cells and naïve CD8 cells.
The data from ACTG 315 also show that 48 weeks of therapy with this particular three-drug combination produces decreases in markers of cellular activation and decreased apoptosis in tonsillar tissues. These findings were buttressed by Jaramillo et al., who presented data demonstrating a trend toward normalization of the CD4 repertoire following combination therapy lasting more than 15 months. Improvements in immune function were also reported by Markert et al., who found improved lymphocyte proliferative responses to recall antigens and neo-antigens in treated patients.
Despite these significant advances in our understanding of immune reconstitution following maximally suppressive antiretroviral therapy, many questions remain. What role does the thymus play in immune reconstitution? What are the immunologic consequences of viral rebound? Can HIV-specific T-helper cell responses be stimulated in chronically infected individuals? What degree of immune reconstitution will allow for the safe discontinuation of chronic suppressive therapy and primary prophylaxis against such common OIs as MAC, CMV, and PCP? (For a partial answer to this question, see "HAART therapy leads to resolution of MAC infection" in this Newsline section.) It is evident that these questions will shape our research agenda for some time to come.
Kimberly Y. Smith, M.D., M.P.H.
3. Where have all the OIs gone?
The mood at the 5th Conference on Retroviruses and Opportunistic Infections was one of enthusiasm -- and relief -- as presentation after presentation reaffirmed the widespread belief that HAART had drastically reduced the incidence of OIs in patients with advanced HIV disease. These findings accelerate a trend that began before the advent of HAART, presumably due to a combination of earlier intervention, more effective prophylaxis, combination nucleoside therapy, and improved clinical recognition and care.
Michaels, Clark, and Kissinger from New Orleans conducted a retrospective study of a cohort of patients with CD4 counts below 200 cells/mm3. They compared the rates of OIs 18 months before and 18 months after the availability of protease inhibitors. The most striking declines were seen in the incidence of PCP, which fell from 18% to 11.7%, and in the incidence of wasting, which dropped from 9.5% to 4.8%. The investigators did not comment on the role that prophylaxis may have played in effecting this trend.
Dr. Robert Murphy presented an analysis of OI risk based on antiretroviral regimens in 1,057 patients enrolled in the CPCRA 034/ACTG 277 trial, a PCP prophylaxis study. The median CD4 count was 60 cells/mm3 in this cohort, and 49% had a prior AIDS-defining illness. None of the patients were on a protease inhibitor at baseline, but protease inhibitor use increased dramatically during the study: to 9% at 12 months and 72% at 24 months. The clinical event rate declined from 64 per 100 person-years during the first year of the study to 34 during the second year. The most significant declines in relative risk were seen in PCP and in mortality.
Moore and colleagues at Johns Hopkins assessed the incidence rates of OIs and the use of combination antiretroviral therapy in 1,500 patients, and here again the data showed a significant decline in infections. The greatest reduction occurred with CMV, followed by reductions in cryptosporidiosis, toxoplasmosis, MAC, PCP, AIDS dementia, and bacterial pneumonia. Of note, none of the patients with a CD4 count greater than 200 cells/mm3 developed an opportunistic infection.
Dr. Judith Currier presented a very thorough overview of the decreasing incidence of OIs. As she indicated, study after study supports the contention that maximally suppressive antiretroviral therapy has dramatically reduced the number of OIs seen in patients with advanced HIV disease -- but these infections do continue to occur. As my colleague Dr. Steven Deeks noted, a significant number of patients experience "virologic failure" -- rebound of viral load after suppression with HAART -- yet these patients still have stable CD4 counts and have not progressed clinically.
So, what is really going on in these patients? Does HAART really confer protection against OIs? Has immune reconstitution really occurred? This was easily the most controversial -- and most exciting -- topic addressed at the conference. There was compelling evidence presented that the initial increase in CD4 count that is seen with HAART results from peripheral expansion of pre-existing lymphocytes. This rapid expansion is followed, after a year or more of HAART, by a gradual, selective rise in naïve T-cells. What we don't know is how much of the previous memory repertoire is regained after HAART.
What are the clinical implications of this new information? Can we really stop prophylaxis and/or maintenance therapy for OIs in patients who respond well to HAART? Freeman and colleagues presented follow-up data on eight patients with CMV retinitis who discontinued maintenance therapy after their CD4 counts rebounded on combination antiretroviral therapy. These patients still have no evidence of recurrent disease an average of 300 days after the cessation of treatment of their retinitis. In addition, my colleagues and I at San Francisco General Hospital reported on four patients who discontinued MAC therapy after receiving 12 months of macrolide-based antimycobacterial therapy and HAART (see "HAART therapy leads to resolution of MAC infection" in this Newsline section).
We are still faced with many unanswered questions regarding immune reconstitution. OIs still exist. They may be diminished in number and severity, but significant morbidity and mortality does occur. Several clinical trials, ongoing or in development, will address the issue of discontinuing prophylaxis for MAC and PCP and of discontinuing therapy for CMV and MAC. Until they provide us with a better picture of what is happening in these patients, I recommend that clinicians follow the guidelines issued by the Infectious Disease Society of America and continue prophylaxis and maintenance therapy regardless of how high a patient's CD4 count rises.
Judith A. Aberg, M.D.
Another apparent benefit of maximally suppressive antiretroviral regimens
Prior to the introduction of highly-active antiretroviral therapy, disseminated MAC infection was one of the most common life-threatening opportunistic infections seen in patients with advanced HIV infection. DMAC occurred almost exclusively in patients with CD4 counts below 50 cells/mm3. Prognosis was poor: even with optimal antimycobacterial treatment, median survival was only eight to nine months from the time of diagnosis. Despite the widespread use of a multidrug macrolide-based regimen, relapses were common. There were no reports of microbiologic cure of MAC on this regimen, so the standard of care was to continue treatment for the rest of the patient's life.
The advent of HAART has changed this picture, as it has changed so much about the treatment of HIV infection and its sequelae. A group at San Francisco General Hospital reports that four of their patients who developed disseminated infection when their CD4 counts fell below 50 cells/mm3 have apparently been cured by a combination of HAART plus antimycobacterial therapy for DMAC. After more than a year of antimicrobial therapy and HAART all four were asymptomatic and medically stable. Antimicrobial therapy was withdrawn after both peripheral blood cultures and bone marrow cultures were sterile for MAC. All subsequent cultures on all four patients have been negative (range: 5-10 months), and all four of these patients remain clinically asymptomatic.
Aberg JA, Yajko DM, Jacobson MA. Eradication of disseminated Mycobacterium avium complex (DMAC) in four patients after twelve months anti-mycobacterial therapy and response to highly active antiretroviral therapy (HAART). 5th Conference on Retroviruses and Opportunistic Infections, Chicago, IL, January 31 to February 5, 1998. Abstract 729.
Dr. Judith A. Aberg, an author of this report and a member of the editorial advisory board of HIV Newsline, comments:
To our knowledge this is the first report of the successful discontinuation of antimycobacterial therapy for DMAC in patients with AIDS after presumed immune reconstitution following HAART. There were no reports of microbiologic cure in the pre-HAART era. Although median survival with optimal antimycobacterial therapy in the pre-HAART era was less than one year, our four patients were asymptomatic after one year of combined antimycobacterial therapy and potent antiretroviral therapy, had sterile blood and bone marrow cultures, and had no clinical or microbiologic evidence of MAC relapse up to ten months after discontinuing antimycobacterial therapy. These observations suggest that AIDS-related DMAC can be cured in patients who demonstrate immunologic improvement with HAART. ACTG 393, now in development, will further elucidate which patients can safely discontinue MAC maintenance therapy.
Evidence continues to accumulate that HAART has a significant impact on AIDS-related morbidity. There have been multiple anecdotal reports that HAART has a positive therapeutic effect on such previously untreatable OIs as progressive multifocal leukoencephalopathy, cryptosporidiosis, and microsporidiosis. Torriani et al. have reported that eight of their patients were able to discontinue CMV maintenance therapy on HAART. These patients had a median CD4 count of 39 cells/mm3 at the time their CMV retinitis was diagnosed; at the time their CMV maintenance therapy was discontinued, the median CD4 count was 172 cells/mm3 (range: 63-404).
None of these individuals experienced progression of CMV disease after a mean follow-up of 146 days (range: 72-205). CD4 counts remained elevated (mean: 198 cells/mm3) even though six out of the eight patients had detectable viral load (mean: 40,000; range: 409-423,000). These findings suggest that HAART may restore CMV-specific immunity even in patients who do not achieve complete suppression of plasma viremia.
Studies are needed to further characterize the immunopathogenesis of DMAC, so that those patients at highest risk for disseminated infection can be identified. It would then be possible to target prophylaxis or pre-emptive therapy for that population -- and then discontinue that treatment if HAART restores the immune responses associated with MAC protection. A better understanding of these immune mechanisms would help clinicians predict which patients with DMAC can be expected to be cured of their infection after a course of antimycobacterial treatment, and it would also provide data for the development of immune-based therapies.
A novel antiretroviral agent shows early promise
The first member of what might be considered a fourth class of anti-HIV agents is now in Phase III clinical trials. Adefovir dipivoxil is a decoy for reverse transcriptase, which mistakenly adds the tri-phosphorylated form of the drug to a DNA chain, thus terminating it. Nucleotides consist of a nitrogen-containing base, a five-carbon sugar moiety, and a phosphate group. Earlier drugs, like ZDV, ddI, and ddC, are analogs of nucleosides, which are the same as nucleotides but without a phosphate group.
Three phosphates are eventually needed to provide the energy to keep the DNA chain growing. The enzyme that adds the first phosphate group is only expressed in certain cells at certain times, a fact that limits the antiretroviral activity of nucleoside analogs. Nucleotides are one step ahead of the game, with the first phosphate already in place. A separate enzyme, one found in a wider variety of cells for longer periods of time, adds the other two phosphate groups.
Since adefovir requires only the more broadly available enzyme, it should be a more versatile drug than the venerable nucleoside analogs. Adefovir was recently assessed in a small, randomized, placebo-controlled trial over a period of 16 weeks. Treatment was for 12 weeks, and patients were re-evaluated four weeks after cessation of any antiretroviral therapy. The 72 patients recruited for this study had a median baseline CD4 count of 339 cells/mm3 and RNA level of 4.9 logs. During the first six weeks of the trial, two-thirds of the participants received drug, of which half took 125 mg once daily and the other half took 250 mg once daily. The remaining patients were randomized to placebo.
After six weeks, everyone was given open-label drug. As a group, the patients had significant prior antiretroviral exposure, with median duration ranging from 2.3 years in the low-dose arm to 3.5 years in the original placebo group. This difference between drug and placebo recipients was statistically significant.
Changes in CD4 counts were not particularly impressive, but after six weeks of therapy there was a small, significant rise in CD4 counts among patients assigned to the 125-mg dose. The authors were puzzled that this benefit was not seen in patients on the higher dose. HIV RNA responses were more consistent.
A statistically significant decline in HIV RNA levels was noted in drug recipients at both dose levels after six weeks. RNA rebounded close to baseline during the four weeks off treatment. Placebo recipients had no change in HIV RNA from baseline to six weeks, but they did exhibit a decline in viral levels after being switched to drug.
Adefovir also has in vitro activity against CMV and other viruses. The authors conducted a subset analysis of 18 patients who had positive CMV titers in semen samples. Of the 13 evaluable patients, all drug recipients (n=10) showed a decrease in semen CMV halfway through the trial. By contrast, the three placebo recipients in this cohort had increases in semen CMV.
The drug appeared to be well tolerated. Nausea was the most frequent adverse effect, and it seemed to be dose-dependent. Four patients in the higher-dose arm left the trial due to drug toxicity; two had nausea and vomiting, one developed dysuria and a genital ulcer, and the fourth patient had fever and chills. No patients in the lower-dose arm discontinued the drug because of adverse effects.
In summary, this agent shows promise against HIV, with possible anti-CMV activity as well. Early results indicate that adefovir is well tolerated, and resistance does not seem to develop rapidly or consistently. It will be interesting to see how well this agent performs in combination with the many other drugs now in clinical use.
Deeks SG, Collier A, Lalezari J, Pavia A, Rodriguez R, Drew WL, et al. The safety and efficacy of adefovir dipivoxil, a novel anti-human immunodeficiency virus (HIV) therapy, in HIV infected adults: a randomized double-blind, placebo-controlled trial. J Infect Dis 1997:176:1517-1523.
A therapeutic option in some patients who have developed resistance to ZDV
Stavudine (d4T) and lamivudine (3TC) are commonly used together because they are known to be synergistic and because they have non-overlapping toxicity profiles. The rationale for their concomitant use is supported by studies that show them to be safe and efficacious in patients with limited prior antiretroviral therapy.
Rouleau and colleagues, working at the University of British Columbia, gave this combination of nucleoside analogs to a group of HIV-infected patients who were failing, or intolerant of, combination regimens that contained ZDV. More than half of the participants had previous experience with one or both of the study medications -- meaning that the study reflects what is commonly seen in the real world of clinical practice.
Of 58 patients recruited for this open-label study, 48 patients were evaluated; 10 others did not complete the trial for various reasons. Two dropped out when they developed rash that may have been associated with a study medication. Mean CD4 at baseline was 135 cells/mm3 and mean viral load was 4.7 logs. One-third of these patients had experienced an AIDS-defining event. ZDV had been taken for a median of 12 months by trial participants, and 30 of the participants also had prior exposure to d4T or 3TC.
During the eight-week trial, subjects received 150 mg of 3TC twice daily and 20-40 mg of d4T twice daily. Neutropenia, associated with 3TC therapy, developed or worsened in 11 patients, but only one needed to discontinue the drug as a result. Twelve patients showed increased liver enzymes, an adverse reaction sometimes seen when patients take d4T, and four of these reactions were indeed considered to be therapy-related. None of the 12 left the trial or suffered adverse consequences. Grade 1 peripheral neuropathy, possibly related to d4T administration, was seen in nine patients. One additional patient developed a Grade 3 neuropathy, prompting discontinuation of study medications.
After two weeks of therapy, HIV RNA levels reached their nadir, with a median decrease of 0.86 log. Over the next six weeks the median RNA level climbed steadily, but it remained well below baseline at eight weeks. By the end of the trial, 16% of patients had undetectable viral load by the Amplicor assay. The median CD4 change was an increase of 30 cells/mm3 above baseline at eight weeks.
The patients who benefited the most from the two-nucleoside combination of 3TC and d4T, as reflected in viral load and CD4 measurements, were those who began the trial with higher CD4 counts, no prior exposure to the study medications, and no AIDS-defining event. However, even those patients with lower CD4 counts, prior exposure to d4T or 3TC, and an AIDS diagnosis showed some response to the d4T-3TC combination, suggesting that it overcomes some degree of therapy-induced resistance. The authors conclude that prior d4T and/or 3TC therapy does not preclude the ability to achieve a response to these two drugs in combination.
Rouleau D, Conway B, Raboud J, Rae S, Fransen S, Shillington A, et al. Stavudine plus lamivudine in advanced human immunodeficiency virus disease: a short-term pilot study. J Infect Dis 1997; 176: 1156-1160.
Dr. Paul A. Volberding, the editor-in-chief of HIV Newsline, comments:
Although the current standard of care for people with HIV is therapy with a combination of at least three antiretroviral agents -- usually two nucleoside analogs plus a protease inhibitor, less often two nucleoside analogs plus an NNRTI -- a significant number of patients are still being treated with a combination of two nucleosides, and a distressing number remain on monotherapy.
Dual-nucleoside regimens are not the most potent or the most appealing of current therapeutic options, but for some patients they may be the best practical choice, especially for patients who cannot obtain or tolerate more powerful antiretroviral drugs. Certainly they are indicated for those who cannot comply with complicated multidrug regimens. For patients who have not begun triple-drug therapy, d4T plus 3TC is a safe and moderately effective therapeutic combination. It will not consistently suppress viral load to undetectable levels, but it does leave patients the option of switching to more potent combinations at a later date. An attractive feature of combining 3TC and d4T is that both drugs are given twice a day and there are no dietary restrictions.
Women are at particular risk for OIs and other complications
Poor nutritional status has been associated with decreased survival, increased disease progression, and more frequent development of opportunistic infections in patients with AIDS. Intravenous drug users are at particularly high risk for inadequate nutrition, and this risk factor represents a special challenge for healthcare professionals who treat IVDUs with HIV infection. A new study suggests that female IVDUs with advanced immune suppression secondary to HIV infection are disproportionately in need of interventions aimed at improving their nutritional status.
Baum et al. recruited 82 men and 43 women from a cohort of drug-using HIV-infected individuals followed for the previous nine years. The group was overwhelmingly African-American (88%), with a sampling of Hispanic (8%) and white participants (4%). The mean baseline CD4 value was 407 cells/mm3 for men and 470 cells/mm3 for women, a difference that was not statistically significant. Men and women in the study had comparable dietary intake. However, there were significant differences in the nutritional status of men and women, reflected in different concentrations of micronutrients and proteins in blood samples.
These differences were noted only in patients with CD4 counts below 200 cells/mm3, a relatively small segment of the cohort (28 men and 11 women). Nevertheless, the numbers proved to be of statistical significance. Women with low CD4 counts had lower levels of selenium and of vitamins A and E. Furthermore, sensitive surrogate markers of overall nutrition were diminished in this group of female IVDUs. The average levels of prealbumin in men with CD4 counts below 200 cells/mm3 were 20.8 mg/dl, and the average retinol-binding protein levels were 4.6 mg/dl in this group. The comparable figures among women with CD4 counts below 200 cells/mm3 were 11.3 mg/dl and 2.2 mg/dl, respectively. The reason for these differences remains obscure to the authors, who postulate that it is probably multifactorial. They call for further study to determine the etiology of the differences they noted.
Some studies have shown differences in disease progression and survival between men and women, with the latter group generally having a less favorable course. Other studies contradict this observation. The findings of Baum et al., in this select group of patients with HIV infection, merit follow-up. If they are corroborated, it will be important to assess the reasons for the marked nutritional deficiencies seen in female IVDUs with low CD4 counts, so that specific interventions can be developed.
Baum MD, Shor-Posner G, Zhang G, Lai H, Quesada JA, Campa A, et al. HIV-1 infection in women is associated with severe nutritional deficiencies. JAIDS 1997; 16: 272-278.
CSF RNA levels appear to correlate with AIDS dementia
The pathophysiology of HIV in the central nervous system has been difficult to characterize. It is well known that the CNS is a viral reservoir, and because most antiretroviral agents have poor CNS penetration this reservoir represents a major therapeutic challenge in the quest to eradicate HIV infection. A more immediate goal is to understand the relationship, if any, between viral levels in the CNS and the neurological sequelae of HIV infection. Using state-of-the-art viral quantitative techniques, McArthur and colleagues have generated data that move us closer to understanding how HIV affects the tissue of the CNS.
Specifically, this group, which represents a collaboration between researchers at Johns Hopkins, Glaxo Wellcome, and Organon Teknika Corporation, examined the relationship between HIV RNA load and neurologic status in 207 HIV-infected patients. The subjects were recruited from the Multicenter AIDS Cohort Study (MACS) and the neurology clinic at Johns Hopkins in Baltimore. They were divided by clinical neurologic status: 37 patients had a diagnosis of HIV dementia (HIV-D) at baseline, 77 had HIV-associated minor cognitive/motor disorder (HIV-MCMD), and the remaining 93 were without neurological symptoms (HIV-NML). Patients with opportunistic infections of the CNS or cytomegalovirus infections were excluded. When available, frozen, viable CSF samples were used; otherwise participants underwent lumbar puncture. The samples were collected before HAART became the standard of care for patients with HIV infection.
This was the first study to use the nucleic acid sequence-based amplification assay (NASBA) to examine the relationship between neurologic disease and viral load. In this cohort, plasma HIV RNA was isolated with equivalent frequency across the whole clinical spectrum of participants. However, there was a significantly higher percentage of RNA isolated from CSF samples of patients with dementia (81%) versus patients with HIV-MCMD (38%) or those without neurological symptoms (33%).
Viral load in CSF was also significantly higher in the patients with dementia compared to the other two groups, a correlation not observed with plasma RNA measurements. Furthermore, the authors found a correspondence between plasma RNA and CSF RNA levels in patients with CD4 counts below 200 cells/mm3. Plasma RNA levels were not independently associated with neurological symptoms, however.
For the group with CD4 counts below 200 cells/mm3, an association was also found between CSF RNA levels and CSF-ß2 microglobulin levels. This last finding is considered by the investigators to reflect a parallel increase between viral load in the CSF and activation of an immune response. Twenty-two post-mortem brain samples were available for study; only six were from demented patients. The authors found no correlation between HIV RNA levels in the tissue and clinical neurological status.
There is some question as to whether HIV in the CNS is mostly a result of local replication or of trafficking through the blood-brain barrier via white blood cells. The authors assert that the number of white blood cells they observed was insufficient to explain the levels of viral load they measured in CSF with the NASBA assay. They suggest that brain tissue is a significant source of HIV in this compartment.
These findings strengthen the case for CSF HIV RNA as a surrogate marker for HIV dementia and suggest a relationship between plasma RNA and CSF RNA levels in patients with low CD4 counts. In addition, they provide insight concerning the pathogenesis of HIV infection in the CNS.
McArthur JC, McClernon DR, Cronin MF, Nance-Sproson TE, Saah AJ, St. Clair M, and Lanier ER. Relationship between human immunodeficiency virus-associated dementia and viral load in cerebrospinal fluid and brain. Ann Neurol 1997; 42: 689-98.
Back to the February 1998 HIV Newsline contents page.
This article was provided by San Francisco General Hospital. It is a part of the publication HIV Newsline.


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CES 2013: Ford Opens Doors to App Developers
Ford launches a new mobile app development program that connects developers with Ford's engineers. Ford Connected Services Solutions director Doug VanDagens joins digits from the Consumer Electronics Show in Las Vegas. Photo: Ford Motor Company, Inc.
This transcript has been automatically generated and may not be 100% accurate.
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K ... this week it's the Consumer Electronics Show and last but yes and we will have a lot of reports from ... the week ... for that but is popping open the wood to app developers will have back and mall right and right now on Digits good afternoon and welcome I'm Simon Constable legal someone from for joining us now ... live from the consumer electronics show in last I guess ... it's a document Aikens a is a services solutions director that thanks for joining us now ... slow apps in cars and hit explain exactly what you doing ... with passing cars and and and one a popping up and looked to developments ... so we've been doing this for awhile we started with our Apple in Korea which is fundamentally technology and the people cited that we get developers to integrate into their smartphone apps ... that allows the controls and be able to control your smartphone ... so the boys in June this year will find the bonds on touch screen ... will be announced here today it's really ... developers are and it has all the cool assets necessary ... opened up to kill thousands and thousands of developers and that the customs statistics hoping this site recently had about three thousand requests ... from developers to get on the site and ... then use our schools ... since three thousand requests ... analysts ... on the view of what he hoped to gain from this Avici Ford is a massive company ... 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subset: commoncrawl


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Secondary Operations
Decorating, Shielding and Plating Secondary Operations
Decorating, shielding and plating are a few of the many secondary operations available to you from Phillips-Medisize – your source for manufacturing support from concept to commercialization.
When you partner with us, you benefit from our commitment to implementing continuous-improvement technologies and processes. From state-of-the-art technology and clean room-like facilities to leading edge equipment, Phillips-Medisize is equipped to provide you with the quality outcomes you expect.
The high standards of service you receive results in superior components, lower rejects, and unparalleled part-to-part repeatability in the marketplace.
Starkey Pumps Up the Volume
Starkey partnered with Phillips-Medisize to decorate parts used in the Zon™ with BluWave™ SP series hearing aids. Phillips-Medisize met the Starkey timeline and acquired the knowledge and tools required to alter the surface energy of, and thereby paint, Starkey's chemically resistant nylon resin of choice. Read more.
Innovators in Secondary Operations
Phillips-Medisize has been an innovator in ushering these secondary operations processes to new levels of quality and cost-effectiveness:
- Decorating
- Paint and Laser Etching – a process for creating backlit components
- Masking
- Painting
- Plating
- Shielding


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Fleetwood Paintball Site's Listing
Paintball Blackpool12
24 minute drive from Fleetwood
Blackpool is the closest Paintball site to Fleetwood
Being located in Blackpool we are in the unique position of being located in the UK's entertainment capital and you can even see the world famous Blackpool Tower from our Lasertag and Paintball Arenas. Paintball is the ideal activity for Stag & Hen Do's, Birthday Parties, your Corporate Event or just a group of mates. All players on site are wrist banded and a paint list is with you at all times so they know exactly what you are spending at any point during the session.
The ideal Blackpool venue for your Stag Do, Hen Party, Birthday, or Corporate Day Out being just based minutes away from the town center and just of Junction 4 off the M55 motorway.
Alternative Venues Near Fleetwood
Paintball Preston
Preston is the closest Paintball site to Fleetwood
45 minute drive from Fleetwood
A brilliant site with 6 game zones to tackle, like Octopus, Dracula, The Fort and The Hulk Field. Each zone is crammed with barricades and bridges and more. Plenty of room to dive around, make a mess and take no prisoners.
Paintball Wigan, Lancashire
57 minute drive from Fleetwood
Paintballing is great fun and a physically challenging team-orientated group experience. We have considerable experience in running paintball group games for birthday and stag parties, sports clubs, schools and colleges and company team building events. Our fantastic 40 acre playing area has been constructed within perfect paintball Woodland. Our woodland site is organised into many different game playing areas.
Paintball Ormskirk
59 minute drive from Fleetwood
A 16 acre war zone, set within dense north west forest terrain, full to bursting with purpose-built barricades, forts and abandoned vehicles. Home to all the classic paintball skirmishes like capture the flag. A fast and furious, action packed venue.
100 FREE Paintballs!
Paintball Manchester
64 minute drive from Fleetwood
This fantastic site, easily accessible from Manchester and the north-west, features several gaming areas across our woodland battleground and several unique features including ditches, streams, swamps, forts, pillboxes and much more!
Indoor Paintball Oldham Indoor
68 minute drive from Fleetwood
This thumping indoor paintball arena caters for frantic action and lots of close quarters combat. Sink your teeth into demanding team missions with a variety of objectives and don't forget to pummel the enemy along the way.
Paintball Knowsley
68 minute drive from Fleetwood
A massive woodland battleground is the stage for your electrifying paintball shoot-outs. 200 splattering soldier can compete here at any one time with wicked environments to blast through. Lead your team to victory, but watch out. Something lurks in the trees. It's the Predator, just like the Hollywood movie.
Indoor Paintball Liverpool
76 minute drive from Fleetwood
Paintball Brighouse, West Yorkshire
88 minute drive from Fleetwood
Welcome to one of the most easiest and enjoyable sites to find and play at. For an action-packed and utterly unique paintball experience, rally your troops at our Brighouse site. With a selection of adrenaline packed game zones to play in including a Western style village It is time to prepare to lose yourself in another world of action and excitement. Live out your own thrilling combat epic, and be the hero of the story.
100 FREE Paintballs!
Paintball Frodsham, Cheshire
88 minute drive from Fleetwood
Located within 200 acres of stunning Cheshire countryside. The ideal location for businesses throughout the North West seeking a venue to host corporate days, team building events and conferences.
We are also an extremely popular venue for hen & stag parties, private groups and individuals looking for a fun day out in the country.
Distances and drive times have been collated using third party software.
They are approximate and meant only as a guide.


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Re: Move Between Windows
I use VS 2005 in the standard "Tabbed documents" Window layout. There are usually 3 or 4 vertical tab groups across two physical monitors. On a nontrivial solution there can be 5 or 6 tabs in each tab group.
As I get better with ViEmu it is more and more of an annoyance to have to mouse-click the various windows to move focus. Are there key combinations to move from window to window? In the vim manual I just discovered CTRL-W followed by the navigation keys hjkl, which would be ideal. gt and gT are buffer related, and don't correspond to the windows. The VS built-in Ctrl-Tab and Ctrl-Shift-Tab are suboptimal too.
Once I'm in a tab group, are there keystrokes to cycle through the files *just in that tab group*?
Last edited by gandalf (2009-03-26 22:12:27)


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California Department of Transportation
District 10 - Stockton
Lisa Balcom
(209) 941-6562
February 17, 2010
Merced County - Caltrans today announced construction has begun on the $34.3 million West Merced Overhead Project on State Route 99. The project will primarily be financed by an infusion of almost $30 million in American Recovery and Reinvestment Act (Recovery Act) funds.
"My Administration is working hard to ensure Recovery Act dollars go toward funding jobs and investing in the future of California's transportation infrastructure," said Governor Amold Schwarzenegger.
Scheduled for completion by spring 2012, this project will replace two bridges at the West Merced Overhead and retrofit two Bear Creek Bridges. All of the bridges are located on State Route 99 in Merced. The project's contractor is RGW Construction Incorporated of Livermore.
"The Recovery Act is providing vital funding to improve transportation in every region of California, including the Central Valley. We're investing Recovery Act dollars where they are most effective - supporting our economy by preserving and funding jobs," said Caltrans Director Randy Iwasaki.
'We look forward to a successful partnership with Caltrans in building this project, ~ said David Kennedy, Operations Manager, RGW Construction Incorporated. wThis project is good for the traveling public, the construction industry, and California's economy."
Today marks the one-year anniversary of the Recovery Act and under Governor Schwarzenegger's leadership, California leads the nation with $2.47 billion in Recovery Act funding obligated to 898 highway and local street transportation projects statewide. Of these, 481 projects worth $2.45 billion have been awarded contracts to begin work, with an additional $317 million in Recovery Act funds expected to be awarded to 94 projects by April. For more information on the Recovery Act visit: recovery.ca .gov


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East 09 Talks
Jim Moldgenski
Architecting Your PostgreSQL Application for the Cloud
The cloud is a powerful environment for deploying applications, but like any type of infrastructure, it has strengths and weaknesses. This session will discuss how to leverage those
Greg Sabino Mullane
Bucardo is a replication system for Postgres that uses triggers to asynchronously copy data from one server to many others (master-slave) or to exchange data between two servers (master-master). We'll look at replication in general and where Bucardo fits in among other solutions, we'll take a look at some of its features and use-cases, and discuss where it is going next. We'll setup a running system along the way to demonstrate how it all works.
Monisha (Sarah) Pulimood
Building A Collaborative Environment With PostgreSQL To Enhance The Learning Experience | Slides
This talk will focus on CAFE, a Collaboration And Facilitation Environment, built on top of PostgreSQL, that we developed to support a pilot interactive journalism institute for middle schoolers. Using this environment, which is more than a content management system, we are introducing young people to
Stephen Frost
Column-Level Privileges
PostgreSQL has recently gone through some changes to the privilege/GRANT system, especially with 8.4. We will discuss the implementation of column-level privileges in 8.4 and what can, and can't, be done with them, including what happens in JOINs and partial INSERTs. We will also review the various permissions which can be GRANT'd at each of the PG levels: database, schema, table, and the new-in-8.4 column-level privileges. We'll go over the default permissions, the new TRUNCATE permission and why it's a separate and distinct permission, and the implications and side-effects of certain related commands.
Joshua D. Drake
Configuring a Warm Standby, the Easy Way
A 45 minute talk discussing PostgreSQL PITR and using PITRTools.
Lacey Powers
Converting your database and application from Sybase/MSSQL to PostgreSQL
This talk will cover a practical example of how to convert your database and application from Sybase/MSSQL to PostgreSQL, including ddl, data, stored procedures, and code. Code snippets will be Java and PHP, but the concepts should be applicable to any codebase.
Chris Browne
Database Development Policies
|PostgreSQL is a sophisticated database system (as we all know!), and has all sorts of features that can be used for good and for ill. This talk will discuss the sorts of development policies useful to encourage consistency of usage, compatibility with administrative policies (e.g. - so that the DBAs don't hate the developers!) and interoperability with third party components (such as replication using Slony-I!).
Jignesh K. Shah
Effects of Flash and SSDs on PostgreSQL
With the advance of Flash based SSDs, we look at the impact of using such drives with PostgreSQL. Primarily the talk will talk about observed impact on PostgreSQL using some well known workloads.
John Rogelstad
I want my ERP: Money for nothing, toolkit for free
While it seems as though a new application development toolkit pops up almost weekly, until now most extensible accounting and business applications still mostly rely on expensive and proprietary technology to make customized solutions and modules. But who wants to write an Accounting system with a toolkit from scratch? Learn how Postgres and other open source tools were used to create a powerful yet friendly end user development environment for xTuple ERP that can be used by novices
Jeff Brown
Grails In Practice
Grails is a full stack MVC framework for building web applications for The Java Platform. Grails makes web application development both fun and easy. This session covers all of the fundamentals of building web applications with Grails. Businesses need rich web applications and developers want to be
Jeff Brown
Grails Workshop
Grails Workshop. For those who want to get their hands dirty with Grails, this is a three hour workshop that follows up on the Grails in Practice mini-tutorial.
Gavin M Roy
Introduction to Golconde | Slides
Learn about Golconde, a queue-based data distribution system developed at myYearbook.com. In implementing data distribution via external message queues, Golconde differentiates itself from traditional PostgreSQL replication tools, moving the workload for replication management outside of PostgreSQL itself. We will review the design decisions that resulted in Golconde as well as see it in action. Golconde is a queue based replication solution for PostgreSQL written in Python. It is designed to be loosely coupled and rely upon existing enterprise messaging systems that have STOMP protocol support. Designed to scale easily and with multi-data center implementations in mind, the application and message queues for distribution live outside of the database. By decoupling Golconde from PostgreSQL it
Mike Coyle
Introduction to the Pylons Web Application Framework | Slides
Pylons is a lightweight web framework for the Python programming language. It emphasizes flexibility and rapid development, and is built atop open standards. This mini-tutorial will explain the features, benefits, and general architecture of Pylons, and its unique value proposition among the many web application frameworks available today. It will also cover the use of PostgreSQL in Pylons applications, using the SQLAlchemy object/relational mapping library.Discussion materials will be targeted to IT professionals who are not necessarily Python developers.
Bruce Momjian
Mastering PostgreSQL Administration | Slides
|A four hour training on Mastering the intricacies of PostgreSQL Administration.
Greg Sabino Mullane
Monitoring Postgres with check_postgres.pl
What should you monitor? And how? We'll look at the sort of things you should care about when watching over your Postgres databases, as well as ways to graph and analyze metadata about about your database, with a focus on the check_postgres.pl script.
Josh Williams
More Than Storage: Intro to PL/pgSQL
You give it data, it gives it back when you ask for it. But PostgreSQL can do much more for you. Meet the PL. Procedural Languages let you execute code inside the database itself. We'll look at PL/pgSQL and some of its friends. Using PL's you can combine complex database logic into a single function to execute manually or define triggers that maintain things automatically, separating out those tasks and freeing your application. It's a laz^H^H^H smart programmer's dream come true!
Robert Treat
No More Waiting, A guide to PostgreSQL 8.4
Another year, another PostgreSQL release, and once again this release packed full of new features that will help you whether you develop apps inside or outside the database, or you just need to keep them running. This talk will give an overview of the new features available in 8.4, and give you pointers to talks during the rest of the conference you'll want to focus on to get the most out of 8.4.
Larry Price
pgcrypto benchmarking
A sample database and test script for benchmarking the performance of the cryptographic operations available from the pgcrypto package on different classes of hardware is presented. Along with results from running the test in multiple hardware and OS environments. Including also some side notes for structuring search indices for encrypted fields, and a discussion of the role of cryptography in a database security plan.
Robert Treat, Greg Smith, Joshua Drake, Andrew Dunstan
Performance Roundtable
Ever wonder about PostgreSQL performance? Have a particular problem you are trying to conquer? Do you need to know best performance practices? Learn from the recognized masters in the community in this 90 minute performance round table.
Jonah Harris
Playing with Playr: The Postgres Application Testing Tool
Have you ever wondered how well your application is going to perform when moving to new server hardware or upgrading to a newer version of Postgres? Do you want to know what queries will
Brent Friedman
Postgresql and Java
Introductory level talk on using Postgres with
Kevin Kempter
PostgreSQL Backup/Recovery and Replication | Slides
Newbie track talk around developing a "data availability" strategy. Covered topics will be: - PostgreSQL dumps (pg_dump & pg_dumpall)- PITR (Point in time Recovery)- Warm Standby server- SLONY- Putting it all into a 'data availability' strategy.
Jonah Harris
Predicting Postgres Performance: Practical Queueing Theory for
So, you've solved all of your current performance problems, but are you ready for tomorrow? Suppose your website traffic increases three-fold, or your company has a huge end-of-year processing job to run, at what point will your system become unusable? In this case, is it a CPU problem, I/O problem, or both? Should you add additional CPUs or can you just get faster CPUs? How fast does your I/O subsystem need to be in order to handle your workload? How much would query tuning help? This session is designed to help you answer those questions. While often misunderstood and underutilized, queueing theory has long-since provided us with the ability to model behaviors and performance characteristics of complex computing systems. Unfortunately, many people shy away from queueing theory because it is often expressed using complex mathematical equations. However, in this session, we'll cover the basics of queueing theory and demonstrate how to apply its concepts and equations to practical, real-world
Norman Yamada
Reconciling and comparing databases using schemas, DBI-Link and Slony | Slides
The Millburn Corporation is a hedge fund which uses complex data-driven trading models based on the daily prices of various commodities, currencies and other inputs. As part of our application development process, we use independent stage and test instances of our production database to let us have a smoother and less mistake-prone deployment of new models and price streams. In this talk, I will discuss our setup, which makes heavy use of schemas, Slony, DBI-link, pgTAP and custom deployment tools in
Joshua D. Drake
Replication using PostgreSQL Replicator
Configure the Open Source Replicator for PostgreSQL.
Aurynn Shaw
Simpycity, Pylons, and non-ORM Database Usage | Slides
Discussion on the basic philosophy of Simpycity, the benefits of a stored procedure- based architecture vs. a conventional ORM. Using Simpycity, and effective use cases. Easy to use advanced tricks to provide ORM-like functionality in Simpycity. Time allowing, experimental concepts that can be easily implemented in Simpycity (transparent 2-phase commit)
Monisha (Sarah) Pulimood
Socially Relevant Database Projects in the Undergraduate
In this session I will talk about how database concepts, including data management, privacy, security, and reliability, are reinforced through building socially relevant projects in my undergraduate database systems course and mentored research. Some examples I will talk about are a system to aid investigative reporters analysis data on crimes in a large city; a volunteer registration system for Habitat for Humanity; and a content management system for the College online magazine.
Josh Williams
The Art of Indexes | Slides
Figuring out the correct indexes to create can sometimes seem more art than science. In this session we'll decipher the multiple index types and their uses, cover multi-column versus multiple single-column indexes, and look at expression-based and partial indexes. Armed with this overview, an
Greg Sabino Mullane
The power of psql
All about everyone's favorite Postgres utility, psql, the best command-line database interface, period. We'll cover basic and advanced usage.
David Fetter
Trees and More in PostgreSQL: Common Table Expressions | Slides
With SQL:2008-compliant Common Table Expressions, PostgreSQL has whole new capabilities you can use and a simple syntax to use them. Find out how to do tree structures inside the database, and much, much more.
Joshua Drake
Welcome to PostgreSQL Conference East 2009 (Keynote)
A 45 minute talk welcoming the members of the talk and discussing the current focuses of PgUS.
David Fetter
Windowing Functions: Putting the TPS in TPS Reports Slides
PostgreSQL 8.4 will include SQL:2008 windowing functions, useful for those all-important TPS reports. They'll even supply the new cover sheets. In addition, they provide ways to slice, dice, and re-order results to your liking. Find out how!


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Elizabeth Taylor Van Gogh fetches $US40m
Vincent van Gogh's only painting that captures the views outside the French asylum in which he voluntarily stayed has sold for $39.7 million ($A52.96 million) at Christie's auction house in New York.
In 1889, just one year before his death, Van Gogh painted the "Vue de l'asile et de la Chapelle de Saint-Remy" depicting the scenery he saw from the hospital in Saint-Remy where he voluntarily stayed to treat psychological problems that had led him to cut off his own ear a year earlier.
Van Gogh used to paint bucolic views he saw inside the hospital but the "Vue de l'asile" is the only painting among the 150 he produced during his stay that shows the outside.
The painting was on display in Elizabeth Taylor's living room from 1963 until her death in 2011, after which it was auctioned for $US16 million.
Australian Associated Press


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Canucks snap nine-game losing streak to Sharksby Eric Gilmore
SAN JOSE -- The game was just 77 seconds old Thursday night when San Jose Sharks captain Joe Thornton scored a believe-it-or-not goal against the Vancouver Canucks.
Thornton fired the puck wide left of the goal. The puck ricocheted off the back boards, climbed up the net and over the crossbar, hit goaltender Roberto Luongo in the shoulder, and dropped behind the goal line.
You couldn't have blamed the Canucks if they thought they were in for another rough night against a Sharks team that had defeated them nine straight times.
Instead of following the same old script, the Canucks fought back for a decisive 4-2 victory against the Sharks at SAP Center.
Getting goals from Brad Richardson, Mike Santorelli, Chris Higgins and Zack Kassian, the Canucks beat San Jose for the first time since Jan. 21, 2012.
"I think it feels good because we just beat a pretty good team on home ice," Canucks defenseman Kevin Bieksa said. "You guys have made us well aware that we've lost nine in a row to these guys, so to end that little skid and more importantly to get a big two points. We played well in Phoenix, but didn't get that second point. We know we still got two tough games ahead of us on this road trip. This was a big one."
During their drought, the Canucks lost five regular-season games to the Sharks and were swept 4-0 last season in a first-round series of the Stanley Cup Playoffs. The Sharks won the first two games in the season series this year, beating the Canucks 4-1 in the opener in San Jose and 4-1 a week later at Vancouver.
The loss was San Jose's fourth straight, their longest skid since losing four straight March 6-12 last season. It was their first regulation loss at home after a 5-0-2 start.
"We were clearly outworked," Sharks coach Todd McLellan said. "In the real world, you work for eight hours, and in the hockey world, you work for 60 minutes. And we didn't even come close to that. ... When you have a busload that didn't show up to play, it's pretty hard."
The Canucks, under new coach John Tortorella, had gone 5-1-1 in their previous seven games before beating the Sharks in yet another strong game.
The Sharks (10-2-4) entered the game averaging 38.3 shots per game, but Vancouver outshot them 34-24. The Sharks had six shots in the first period and five in the second. The Canucks had 26 shots entering the final period.
"I thought it was probably one of our better games with our sticks, as far as stick on puck," Tortorella said. "They're such a big team, they protect the puck well. So, our sticks were on the ice, and I thought we disrupted them that way. I thought it was probably one of our better defensive games that way, and I felt we competed really hard. That's a good win for us."
Joe Thornton and Mike Brown scored the Sharks' goals.
Luongo made 22 saves, while Sharks goalie Antti Niemi gave up four goals on 13 shots and was pulled for backup Alex Stalock at 5:22 of the second period with Vancouver leading 4-2. Stalock stopped all 21 shots he faced. Niemi has allowed 14 goals on 102 shots over his past four games.
"Nemo hasn't been sharp," McLellan said. "He was like the rest of the team. When you are back there with the pads, you get singled out a bit -- you think of all the goals and there are five other guys with skates in front of him. But he hasn't been sharp. He has not been sharp. He has to be better."
McLellan spent the rest of the night shuffling his lines, looking for some combinations that would work, with little success.
"In the last couple games, when our best players aren't our best players, we aren't going to win," Sharks center Logan Couture said. "That's what has been happening. Especially in the Western Conference. Our top guys have to be better, including myself. Tonight, we'll go home and look in the mirror and realize we all have to work. We didn't do a good job until the third period. It was just like the [5-4 shootout loss to the Buffalo Sabres on Tuesday]."
Vancouver dominated the Sharks despite not getting a single point from anyone on their stellar top line of Henrik and Daniel Sedin and Ryan Kesler. All four goals came from members of the second and third lines.
"It probably won't happen too often," Higgins said. "Give them a little rest on that. It seems like they carry a lot of the burden. They're great players. Obviously, they want that burden. It's good that we can get a win without those guys getting points."
The Canucks (11-5-2) built a 3-2 lead in a wild first period.
Thornton started the scoring with his trick-shot goal, but Vancouver responded quickly, pulling even on Richardson's fifth goal of the season at 4:28.
"Quite comical the way the game started, but like we've been doing all year, we answered right back and we get ourselves right back in the game," Luongo said. "I thought we had a great second period, probably one of our best periods of the year."
The Canucks improved to 6-3-1 after giving up the first goal in a game.
"There's been some weird goals this season scored," Bieksa said of Thornton's goal. "I think that's right up there. I don't think a goal like that can really deflate you because it's just such a fluky goal, you almost laugh at it. So, I think we definitely wanted to get that first one because we know how good a team these guys are on home ice, but we've been playing from behind a lot this year, unfortunately. We've been used to it and been pretty good at it. To get the next one's huge, though. If they go up 2-0, it's a different story."
The Canucks took a 2-1 lead at 9:25 when Santorelli scored his fifth goal of the season, this one on a rebound. Bieksa forced a turnover by Tyler Kennedy, and Alexandre Burrows sent the puck ahead to Higgins, who fired a sharp-angle shot from the left circle. Niemi stopped Higgins' shot but couldn't control the rebound, and Santorelli knocked it home from the crease.
San Jose made it 2-2 at 10:45 when Brown scored his first goal with the Sharks and ended his 35-game stretch without a goal. Brown and James Sheppard got behind the Canucks' defense and didn't waste the opportunity. Brown sent a pass to Sheppard on his left, got the puck back and beat Luongo from close range.
Vancouver capitalized on another Sharks miscue to take a 3-2 lead at 18:55. This time, Sharks defenseman Jason Demers turned the puck over in the San Jose end. Burrows got to the puck and, as Demers and Scott Hannan converged on him, got it to Higgins, who fired a shot over Niemi's shoulder and into the net.
"It seemed like three guys went to the same spot and got a little tangled up, and I was hiding in the weeds a little bit and was able to chip one over his shoulder, and it got around him," Higgins said.
The Canucks increased their lead to 4-2 just 5:22 into the second period. Bieksa blasted a shot from near the blue line that deflected off Kassian and past Niemi. That was it for Niemi.
Couture nearly cut the Canucks' lead to one goal with just under 12 minutes left to play, redirecting a pass from Marty Havlat toward the net, but Luongo made a brilliant save with his left pad.
"No matter what happens in the game, we've been resilient as far as staying focused," Luongo said. "Just sticking to the game plan. Lots of things have happened already this year, but we've responded every time. That's a really good sign for our team."


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In honour of Earth Day, Aveda has dedicated the month of April as a time to raise mone to protect the earth and it's people. They've raised more than $26 million since 1999 and $20of the funds have supported clean water projects all over the world.
Their goal is to raise $5million and here are some of the ways you can help;
- Aveda Light the Way Candle
- Aveda Earth Month 24 Hour Global Cut-A-Thon.
The Cut-A-Thon will be raising money and and also attempting to set a Guinness World Record for the 'most money raised for a charity by haircuts in a 24-hour period'.
Aveda salons across the globe will be donating their time to cut, style and pamper guests with ALL the proceeds going towards clean water projects in struggling communities. The Aveda Institute High Holborn and participating salons nationwide will be in full support from 11am – 7pm.
- PR Aveda Earth Month Yoga Challenge
The girls from the Aveda Communications Team will be participating in the Aveda Earth Month Yoga Challenge with Glow Yoga Studio, Good Vibes to help raise funds for Water Aid. You can sponsor the girls at Just Giving; to help them reach their target of £500.
I'm a massive Aveda fan, I will definitely purchase a candle (theirs are divine). How about you?


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HP Pavilion DV9812US 17" Notebook PC
Unsurpassed StyleHP innovation is most visible in its breakthrough notebook PC designs that truly integrate fashion and technology for todays mobile, digital lifestyle. High-gloss HP Imprint Finish encases the elegant, curvilinear form and is more durable than traditional painted surfaces. It features a subtle HP-exclusive Influx special edition pattern that expresses the flow of our ever-changing universe. Departing from the original pattern of concentric waves, Influx captures the dichotomy of randomness and order. It changes color as well, moving from a piano black exterior with silver interior to a clean ceramic white and silver finish throughout plus a coordinating sliver keyboard. Its freshness sets it apart. Encouraging more direct interaction, the backlit media control panel responds to the touch or sweep of a finger. HP's Notebook Design Group has been recognized by distinguished design institutions: International CES Innovations Design and Engineering Awards; iF International Forum Design Award; Industrial Design Excellence Awards; ID Magazine Annual Review; Good Design Awards.
Mobile EntertainmentPersonal entertainment is now even easier to enjoy with an updated menu and built-in demos. Providing more choices than ever, HP QuickPlay enables access to DVDs, videos, photos, music, karaoke, games, Internet TV, and streamed or recorded TV (with an optional TV Tuner) at the touch of a button. Watch DVD movies on the full screen using simple media controls. Add music to your slide shows or videos with drag-and-drop functionality. Watch Internet TV. Throw an impromptu karaoke party or play preinstalled games from leading brands. Find and stream media from universal plug-and-play devices such as WindowsMedia Connect. Listen without disturbing others with included stereo earbud headphones. And control content from up to 10 feet away with the HP Mobile Remote Control that can be stored in the ExpressCard slot for convenience. It's time to play!
Designed for your lifeFor those who want innovative digital entertainment capability coupled with desktop-replacement performance, the HP Pavilion dv9800 series Entertainment Notebook PC delivers! Dual headphone jacks and Altec Lansing audio allow you to share your entertainment. And AMD mobile dual-core technology enables use of multiple demanding applications, such as photo editing, DVD burning and playing a game, at the same time. This 7.7lbs (starting weight) light notebook delivers desktop-comparable performance with its 17.0" High-Definition BrightView widescreen display and separate numeric keypad. HP innovation and technology leadership helps you work faster, connect in new ways and play more.
HP Webcam and Integrated Microphone. Turn your next instant message into a live video chat with the integrated webcam, omnidirectional microphone and IM solution of your choice. Optimized for low-light environments, it's great for capturing short videos or photos to e-mail to friends or share on your favorite social networking site.
LightScribe Direct Disc Labeling. Create custom laser-etched disc labels right in the drive with LightScribe and preinstalled Roxio ExpressLabeler. Just burn data on the disc, flip it over and burn the cover image using any scanned image and/or text. Free label designs and color background discs in five vivid shades are now available. Visit the LightScribe Web site for more information
Genuine Windows Vista Home Premium with Service Pack 1


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Matthew Campbell necesitaba un nuevo diseño de otro y lanzó un concurso de diseño en 99designs.
Un ganador ha sido elegido entre 14 diseños de 5 diseñadores freelance.
iOS How To Series
I am an iPhone developer who shows other developers how to make iPhone and iPad apps without a lot of BS. Check out my blog to see what I am all about: http://howtomakeiphoneapps.com and also see me on Twitter @MattjDrake.
My story is that I quit my cubicle job in November 2008 to develop software for my own company full time. What I do is show other developers how to bring their iPhone app visions to life.
iPhone & iPad enthusiasts who want to learn how to make their own iPhone and iPad apps to sell on the Apple App Store. The people who we are looking for are software developers and gadget geeks. Most of them read my website (you can see that above) and love products from Apple (http://apple.com).
We have an online workshop series for learning how to program iPhone apps.
This is actually a series of workshops called "iOS How To Series"
What we really need is something that will feel like a real product (like a book cover, CD cover or even a paper flyer or something like a software icon). The trick is that the product is not exactly any of these things (it is more like an online class).
So the challenge is to find out how to represent the idea of an online workshop as a product that customers can identify immediately.
- we need either one image that will look good large and small OR a regular size image in addition to a small size (200px by 200px) version.
Here are the types of art style we are looking for:
PS: if the design is good we may be able to hire you for some related material (we will need a website design for the sales page and more)


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jrstafford1 needed a new web page design and created a contest on 99designs.
A winner was selected from 83 designs submitted by 20 freelance designers.
Need homepage design for Veterinarian Clinic.
We have held other contests here and similar sites...we ALWAYS select a winner and payout the prize money!! Contact us for references.
Please read the creative brief for detailed information. I will also be leaving feedback on a regular basis so be sure to read all discussion notes for more information.
Bush Veterinary Service
Client likes the swinems.com site. They would like to separate small vs. large animal visitors. They prefer a more professional feel like a physician's office site vs. a playful/pet-focused site of a strictly small animal veterinarian. Imagery should reflect this professional feel...possibly doctors working with animals rather than just a cute picture of a cuddly kitten.
Main navigation should be: Home, Services, Facility, Staff, Pharmacy, Contact Us
- professional feel
- differentiate between large and small animal visitors
- do not want playful/pet focused site


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IEEE Experts Identify the Fourth R-Word in Sustainability: Repair
IEEE Experts Provide Insight on How Repairability of Cellphones Can Lead to a More Environmentally Friendly Consumer Electronics Industry
22 April 2013 – Reduce, reuse, and recycle is the foundation of sustainable living. However, experts from IEEE, the world's largest technical professional organization, identified repair as an equally important, environmentally friendly R-word, especially when it comes to the consumer electronics industry. Through modest design changes, cellphone manufacturers can improve the repairability of its products and streamline the upstream manufacturing process, thereby minimizing environmental impact while also improving global commerce and social development.
According to the International Data Corporation (IDC)'s Worldwide Mobile Phone Tracker, vendors will ship more than 1.7 billion mobile phones in 2013, and this number is forecasted to grow 1.4 percent year-over-year. There is a considerable environmental impact to manufacturing this volume of cellphones when you consider that it takes approximately 165 pounds of raw materials to manufacture a cellphone and over eight gallons of water to produce one microchip.
"Life Cycle Assessment of the Mobile Communication System UMTS: Towards Eco-Efficient Systems," a paper from the IEEE International Symposium on Electronics and the Environment, indicates that extending the service life of the phone from one to four years decreases the environmental impact by about 40 percent. While innovations are being made to improve the sustainability of this process, cellphone manufacturers can garner more immediate environmentally friendly benefits by making their products more easily repairable.
"Cellphone companies manufacture a wide range of devices to meet the technological and budget requirements from early adopters to first-time cellphone owners in leading world markets and developing nations across the globe," said Stu Lipoff, IEEE Fellow and president of IP Action. "Upstream cellphone manufacturing, which includes the mining of raw materials, mine tailings, and fresh water polluted in the process, as well as the energy required to refine and manufacture the device, can be reduced by employing designs that enable easier and more economic device repairability. In this way, refurbished phones from the first market can have an extended life through use in secondary and tertiary markets. This process would not only help reduce the environmental impact from the manufacturing process but also provide more advanced technology for developing nations, helping to stimulate global commerce."
Making a Screwdriver a Tool of Sustainability
Advancements in technology are enabling manufacturers to make devices smaller and sleeker. However, along with this trend, they are also employing more closed designs and using materials that are making devices nearly unfixable.
"Regardless of size, there are numerous design features that manufacturers can use to improve the repairability of their products," said Kyle Wiens, IEEE member and CEO of iFixit. "Simple things like utilizing openable cases, using screws rather than adhesives, and providing easy access to parts that are most likely to break, like screens, greatly improve the repairability of cellphones and significantly extend their life. It is imperative for designers to incorporate sustainable features into their products not only to make them last longer but to help promote a more sustainable and environmentally friendly future."
Francine Tardo
+1 732 465 5865
Monika Stickel
+1 732 562 6027


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AT&T and Numera Combine Personal Safety and Home Health Management with New Personal Health Gateway
AT&T Provides Wireless Network and Location Services for Numera Libris™, Marking a Move Beyond Traditional Emergency Response to More Comprehensive Health Support
Feb 21, 2013, 11:36 ET
DALLAS, Feb. 21, 2013 /PRNewswire/ -- As 78 million baby boomers continue to age, falling is a serious issue that is often a precursor to many other serious and chronic health concerns. One-third of adults over 65, or 14.8 million people in North America, fall each year with many more falls unreported. Chronic conditions affect 21 percent of those between the ages of 45 – 64, and that percentage climbs to 45.3 percent of those over the age of 65. For those who are living with chronic conditions or are transitioning from hospitalization, continuity of care is critical for measurably better health.
To respond to this rapidly growing market, AT&T* and Numera today announced that AT&T will be the wireless network and location services provider for Numera Libris™. Libris brings together home health management and a personal emergency response system (PERS) in one simple, mobile solution. Advances in wireless technology and activity and biometric monitoring have made Numera Libris possible – a comprehensive mobile solution designed to better address the needs of active adults, as well as the chronically ill and homebound.
This "Personal Health Gateway," a new category of device, integrates safety functions including mobile emergency response services, two-way voice, automated fall detection, and location tracking with telehealth functionality. Numera Libris will be on display in the AT&T Connected City at Mobile World Congress in Barcelona on February 25 – 28, 2013 and also the AT&T exhibit, booth 3727, at HIMSS on March 4-6, 2013.
"Incorporating continuous monitoring of an individual's activity, location and important health measurements, the Numera Libris system breaks new ground in bringing together personal safety and telehealth in a mobile device," said Chris Penrose, senior vice president of emerging devices, AT&T. "With the addition of wireless connectivity, the Numera Libris creates an affordable solution that connects individuals with their caregivers in an efficient manner."
Libris connects with the Numera Net™ telehealth+telecare platform, which enables an individual to upload biometric measurements from a variety of wireless health devices. They can then quickly, easily and securely send that information via either a PC or Numera's home hub to their extended health care team, including family, friends, and healthcare professionals.
"Unlike traditional PERS, which target individuals in their 80s, Libris offers an adaptive, personal health gateway for the healthy aging population as well as those living with chronic conditions," said Tim Smokoff, CEO of Numera. "This goes beyond fall detection, enabling these consumers and their family members to better manage their healthcare needs and ultimately to stay healthier and independent longer. Now individuals can stay connected to their health professionals between office visits from wherever they are through mobile health and safety monitoring done both in and outside of the home."
The telecare and telehealth market is expected to exceed $1 billion by 2016 and grow to $6 billion by 2020. With AT&T mobile broadband network connectivity, Numera has begun Libris pilot programs with select solutions providers. The companies are planning for full commercial availability this spring.
For the complete array of AT&T offerings, visit www.att.com.
*AT&T products and services are provided or offered by subsidiaries and affiliates of AT&T Inc. under the AT&T brand and not by AT&T Inc.
1 Tinetti et al. Predictors and prognosis of inability to get up after falls among elderly persons. Journal of the American Medical Association 1993; 269:65
2 "A CDC Compendium of Effective Fall Interventions," Centers for Disease Control, 2010
3 AARP Public Policy Institute. Falls Among Older Persons and the Role of the Home: An Analysis of Cost, Incidence, and Potential Savings from Home Modification.
4 Fried et al, "Multiple chronic conditions among adults age 45 and over: trends over the past 10 years" http://www.cdc.gov/nchs/data/databriefs/db100.htm.
5 "The World Market for Telehealth – A Quantitative Market Assessment – 2011 Edition," by InMedica, the medical electronics market research group within IMS Research, the leading independent provider of market research and consultancy to the global electronics industry.
6 US Census.^ CDC http://www.cdc.gov/nchs/products/vsus.htm "Vital Statistics of the United States, 2003, Volume I, Natality", Table 1-1 "Live births, birth rates, and fertility rates, by race: United States, 1909–2003."
About AT&T
AT&T Inc. (NYSE: T) is a premier communications holding company and one of the most honored companies in the world. Its subsidiaries and affiliates – AT&T operating companies – are the providers of AT&T services in the United States and internationally. With a powerful array of network resources that includes the nation's largest 4G network, AT&T is a leading provider of wireless, Wi-Fi, high speed Internet, voice and cloud-based services. A leader in mobile Internet, AT&T also offers the best wireless coverage worldwide of any U.S. carrier, offering the most wireless phones that work in the most countries. It also offers advanced TV services under the AT&T U-verse® and AT&T │DIRECTV brands. The company's suite of IP-based business communications services is one of the most advanced in the world.
Additional information about AT&T Inc. and the products and services provided by AT&T subsidiaries and affiliates is available at http://www.att.com. This AT&T news release and other announcements are available at http://www.att.com/newsroom and as part of an RSS feed at www.att.com/rss. Or follow our news on Twitter at @ATT.
© 2013 AT&T Intellectual Property. All rights reserved. 4G not available everywhere. AT&T, the AT&T logo and all other marks contained herein are trademarks of AT&T Intellectual Property and/or AT&T affiliated companies. All other marks contained herein are the property of their respective owners.
About Numera
Numera (www.numera.com) works with partners to achieve measurably better health and wellness for those in their care through encouragement, support and accountability. The company combines the power of caregivers, friends and peer groups, subjective and objective health information, and the ability to make this information actionable via extensible, scalable, and custom-branded solutions. These solutions extend beyond traditional emergency response to home health management, population care management and social engagement – all based on Numera's telehealth+telecare platform.
Numera is headquartered in Seattle, with corporate offices in Mountain View, CA, Orlando, FL, and Camberley, UK.
© 2013 Numera, Inc. Numera, Numera Libris, and "Measurably Better Health" are trademarks of Numera. All other company and product names used herein may be trademarks, or registered trademarks of the respective companies.
Cautionary Language Concerning Forward-Looking Statements
Information set forth in this press release contains financial estimates and other forward-looking statements that are subject to risks and uncertainties, and actual results might differ materially. A discussion of factors that may affect future results is contained in AT&T's filings with the Securities and Exchange Commission. AT&T disclaims any obligation to update and revise statements contained in this news release based on new information or otherwise.
SOURCE AT&T Inc.


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Planning on being in La Ventana again Jan 7th-17th with my wife. She would like to do some fishing and we're looking for recommendations based on the past experience of others. Not looking for a multi-day experience, just an early morning departure coming back sometime in the late morning or early afternoon.
I know Palapas Ventana has such an experience for about $250/day for up to 3 people. Are there any other options? We would prefer English speaking captain/guide since our Spanish skills are nearly worthless.
Any insight from those who've done it would be greatly appreciated!!


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N's Castle
As soon as you descend into the ruins of N's Castle, you'll run into none other than N himself! He'll say a bunch of stuff and then will ask if he can follow you around, which you should say yes to.
There aren't any wild Pokemon in here, unfortunately, but you can enter the room just to the north of the entrance to find N's old room, which he will talk about if you bring him inside. There's a Luxury Ball over by the train set, but that's about it.
Out in the main hall, you won't be able to head straight east, so climb down into where the water once flowed, picking up the Protein over to the west before heading east.
In the eastern-most part of the room, down one of those little ledge things, you can find TM50 (Overheat), a powerful Special-base Fire-type attack that lowers the user's Special Attack by two stages afterwards.
Climb up the stairs and follow the path forward until N stops you, saying you should go forward alone. Keep going and you'll enter the room where the you fought Reshiram/Zekrom, N, and Ghetsis in the original Black and White, except it's in shambles.
Head forward and N will follow after you. After some talking, he'll release his Zekrom (Black 2) or Reshiram (White 2) and will then ask if you want to battle. If you're ready to take him on, say Yes, otherwise say No and you'll be given a chance to heal and save.
N uses Zekrom if you're playing Pokemon Black 2 or Reshiram if you're playing Pokemon White 2. He does NOT use both on his team.
Even though he uses only one Pokemon, it's an uber legendary Pokemon and is very strong, meaning you will be in for one heck of a fight, especially if you haven't done much training after beating the game.
Catching a Pokemon like Excadrill can help a lot against Zekrom, because it is immune to its powerful Fusion Bolt attack while resists its other attacks, Zen Headbutt and Dragon Claw. You may have to train it up a bit, though.
If you're playing Pokemon White 2, catching a high-level Pupitar on Route 15 (east of Nimbasa City and across the bridge) and then evolving it into Tyranitar is an effective strategy. Tyranitar resists Fusion Flare, is immune to Extrasensory, and gains a Special Defense boost from the Sandstorm it whips up thanks to it being a Rock-type, meaning it will reduce the power of Reshiram's Dragon Pulse.
Regardless of which one you have to fight, getting TM26 (Earthquake) on Route 15 is very helpful, as is any Dragon-type attacks you may have. Be careful about using your own Dragon-type Pokemon, because his are both fairly quick and their high level doesn't make it a walk in the park.
N's Revenge!
After beating N in his castle, you'll be able to run into him in the Ferris Wheel on Fridays in Nimbasa City. Once you've ridden with him on the Ferris Wheel, he'll return to his castle, where you'll be able to battle him.
He uses a different team depending on which season it is, with levels ranging from level 75 to 77, making him very tough to take down. You can only fight him once per season.
After beating him, he'll talk for awhile and eventually return the legendary Pokemon to its stone. This means he'll return Zekrom to the Dark Stone in Black 2 and Reshiram to the Light Stone in White 2. He'll give you that stone afterwards, which you then need to bring back to the Dragonspiral Tower north of Icirrus City.
This means you should return back to Opelucid City, head west onto Route 9, and then enter the Tubeline Bridge, which is finally open.
Meet your Meteor!
While you're visiting Opelucid City, you can return to Drayden's house in the middle of town with just about any Dragon-type Pokemon to have him teach it the powerful Dragon-type Draco Meteor attack. He will teach it for free and as many times as you like, so feel free to reward your dragons with a powerful attack! Just keep in mind that it lowers the user's Special Attack by two stages afterwards, but it can be a nice attack on Dragon-type Pokemon with high Attack so they can keep attacking afterwards.