The C-Band All-Sky Survey (C-BASS): Simulated parametric fitting in single pixels in total intensity and polarization.

The cosmic microwave background (CMB) B-mode signal is potentially weaker than the diffuse Galactic foregrounds over most of the sky at any frequency. A common method of separating the CMB from these foregrounds is via pixel-based parametric-model fitting. There are not currently enough all-sky maps to fit anything more than the most simple models of the sky. By simulating the emission in seven representative pixels, we demonstrate that the inclusion of a 5 GHz data point allows for more complex models of low-frequency foregrounds to be fitted than at present. It is shown that the inclusion of the C-BASS data will significantly reduce the uncertainties in a number of key parameters in the modelling of both the galactic foregrounds and the CMB. The extra data allow estimates of the synchrotron spectral index to be constrained much more strongly than is presently possible, with corresponding improvements in the accuracy of the recovery of the CMB amplitude. However, we show that to place good limits on models of the synchrotron spectral curvature will require additional low-frequency data.

Development and Characterization of 12 Novel Polymorphic Microsatellite Loci for the Mammal Chewing Louse Geomydoecus aurei (Insecta: Phthiraptera) and a Comparison of Next-Generation Sequencing Approaches for Use in Parasitology.

Next-generation sequencing methodologies open the door for evolutionary studies of wildlife parasites. We used 2 next-generation sequencing approaches to discover microsatellite loci in the pocket gopher chewing louse Geomydoecus aurei for use in population genetic studies. In one approach, we sequenced a library enriched for microsatellite loci; in the other approach, we mined microsatellites from genomic sequences. Following microsatellite discovery, promising loci were tested for amplification and polymorphism in 390 louse individuals from 13 pocket gopher hosts. In total, 12 loci were selected for analysis (6 from each methodology), none of which exhibited evidence of null alleles or heterozygote deficiencies. These 12 loci showed adequate genetic diversity for population-level analyses, with 3-9 alleles per locus with an average HE per locus ranging from 0.32 to 0.70. Analysis of Molecular Variance (AMOVA) indicated that genetic variation among infrapopulations accounts for a low, but significant, percentage of the overall genetic variation, and individual louse infrapopulations showed FST values that were significantly different from zero in the majority of pairwise infrapopulation comparisons, despite all 13 infrapopulations being taken from the same locality. Therefore, these 12 polymorphic markers will be useful at the infrapopulation and population levels for future studies involving G. aurei. This study shows that next-generation sequencing methodologies can successfully be used to efficiently obtain data for a variety of evolutionary questions.

Evaluation of the Cockroft-Gault, Jelliffe and Wright formulae in estimating renal function in elderly cancer patients.

BACKGROUND: More elderly patients are being treated with chemotherapy. Reliable and accurate measures of renal function are needed to obtain predictable, safe and effective exposure to renally excreted drugs. The Jelliffe, Cockroft-Gault and Wright formulae have been used to evaluate renal function, although they have not been validated in elderly oncology patients. We performed a retrospective evaluation of these formulae using the [51Cr]-ethylenediamine tetraacetic acid ([51Cr]-EDTA) method of measuring glomerular filtration rate (GFR) as the 'gold standard'. PATIENTS AND METHODS: Inclusion criteria were age > or = 70 years and serum creatinine <250 micromol/l, performed within 4 weeks of glomerular filtration rate (GFR) measurement. Creatinine clearance was calculated using the Cockroft-Gault, Jelliffe and Wright formulae. The precision and accuracy of the three formulae were compared with the gold standard. RESULTS: Two hundred and twenty-five patients were evaluated: median age, 74 years (range 70-89); males, 108; females, 117; median creatinine, 84 micromol/l (range 44-186). Correlation coefficients of the Jelliffe, Cockroft-Gault and Wright formulae were similar. In the specific GFR ranges of 50-70, 70-90 and 90-120 ml/min, the bias [mean percentage error (MPE)] was +8%, -4% and -13%, respectively. The degree of bias was greater with the Cockroft-Gault and Jelliffe formulae across the same range of GFR with the MPE being -15%, -25%, -32% and -12%, -19% and -23%, respectively. All three formulae have reduced precision and greater bias at the extremes of GFR. CONCLUSIONS: The Wright formula is the most accurate, precise and least biased formula for the calculation of GFR in elderly patients with a GFR >50 ml/min. These results allow the physician to make a decision regarding the use of the formula based on an expected degree of bias.

Influence of risk factors on endoscopic and clinical ulcers in patients taking rofecoxib or ibuprofen in two randomized controlled trials.

BACKGROUND: Highly selective inhibitors of the inducible cyclooxygenase-2 enzyme (coxibs) have been associated with less gastrotoxicity than nonselective NSAIDs in clinical studies. AIM: To evaluate the influence of risk factors for NSAID-induced gastrotoxicity on endoscopic and clinical ulcers in patients taking rofecoxib or ibuprofen. METHODS: We analysed pooled data from two identical double-blind, randomized, 12-week endoscopy studies which compared the gastroduodenal toxicity of placebo (n=371), rofecoxib 25 mg (n=390), rofecoxib 50 mg (n=379), and ibuprofen 2400 mg daily (n=376) in patients with osteoarthritis. The potential risk factors evaluated were: age (< 65, > or = 65 years), sex, race (white, nonwhite), Helicobacter pylori status, presence of gastroduodenal erosions at baseline, a history of upper gastrointestinal disease, prior NSAID use within 30 days of study entry, and smoking. We also evaluated these factors for possible association with the development of clinically-evident gastrointestinal perforations, ulcers or bleeds over 12 weeks. RESULTS: Across all treatment groups, the likelihood of detecting endoscopic ulcers, or of clinical presentation with a bleed, over 12 weeks was increased approximately 4-5-fold in patients with previous upper gastrointestinal disease (relative risk [95% confidence interval] of 4.2 [2.5, 7.1] for endoscopic ulcers; 3.8 [1.4, 10.6] for bleeds), or those with gastroduodenal erosions at baseline endoscopy (relative risk of 4.4 [2.6, 7.5] for endoscopic ulcers; 5.0 [1.9, 13.5] for bleeds). H. pylori infection did not increase the risk of endoscopic ulcers or bleeds (relative risk of 1.1 [0.8, 1.6] for endoscopic ulcers; 0.3 [0.1, 0.9] for bleeds). The risk factor sub-group effects were constant across all treatment groups, and the significantly higher incidence of ulcers with ibuprofen as compared to rofecoxib and placebo was maintained in all risk factor subgroups. CONCLUSIONS: Gastroduodenal erosions at baseline and a clinical history of upper gastrointestinal disease, but not H. pylori colonization, increased the risk for endoscopically-detected ulcers and clinical bleeds. Rofecoxib did not magnify the risk in any of the patient subgroups studied.

Economic evaluation of rofecoxib versus nonselective nonsteroidal anti-inflammatory drugs for the treatment of osteoarthritis.

BACKGROUND: Results of phase III clinical trials of rofecoxib, a selective inhibitor of cyclooxygenase 2, have shown that osteoarthritis patients treated with rofecoxib had significantly fewer clinically significant gastrointestinal (GI) adverse events than those who received nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). OBJECTIVE: This paper explores the potential economic implications of the use of rofecoxib versus nonselective NSAIDs for the treatment of osteoarthritis via a decision analytic model based on rofecoxib clinical data and the published literature. METHODS: Base-case 1-year analyses were done with data on GI adverse events, specifically perforations, ulcers, and bleeds (PUBs), obtained from a prespecified pooled analysis of the rofecoxib clinical trials. Analyses were also performed using pooled results of two 12-week endoscopic surveillance trials, with adjustments for silent ulcers of 40% and 85%. RESULTS: Under base-case conditions, the expected cost savings in GI problems and comedications averted with rofecoxib versus NSAIDs was 0.81 dollars per day, representing an 85% offset of the difference in drug price. For rofecoxib versus NSAIDs, the expected cost per PUB avoided with rofecoxib was 4738 dollars, and expected cost per year of life saved was 18,614 dollars. In analyses based on endoscopic data, therapy with rofecoxib was less expensive than therapy with NSAIDs, regardless of silent ulcer adjustment. Results were most sensitive to prophylactic GI comedication rates, and were robust over a range of model assumptions and costs. CONCLUSIONS: In this analysis based on differences in clinically significant GI events for osteoarthritis patients, cost differences between rofecoxib and NSAIDs were markedly offset by expected cost savings in GI problems and comedications averted with rofecoxib. Costs per year of life saved with rofecoxib versus NSAIDs were well within accepted benchmarks for cost-effectiveness. When endoscopic data alone were considered, rofecoxib was cost saving across all assumptions about silent ulcer rates.

Review article: the gastrointestinal safety profile of rofecoxib, a highly selective inhibitor of cyclooxygenase-2, in humans.

Highly selective inhibitors of cyclooxygenase-2, such as rofecoxib, are hypothesized to have an improved gastrointestinal tolerability and safety profile compared with non-selective NSAIDs, which inhibit cyclooxygenase-1 and cyclooxygenase-2 non-selectively. This paper reviews data from randomized, double-blind, placebo-controlled studies which investigated the effects of rofecoxib and NSAIDs on the human gastrointestinal tract. In healthy subjects, rofecoxib 25 mg and 50 mg daily had no effect on gastric mucosal prostaglandin synthesis, whilst naproxen 1000 mg daily caused a 70% reduction. Therapeutic doses of rofecoxib 25 mg and 50 mg daily did not increase intestinal permeability or faecal blood loss in healthy subjects, whereas increases in both measures were seen with indometacin 150 mg or ibuprofen 2400 mg. A supra-therapeutic dose of rofecoxib (250 mg) given daily for 7 days did not induce an increase in gastroduodenal erosions in healthy subjects, whilst increased numbers of erosions were found in subjects given ibuprofen 2400 mg or aspirin 2600 mg. The endoscopic findings in healthy subjects were confirmed in two 6-month clinical studies involving 1516 patients with osteoarthritis; the incidences of ulcers following rofecoxib 25 mg or 50 mg daily were similar to placebo and less than ibuprofen 2400 mg. The advantage of rofecoxib over NSAIDs in these studies appears to translate into clinically relevant benefits; an analysis of 5435 patients with osteoarthritis found a significantly lower incidence of gastrointestinal perforations, ulcers and bleeds in patients taking rofecoxib compared with patients taking NSAIDs. Overall, the findings from these studies suggest that, as a result of cyclooxygenase-1 sparing, rofecoxib is significantly less gastrotoxic than non-selective NSAIDs, and may not differ from placebo.

Gastrointestinal medications and procedures in osteoarthritis patients treated with rofecoxib compared with nonselective NSAIDs.

CONTEXT: Patients treated with nonselective cyclooxygenase inhibitors (nonsteroidal anti-inflammatory drugs [NSAIDs]) often experience dyspepsia and upper gastrointestinal (GI) adverse effects, and frequently require GI comedications and diagnostic procedures. OBJECTIVE: This study combined existing data to test the hypothesis that GI comedications and GI diagnostic procedures occur less frequently in osteoarthritis (OA) patients treated with rofecoxib compared with nonselective NSAIDs. DESIGN: Combined analysis of 8 randomized controlled clinical trials. SETTING: Rheumatology and general practice clinics. PATIENTS: Men and women aged 40 years and older with OA. INTERVENTIONS: Random assignment to placebo (n = 514), rofecoxib (n = 3357; 12.5, 25, or 50 mg daily combined; average 24.7 mg), or NSAIDs (n = 1564; ibuprofen 800 mg thrice daily, diclofenac 50 mg thrice daily, or nabumetone 1500 mg daily, combined). MAIN OUTCOME MEASURES: The cumulative incidence of patients using GI comedications (antacids, antispasmodics, antiflatulents, antiregurgitants, H2 antagonists, proton pump inhibitors, sucralfate, prostaglandins, other antiulcer therapy) and needing GI procedures (upper GI barium studies, upper or lower GI endoscopies) over 12 months. RESULTS: Compared with those treated with NSAIDs, patients treated with rofecoxib had a significantly lower incidence of GI comedication use (17.5% vs 27.0%, P <.001) and GI procedures (3.3% vs 5.3%, P =.02) over 12 months. Similar results were seen in analyses of protocols with placebo; in these studies, rates of GI comedications and procedures were highest with NSAIDs, while those with rofecoxib and placebo were similar to each other. CONCLUSIONS: OA patients treated with rofecoxib for up to 12 months required significantly less GI comedication and significantly fewer GI procedures than those treated with NSAIDs.

Gastrointestinal tolerability of the selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib compared with nonselective COX-1 and COX-2 inhibitors in osteoarthritis.

BACKGROUND: Most nonsteroidal anti-inflammatory drugs (NSAIDs) are nonselective cyclooxygenase (COX-1 and COX-2) inhibitors and are associated with a variety of upper gastrointestinal (GI) tract symptoms. The roles of COX-1 and COX-2 in the pathogenesis of these symptoms are unclear. To test whether COX-2 inhibition with rofecoxib would have greater GI tolerability than nonselective COX-1 and COX-2 inhibition, we compared the incidences of (1) treatment discontinuations for GI adverse events (AEs) and (2) prespecified dyspeptic-type GI AEs among patients with osteoarthritis treated with rofecoxib vs NSAIDs. METHODS: A prespecified, combined analysis of investigator-reported GI AEs in all 8 double-blind, randomized, phase 2b/3 osteoarthritis trials of rofecoxib was conducted. Patients included men and women with osteoarthritis (N = 5435); there was no upper age limit for entry. Treatments tested included rofecoxib, 12.5, 25, or 50 mg (combined), vs ibuprofen, diclofenac, or nabumetone (combined). Primary outcomes were the time (by survival analysis) to (1) treatment discontinuation due to GI AEs and (2) first reported dyspeptic-type GI AE. Between-treatment comparisons were made by log-rank test. RESULTS: The number of treatment discontinuations caused by GI AEs during 12 months was significantly lower (P=.02) with rofecoxib vs NSAIDs (8.2 vs 12.0 per 100 patient-years; relative risk, 0.70; 95% confidence interval, 0.52-0.94). The incidence of prespecified dyspeptic-type GI AEs during the first 6 months was significantly lower (P=.02) with rofecoxib vs NSAIDs (69.3 vs 85.2 per 100 patient-years; relative risk, 0.85; 95% confidence interval, 0.74-0.97). However, the difference between treatments in dyspeptic-type GI AEs was attenuated after 6 months. CONCLUSION: Rofecoxib was associated with a lower incidence of treatment discontinuations due to GI AEs over 12 months and a lower incidence of dyspeptic-type GI AEs over 6 months than treatment with nonselective COX inhibitors, or NSAIDs. Arch Intern Med. 2000;160:2998-3003

Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs.

CONTEXT: Nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal (GI) toxic effects, such as upper GI tract perforations, symptomatic gastroduodenal ulcers, and upper GI tract bleeding (PUBs), are thought to be attributable to cyclooxygenase 1 (COX-1) inhibition. Rofecoxib specifically inhibits COX-2 and has demonstrated a low potential for causing upper GI injury. OBJECTIVE: To compare the incidence of PUBs in patients with osteoarthritis treated with rofecoxib vs NSAIDs. DESIGN: Prespecified analysis of all 8 double-blind, randomized phase 2b/3 rofecoxib osteoarthritis trials conducted from December 1996 through March 1998, including one 6-week dose-ranging study, two 6-week efficacy studies vs ibuprofen and placebo, two 1-year efficacy studies vs diclofenac, two 6-month endoscopy studies vs ibuprofen and placebo, and one 6-week efficacy study vs nabumetone and placebo. SETTING: Multinational sites. Participants Osteoarthritis patients (N = 5435; mean age, 63 years [range, 38-94 years]; 72.9% women). INTERVENTIONS: Rofecoxib, 12.5, 25, or 50 mg/d (n = 1209, 1603, and 545, respectively, combined) vs ibuprofen, 800 mg 3 times per day (n = 847), diclofenac, 50 mg 3 times per day (n = 590); or nabumetone, 1500 mg/d (n = 127) (combined). MAIN OUTCOME MEASURE: Cumulative incidence of PUBs for rofecoxib vs NSAIDs, based on survival analysis of time to first PUB diagnosis, using PUBs that met pre-specified criteria judged by a blinded, external adjudication committee. RESULTS: The incidence of PUBs over 12 months was significantly lower with rofecoxib vs NSAIDs (12-month cumulative incidence, 1.3% vs 1.8%; P = .046; rate per 100 patient-years, 1.33 vs 2.60; relative risk, 0.51; 95% confidence interval, 0.26-1.00). The cumulative incidence of dyspeptic GI adverse experiences was also lower with rofecoxib vs NSAIDS over 6 months (23.5% vs 25.5%; P = .02), after which the incidence rates converged. CONCLUSION: In a combined analysis of 8 trials of patients with osteoarthritis, treatment with rofecoxib was associated with a significantly lower incidence of PUBs than treatment with NSAIDs.

Transmission of hepatitis C within Australian prisons.

Transmission of hepatitis C virus (HCV) within prisons has long been suspected but has not been satisfactorily documented. We present four cases of HCV infection occurring during periods of continuous imprisonment. Each subject was HCV seronegative on entering prison and on repeat testing after 4-52 months in prison, but subsequently became seropositive. Two subjects gave a history of injecting drug use, and the most likely means of infection in the other two subjects were lacerations from barbers shears and lacerations arising from physical assault. There is an urgent need for detailed study of the incidence of HCV infection and the modes of transmission in prisons.

Specific inhibition of cyclooxygenase-2 with MK-0966 is associated with less gastroduodenal damage than either aspirin or ibuprofen.

BACKGROUND: Compared with currently available NSAIDs (which inhibit COX-1 and COX-2 isoforms of cyclooxygenase), MK-0966 (a specific COX-2 inhibitor) is expected to cause less gastrointestinal toxicity. AIM: To compare the effect on the upper gastrointestinal mucosae of a high dose of MK-0966 with that of conventional doses of ibuprofen and aspirin. METHODS: Healthy subjects (n = 170; age range 18-54 years) with endoscopically normal gastric and duodenal mucosa were randomized to either MK-0966 250 mg q.d. (n = 51), ibuprofen 800 mg t.d.s. (n = 51), aspirin 650 mg q.d.s. (n = 17), or placebo (n = 51) in this 7-day, double-blind, parallel-group study. The mucosae were evaluated by endoscopy using a predefined scale; scores could range from 0 to 4. The primary end-point was the percentage of subjects who developed a mucosal score >/= 2 (i.e. the development of one or more erosions). To evaluate COX-1 activity, serum thromboxane B2 levels were determined in a subset of the population. RESULTS: The percentage of subjects who developed a mucosal score >/= 2 in the MK-0966 group (12%) was significantly lower (P < 0.001) than that in the ibuprofen (71%) and aspirin (94%) groups, and was similar to that in the placebo group (8%). Only ibuprofen and aspirin significantly (P < 0.0001) reduced baseline thromboxane B2 levels. All treatments were generally well tolerated. CONCLUSIONS: In this acute short-term endoscopic study, MK-0966 250 mg q.d. (a dose at least 10 times higher than that demonstrated to reduce the signs and symptoms of osteoarthritis) produced significantly less gastrointestinal mucosal damage than either ibuprofen 800 mg t.d.s. or aspirin 650 mg q.d.s. and was comparable to placebo in this regard.

Sin3 corepressor function in Myc-induced transcription and transformation.

Many basic-helix-loop-helix-leucine zipper (b-HLH-LZ) proteins, including the Myc family and non-Myc family, bind a common DNA sequence CACGTG, yet have quite different biological actions. Myc binds this sequence as a heterodimer with Max in the activation of both transcription and transformation. The Myc family members Mad and Mxi1 are known to suppress Myc-induced transcription and transformation and to dimerize with Max to form ternary complexes with the mammalian Sin3 transcriptional corepressor (mSin3). The b-HLH-LZ domain of TFEB, which cannot heterodimerize within the Myc family, does not suppress Myc-induced transcription or transformation. However, transfer of a 25- to 36-aa region from Mad or Mxi1, which interacts with mSin3, to the b-HLH-LZ of TFEB, mediated profound suppression of Myc-induced transcription and transformation. These results suggest that the DNA binding specificities of the Myc family and non-Myc family b-HLH-LZ proteins, in the context of the cellular genes involved in Myc-induced transformation, are shared. The results also demonstrate that targeting mSin3 to CACGTG sites via a non-Myc family DNA binding domain is sufficient to oppose Myc activity in growth regulation.

Regulation of autoimmunity and donor cell engraftment by recipient Lyt-2+ cells during the graft-versus-host reaction.

When lymphocytes from DBA/2 mice are transferred to (C57BL X DBA/2)F1 (BDF1) mice, the ensuing graft-vs.-host reaction (GVHR) causes an autoimmune illness resembling human SLE. To examine the role of recipient T cells in this process, BDF1 mice were depleted of L3T4+ or Lyt-2+ cells by thymectomy followed by treatment with mAbs to L3T4 or Lyt-2. This produced sustained depletion of these T cell subsets. Subsequent grafting with parental DBA/2 lymphocytes produced autoimmune disease in mice depleted of L3T4+ cells and controls but not in mice depleted of Lyt-2+ cells. Analysis of blood lymphocytes 4 wk after donor cell transfer demonstrated that BDF1 recipients depleted of Lyt-2+ cells were virtually repopulated with donor T lymphocytes, compared with less than or equal to 35% donor cell engraftment in all other groups. Thus, recipient Lyt-2+ cells influence both host cell engraftment and autoimmunity during the parent-into-F1 GVHR.