Effects of briakinumab treatment for moderate to severe psoriasis on health-related quality of life and work productivity and activity impairment: results from a randomized phase III study.

BACKGROUND: Psoriasis is known to have a significant negative impact on a patient's health-related quality of life, including social, recreational and work activities. OBJECTIVE: To evaluate the effects of briakinumab on quality of life and work productivity measures in patients with moderate to severe psoriasis. METHODS: Patients received either briakinumab (n = 981) or placebo (n = 484) during the 12-week induction phase of trial M06-890. At week 12, patients with a Physician's Global Assessment score of 'Clear' or 'Minimal' entered the 40-week maintenance phase and were to receive briakinumab every 4 weeks, briakinumab every 12 weeks, or placebo. At weeks 12 and 52, treatment groups were compared using mean change from baseline in health-related quality of life and Work Productivity and Activity Impairment Questionnaire scores and the percentage of patients with minimum clinically important differences. RESULTS: At week 12, more than half of the briakinumab-treated patients achieved improvements meeting or exceeding minimum clinically important differences for Dermatology Life Quality Index (75.9%), and psoriasis- (64.8%), and psoriatic arthritis-related (54.1%) pain scores; 48.4% achieved improvements for activity impairment. Although improvements in quality of life and work productivity measures were maintained at week 52 for both briakinumab regimens, responder rates were consistently greater in the every-4-week group than in the every-12-week group. CONCLUSION: Briakinumab treatment resulted in clinically significant improvements in quality of life and work productivity in adults with moderate to severe psoriasis. Maintenance therapy was associated with a more pronounced benefit for the every-4-week briakinumab regimen.

Widespread expression of the human and rat Huntington's disease gene in brain and nonneural tissues.

We have used RNA in situ hybridization to study the regional expression of the Huntington's disease gene (HD) and its rat homologue in brain and selected nonneural tissues. The HD transcript was expressed throughout the brain in both rat and human, especially in the neurons of the dentate gyrus and pyramidal neurons of the hippocampal formation, cerebellar granule cell layer, cerebellar Purkinje cells and pontine nuclei. Other brain areas expressed lower levels of the HD transcript without pronounced regional differences. Neuronal expression predominated over glial expression in all regions. HD mRNA was also expressed in colon, liver, pancreas and testes. The regional specificity of neuropathology in HD, which is most prominent in the basal ganglia, thus cannot be accounted for by the pattern of expression of HD.

Island rescue PCR: a rapid and efficient method for isolating transcribed sequences from yeast artificial chromosomes and cosmids.

The identification of transcripts from large genomic regions cloned in yeast artificial chromosomes (YACs) or cosmids continues to be a critical and often rate-limiting step in positional cloning of human disease genes. We have developed a PCR-based method for rapid and efficient generation of probes from YACs or cosmids that can be used for cDNA library screening. The method, which we call island rescue PCR (IRP), is based upon the observation that the 5' ends of many genes are associated with (G+C)-rich regions called CpG islands. In IRP, the YAC of interest is digested with a restriction enzyme that recognizes sequences of high CpG content, and vectorette linkers are ligated to the cleaved ends. The PCR is used to amplify the region extending from the cleaved restriction enzyme site to the nearest SINE (Alu) repeat. In many cases this product contains sequences from the 5' end of the associated gene. cDNA clones isolated with these products are then verified by mapping them back to the original YAC. The method allows rapid screening of > 500 kb of human genomic insert in one experiment, is tolerant of contaminating yeast sequences, and can also be applied to cosmid pools. In a control experiment, the method was able to identify cDNA clones for the neurofibromatosis type 1 (NF1) gene using a probe generated from a YAC in the region. Application of IRP has yielded nine other genes from YACs isolated from chromosome locations 4p16.3 and 17q21.

The effect of rifampicin on the in-vitro activity of cefpirome or ceftazidime in combination with aminoglycosides against Pseudomonas aeruginosa.

The in-vitro activity of cefpirome and ceftazidime when combined with aminoglycosides (gentamicin, amikacin, and tobramycin) in the presence and in the absence of rifampicin was evaluated against 32 isolates of Pseudomonas aeruginosa by two methods. Agar dilution susceptibilities demonstrated a marked reduction in synergy (FIC less than or equal to 0.5) when rifampicin was added to the combination. Synergy rates decreased from 59.4-84.4% without to 3.1-9.4% with the addition of rifampicin. In contrast, kill curve tests performed on two P. aeruginosa strains demonstrated synergy at 24 h when rifampicin was added to cefpirome, ceftazidime, gentamicin or a beta-lactam agent plus gentamicin combination. The addition of rifampicin to the combinations of cefpirome or ceftazidime plus gentamicin achieved a 2-log10 lower bacterial count at 24 h than that of the beta-lactam and gentamicin combination alone. When rifampicin was added to the combination cefpirome or ceftazidime plus gentamicin at different times during incubation, a greater bactericidal effect was observed when rifampicin was added at 0 and 1 h of incubation than when added later. No antagonism was observed with rifampicin when used in combination with beta-lactam agents and/or aminoglycosides.

Comparative therapy with cefpirome alone and in combination with rifampin and/or gentamicin against a disseminated Pseudomonas aeruginosa infection in leukopenic mice.

Treatment of disseminated Pseudomonas aeruginosa infection in leukopenic mice was evaluated using cefpirome alone and in combination with gentamicin and/or rifampin. Mice were made leukopenic with cyclophosphamide and infected through a skin incision with an inoculum of 1250 organisms (13 LD50). Antibiotics were administered subcutaneously for 48 h. Although the addition of cefpirome to gentamicin and/or rifampin improved survival significantly at 48 h compared with untreated controls (84.6%-100% vs. 38.5%), therapy with these combinations did not improve survival significantly from that achieved with cefpirome alone. Quantitative blood and tissue (liver, spleen, kidney, lung) cultures in mice treated with cefpirome alone or including rifampin were lower than in infected controls or groups receiving therapy that excluded cefpirome. Highest counts were observed in mice receiving cefpirome plus gentamicin. Except for the cefpirome plus gentamicin group, which demonstrated areas of acute tubular necrosis, the cefpirome group had less tissue pathology than infected controls.

A preliminary study of ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection.

BACKGROUND: Ritonavir is a potent inhibitor in vitro of human immunodeficiency virus type 1 (HIV-1) protease, which is needed for virions to mature and become infective. We assessed the safety and efficacy of ritonavir in patients with HIV-1 infection. METHODS: We administered ritonavir orally to 62 patients in one of four dosages during a 12-week trial containing a 4-week randomized, placebo-controlled, double-blinded phase followed by an 8-week dose-blinded phase. We assessed the response with serial measurements of plasma viremia and serial CD4 cell counts. RESULTS: Fifty-two patients completed the 12-week trial. Diarrhea and nausea were the most common side effects, and reversible elevations in serum triglyceride and gamma-glutamyltransferase levels were the most frequent laboratory abnormalities. Ritonavir had a rapid antiviral effect, with a mean maximal reduction in the number of copies of HIV-1 RNA per milliliter of plasma that ranged from 0.86 to 1.18 log in the four dosage groups. After 12 weeks of treatment, the antiviral effect was partially maintained, with a mean reduction in plasma viremia of 0.5 log. When we used a more sensitive assay for HIV-1 RNA in a subgroup of 20 patients, we found that plasma viremia decreased by a mean of 1.7 log. This antiviral effect was partly sustained at week 12, with a mean reduction of approximately 1.1 log. The patients' CD4 cell counts rose during treatment with ritonavir (median increase, 74 and 83 cells per cubic millimeter at weeks 4 and 12, respectively). CONCLUSIONS: The protease inhibitor ritonavir is well tolerated and has a potent antiviral effect, as shown by substantial decreases in plasma viremia and significant elevations in CD4 cell counts. Expanded clinical trials of ritonavir are warranted.

Characterization of EZH1, a human homolog of Drosophila Enhancer of zeste near BRCA1.

Recent transcription mapping efforts within chromosome 17q21 have led to the identification of a human homolog of the Drosophila gene Enhancer of zeste, E(z). A member of the Polycomb group (Pc-G) of proteins, Drosophila E(z) acts as a negative regulator of the segment identity genes of the Antennapedia and Bithorax complexes. Here we report the full-length protein coding sequence of human EZH1 (Enhancer of zeste homolog 1) and compare the respective protein sequences in both species. EZH1 encodes a protein of 747 amino acids that displays 55% amino acid identity overall (70% similarity) with Drosophila E(z). The strongest homology was noted (79% identity, 89% similarity) within the carboxy-terminal 245 amino acids, including the SET domain, a region of E(z) also conserved in other Drosophila proteins with roles in development and/or chromatin structure. A large Cysrich region with a novel spatial pattern of cysteine residues was also conserved in both EZH1 and E(z). The strong sequence conservation suggest potential roles for EZH1 in human development as a transcriptional regulator and as a component of protein complexes that stably maintain heterochromatin. EZH1 is expressed as two major transcripts in all adult and fetal human tissues surveyed; comparison of cloned cDNAs suggests that alternative splicing may account for at least part of the transcript size difference. Analysis of one cDNA revealed an unusual splicing event involving EZH1 and a tandemly linked gene GPR2 and suggests a potential mechanism for modifying the EZH1 protein in the conserved C-terminal domain. The sequence and isolated cDNAs will provide useful reagents for determining the function of EZH1 and the importance of the evolutionarily conserved domains.