Biomedical subjects

Michael Schiff

Publications and source records attributed to Michael Schiff.

At least 19 recordsLinked to original sources

PubMed2006

The introducer technique is the optimal method for placing percutaneous endoscopic gastrostomy tubes in head and neck cancer patients.

BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) tubes are often placed in head and neck cancer patients to provide nutritional support, but studies have found the complication rates to be higher than other subsets of patients who undergo PEG placement. Complication rates as high as 50% have been reported, with the bulk of these complications being PEG site issues (i.e., cellulitis, abscess, fascitis, and tumor implantation). Because the pull technique has been the primary technique used, the theory is that the transoral tube passage is the source of the complications in these patients. Alternatively, the introducer technique uses a transabdominal approach to place the device, avoiding any tube contamination by upper aerodigestive organisms or tumor cells. At our institution, this technique has been used exclusively for head and neck cancer patients and this article reports our experience. METHODS: One hundred forty-nine head and neck cancer patients who had a prophylactic PEG tube placed were reviewed from January 1, 1999 to December 31, 2003. The rates of placement success, morbidity, and complications were determined. RESULTS: Successful placement was achieved in 148 (99%) patients without any PEG-related deaths. Overall, 17 complications (11%) occurred, with only one major complication (0.7%) identified. PEG site infections were uncommon with only five cases (3.4%) and all were mild cellulitis. CONCLUSIONS: The introducer technique is the safest method for PEG tube placement in head and neck cancer patients. The overall rate of complications is low and PEG site infectious complications are rare. The introducer technique should be the method of choice for PEG tubes in head and neck cancer patients.

Enteral Nutrition↗

PubMed2006

Selective costimulation modulation using abatacept in patients with active rheumatoid arthritis while receiving etanercept: a randomised clinical trial.

OBJECTIVE: To investigate the efficacy and safety of abatacept in combination with etanercept in patients with active rheumatoid arthritis during a 1-year, randomised, placebo-controlled, double-blind phase, followed by an open-label, long-term extension (LTE). METHODS: Patients continued etanercept (25 mg twice weekly) and were randomised to receive abatacept 2 mg/kg (n = 85) or placebo (n = 36). As the effective dose of abatacept was established as 10 mg/kg in a separate trial, all patients received abatacept 10 mg/kg and etanercept during the LTE. RESULTS: A total of 121 patients were randomised; 80 completed double-blind treatment and entered the LTE. During double-blind treatment, the difference in the percentage of patients achieving the primary end point (modified American College of Rheumatology (ACR) 20 response at 6 months) was not significant between groups (48.2% v 30.6%; p = 0.072). At 1 year, no notable changes in modified ACR responses were observed. Subsequent to the dosing change, similar modified ACR responses were seen during the LTE. Significant improvements in quality of life were observed with abatacept and etanercept versus placebo and etanercept in five of the eight short-form 36 subscales at 1 year. More abatacept and etanercept-treated patients experienced serious adverse events (SAEs) at 1 year than patients receiving placebo and etanercept (16.5% v 2.8%), with 3.5% v 0% experiencing serious infections. CONCLUSION: The combination of abatacept (at a dose of 2 mg/kg during the double-blind phase and 10 mg/kg during the LTE) and etanercept was associated with an increase in SAEs, including serious infections, with limited clinical effect. On the basis of the limited efficacy findings and safety concerns, abatacept in combination with etanercept should not be used for rheumatoid arthritis treatment.

Abatacept↗

PubMed2006

Efficient virus-induced gene silencing in Arabidopsis.

Virus-induced gene silencing (VIGS) is a plant RNA-silencing technique that uses viral vectors carrying a fragment of a gene of interest to generate double-stranded RNA, which initiates the silencing of the target gene. Several viral vectors have been developed for VIGS and they have been successfully used in reverse genetics studies of a variety of processes occurring in plants. This approach has not been widely adopted for the model dicotyledonous species Arabidopsis (Arabidopsis thaliana), possibly because, until now, there has been no easy protocol for effective VIGS in this species. Here, we show that a widely used tobacco rattle virus-based VIGS vector can be used for silencing genes in Arabidopsis ecotype Columbia-0. The protocol involves agroinfiltration of VIGS vectors carrying fragments of genes of interest into seedlings at the two- to three-leaf stage and requires minimal modification of existing protocols for VIGS with tobacco rattle virus vectors in other species like Nicotiana benthamiana and tomato (Lycopersicon esculentum). The method described here gives efficient silencing in Arabidopsis ecotype Columbia-0. We show that VIGS can be used to silence genes involved in general metabolism and defense and it is also effective at knocking down expression of highly expressed transgenes. A marker system to monitor the progress and efficiency of VIGS is also described.

Arabidopsis↗

PubMed2006

Infliximab treatment maintains employability in patients with early rheumatoid arthritis.

OBJECTIVE: To evaluate the impact of infliximab therapy on the employment status of patients with early rheumatoid arthritis (RA). METHODS: Methotrexate (MTX)-naive patients with active early RA were randomly allocated to receive MTX plus placebo or MTX plus infliximab (3 mg/kg or 6 mg/kg) at weeks 0, 2, and 6 and then every 8 weeks through week 46. Data for patients younger than age 65 years were included in the analyses. A patient was categorized as employable if he or she was employed or felt well enough to work if a job were available. RESULTS: The change in actual employment was not significantly different between patients receiving MTX plus infliximab and those receiving MTX plus placebo (0.5% versus 1.3%; P > 0.5). However, the proportion of patients whose status changed from employable at baseline to unemployable at week 54 was smaller in the group receiving MTX plus infliximab compared with that in the group receiving MTX alone (8% versus 14%; P = 0.05). Patients who were treated with infliximab plus MTX had a significantly greater likelihood of improvement rather than deterioration in employability (odds ratio 2.4; P < 0.001); this likelihood was not significantly greater in patients receiving MTX alone. The proportion of employed patients who lost workdays during the trial was smaller in the MTX plus infliximab group than in the MTX-alone group (P = 0.010). CONCLUSION: The actual employment rates among patients in the 2 treatment groups were not different. However, patients with early RA who were treated with MTX plus infliximab had a higher probability of maintaining their employability compared with those who were treated with MTX alone.

Antibodies, Monoclonal↗

PubMed2006

Predictors of joint damage in patients with early rheumatoid arthritis treated with high-dose methotrexate with or without concomitant infliximab: results from the ASPIRE trial.

OBJECTIVE: To identify disease characteristics leading to progression of joint damage in patients with early rheumatoid arthritis (RA) treated with methotrexate (MTX) versus those treated with infliximab plus MTX. METHODS: Patients who had not previously been treated with MTX with active RA were randomly assigned to receive escalating doses of MTX up to 20 mg/week plus placebo or infliximab at weeks 0, 2, and 6, and every 8 weeks thereafter through week 46. Radiographic joint damage was assessed using the modified Sharp/van der Heijde score (SHS). The relationship between disease activity measures at baseline and week 14, as well as those averaged over time, were examined in relation to the change in SHS from baseline through week 54. RESULTS: C-reactive protein (CRP) levels, erythrocyte sedimentation rate (ESR), and swollen joint count were associated with greater joint damage progression in the MTX-only group, while none of these parameters was associated with progression in the infliximab plus MTX group. Mean changes in SHS among patients in the highest CRP (> or = 3 mg/dl) and ESR (> or = 52 mm/hour) tertiles in the MTX-only group were 5.62 and 5.89, respectively, compared with 0.73 and 1.12 in the infliximab plus MTX group (P < 0.001). Patients with greater joint damage at baseline (SHS > or = 10.5) showed less progression with infliximab plus MTX compared with MTX alone (-0.39 versus 4.11; P < 0.001). Patients receiving MTX alone who had persistently active disease at week 14 showed greater radiographic progression of joint damage than those taking MTX plus infliximab. CONCLUSION: High CRP level, high ESR, or persistent disease activity was associated with greater radiographic progression in the group taking MTX alone, while little radiographic progression was seen in patients receiving both MTX and infliximab, regardless of the abnormal levels of these traditional predictors.

Adolescent↗

PubMed2005

Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition.

BACKGROUND: A substantial number of patients with rheumatoid arthritis have an inadequate or unsustained response to tumor necrosis factor alpha (TNF-alpha) inhibitors. We conducted a randomized, double-blind, phase 3 trial to evaluate the efficacy and safety of abatacept, a selective costimulation modulator, in patients with active rheumatoid arthritis and an inadequate response to at least three months of anti-TNF-alpha therapy. METHODS: Patients with active rheumatoid arthritis and an inadequate response to anti-TNF-alpha therapy were randomly assigned in a 2:1 ratio to receive abatacept or placebo on days 1, 15, and 29 and every 28 days thereafter for 6 months, in addition to at least one disease-modifying antirheumatic drug. Patients discontinued anti-TNF-alpha therapy before randomization. The rates of American College of Rheumatology (ACR) 20 responses (indicating a clinical improvement of 20 percent or greater) and improvement in functional disability, as reflected by scores for the Health Assessment Questionnaire (HAQ) disability index, were assessed. RESULTS: After six months, the rates of ACR 20 responses were 50.4 percent in the abatacept group and 19.5 percent in the placebo group (P<0.001); the respective rates of ACR 50 and ACR 70 responses were also significantly higher in the abatacept group than in the placebo group (20.3 percent vs. 3.8 percent, P<0.001; and 10.2 percent vs. 1.5 percent, P=0.003). At six months, significantly more patients in the abatacept group than in the placebo group had a clinically meaningful improvement in physical function, as reflected by an improvement from baseline of at least 0.3 in the HAQ disability index (47.3 percent vs. 23.3 percent, P<0.001). The incidence of adverse events and peri-infusional adverse events was 79.5 percent and 5.0 percent, respectively, in the abatacept group and 71.4 percent and 3.0 percent, respectively, in the placebo group. The incidence of serious infections was 2.3 percent in each group. CONCLUSIONS: Abatacept produced significant clinical and functional benefits in patients who had had an inadequate response to anti-TNF-alpha therapy.

Abatacept↗

PubMed2005

Autophagy regulates programmed cell death during the plant innate immune response.

The plant innate immune response includes the hypersensitive response (HR), a form of programmed cell death (PCD). PCD must be restricted to infection sites to prevent the HR from playing a pathologic rather than protective role. Here we show that plant BECLIN 1, an ortholog of the yeast and mammalian autophagy gene ATG6/VPS30/beclin 1, functions to restrict HR PCD to infection sites. Initiation of HR PCD is normal in BECLIN 1-deficient plants, but remarkably, healthy uninfected tissue adjacent to HR lesions and leaves distal to the inoculated leaf undergo unrestricted PCD. In the HR PCD response, autophagy is induced in both pathogen-infected cells and distal uninfected cells; this is reduced in BECLIN 1-deficient plants. The restriction of HR PCD also requires orthologs of other autophagy-related genes including PI3K/VPS34, ATG3, and ATG7. Thus, the evolutionarily conserved autophagy pathway plays an essential role in plant innate immunity and negatively regulates PCD.

Amino Acid Sequence↗

PubMed2005

Evaluation of the efficacy of etoricoxib in ankylosing spondylitis: results of a fifty-two-week, randomized, controlled study.

OBJECTIVE: To assess the efficacy, safety, and tolerability of etoricoxib, a cyclooxygenase 2 (COX-2) selective inhibitor, administered continuously over 52 weeks for the treatment of ankylosing spondylitis (AS). METHODS: This 2-part, multicenter, double-blind, parallel-group, 52-week study evaluated 2 doses of etoricoxib (90 and 120 mg) compared with naproxen at 1,000 mg. A 6-week, active-comparator- and placebo-controlled period (part I) was followed by a 46-week active-comparator-controlled period (part II). The primary outcome measures (on 100-mm visual analog scales) were patient's assessment of spine pain, patient's global assessment of disease activity, and the Bath Ankylosing Spondylitis Functional Index. RESULTS: Of the 387 patients randomized to receive treatment, 301 (77.8%) completed part I and 284 (75.9%) completed part II. Compared with placebo over 6 weeks, those receiving 90 mg etoricoxib, 120 mg etoricoxib, and naproxen demonstrated significantly (P < 0.001) greater improvement in all primary end points; treatment effects (expressed as the difference in least squares mean change versus placebo) were 21-29 mm for spine pain, 18-25 mm for disease activity, and 11-15 mm for function. Compared with patients receiving naproxen, significantly greater improvement in all primary end points was demonstrated in the combined group receiving either 90 mg etoricoxib or 120 mg etoricoxib over 6 weeks, in each individual etoricoxib treatment group over 6 weeks, and in the combined etoricoxib group over 1 year (all P < 0.05); results for secondary and exploratory end points were generally consistent with those from the primary analysis. Among all groups, there were no significant differences in the incidence of overall clinical, drug-related, or serious adverse experiences (AEs) and discontinuations due to AEs. Safety observations during part II were generally consistent with those in part I. CONCLUSION: Etoricoxib at doses of 90 mg and 120 mg demonstrated superior efficacy compared with placebo over 6 weeks, and compared with naproxen over 1 year. These study results demonstrate that etoricoxib is generally safe, well-tolerated, and efficacious for the treatment of AS.

Adolescent↗

PubMed2005

Effects of prasterone on bone mineral density in women with systemic lupus erythematosus receiving chronic glucocorticoid therapy.

OBJECTIVE: To assess the effects of treatment with prasterone (dehydroepiandrosterone) on bone mineral density (BMD) in female patients with mild to moderate systemic lupus erythematosus (SLE) receiving chronic treatment with glucocorticoids. METHODS: Fifty-five female patients with SLE who had received prednisone (or glucocorticoid equivalent) </= 10 mg/day for >/= 6 months were treated for 1 year with either prasterone 200 mg/day (n = 24) or placebo (n = 31) in this randomized, double blind trial. Prasterone or placebo was added to each patient's one or more concomitant standard SLE medications, including glucocorticoids, nonsteroidal antiinflammatory drugs, antimalarials, methotrexate, azathioprine, and other immunosuppressives, which were to be maintained at fixed doses for the duration of the study. RESULTS: BMD was significantly improved in patients who received prasterone compared to placebo. At the lumbar spine, there was a mean (SEM) gain in BMD of 1.7 +/- 0.8% in the prasterone group compared to a mean loss in BMD of -1.1 +/- 0.5% in the placebo group (p = 0.003 between groups). For the total hip, mean gain was 2.0 +/- 0.9% in the prasterone group vs a mean loss of -0.3 +/- 0.4% in the placebo group (p = 0.013 between groups). In the prasterone treatment group, the mean gains from baseline at both lumbar spine and hip were statistically significant. CONCLUSION: Prasterone treatment prevented BMD loss and significantly increased BMD at both the lumbar spine and total hip in female patients with SLE receiving exogenous glucocorticoids.

Adjuvants, Immunologic↗

PubMed2005

A phase 2 dose-finding study of PEGylated recombinant methionyl human soluble tumor necrosis factor type I in patients with rheumatoid arthritis.

OBJECTIVE: In a phase 2 study, to assess the efficacy and safety of pegsunercept, a soluble tumor necrosis factor receptor type I, for the treatment of rheumatoid arthritis (RA). METHODS: Patients were randomized to receive weekly subcutaneous injections of placebo (n = 61) or active drug [400 microg/kg (n = 67) or 800 microg/kg (n = 66)] for 12 weeks. The primary efficacy endpoint was American College of Rheumatology 20% response (ACR20) at Week 12. Secondary efficacy measures included ACR50 and ACR70 responses, and changes in individual ACR components at Week 12. Safety assessments included summaries of adverse events including infectious episodes. RESULTS: Treatment with pegsunercept resulted in a significantly higher ACR20 response at Week 12 in the 800 microg/kg group (45%) compared with the placebo group (26%; p = 0.020). The treatment effect of pegsunercept (both doses) over the study period showed statistically significant improvement for most ACR components and health related quality of life, with the 800 microg/kg group showing greater clinical improvements in efficacy measures. The overall incidence of adverse events and infectious episodes was similar among the treatment and placebo groups. CONCLUSION: In this 12 week dose-finding study of 194 patients, weekly subcutaneous dosing with pegsunercept showed beneficial effects in improving the signs and symptoms of RA. It appeared to be safe and well tolerated in this small number of patients. Significant clinical improvements were seen in patients in the 800 microg/kg group; however, this dose may be suboptimal, and further evaluation of this product with higher doses or a more frequent dosing regimen is warranted.

Adult↗

PubMed2004

Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial.

OBJECTIVE: To compare the benefits of initiating treatment with methotrexate (MTX) and infliximab (anti-tumor necrosis factor alpha [anti-TNFalpha] monoclonal antibody) with those of MTX treatment alone in patients with rheumatoid arthritis (RA) of < or =3 years' duration. METHODS: RA patients were eligible if they had active disease and no prior treatment with MTX or a TNFalpha inhibitor. One thousand forty-nine patients were randomly assigned in a 4:5:5 ratio to 3 treatment groups: MTX-placebo, MTX-3 mg/kg infliximab, and MTX-6 mg/kg infliximab. MTX dosages were rapidly escalated to 20 mg/week, and infliximab or placebo infusions were given at weeks 0, 2, and 6, and every 8 weeks thereafter through week 46. RESULTS: At week 54, the median percentage of American College of Rheumatology improvement (ACR-N) was higher for the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups than for the MTX-placebo group (38.9% and 46.7% versus 26.4%, respectively; P < 0.001 for both comparisons). Patients in the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups also showed less radiographic progression than those receiving MTX alone (mean +/- SD changes in van der Heijde modification of the total Sharp score at week 54: 0.4 +/- 5.8 and 0.5 +/- 5.6 versus 3.7 +/- 9.6, respectively; P < 0.001 for each comparison). In addition, physical function improved significantly more in the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups than in the MTX-placebo group. Infliximab therapy was associated with a significantly higher incidence of serious infections, especially pneumonia. CONCLUSION: For patients with active RA in its early stages, combination therapy with MTX and infliximab provides greater clinical, radiographic, and functional benefits than treatment with MTX alone.

Adult↗

PubMed2004

Virus induced gene silencing of a DEFICIENS ortholog in Nicotiana benthamiana.

Traditionally, developmental studies in plant biology have suffered from the lack of a convenient means to study gene function in non-model plant species. Here we show that virus-induced gene silencing (VIGS) is an effective new tool to study the function of orthologs of floral homeotic genes such as DEFICIENS (DEF) in non-model systems. We used a tobacco rattle virus (TRV)-based VIGS approach to study the function of the Nicotiana benthamiana DEF ortholog (NbDEF). Silencing of NbDEF in N. benthamiana using TRV-VIGS was similar to that of Antirrhinum def and Arabidopsis ap3 mutants and caused transformation of petals into sepals and stamens into carpels. Molecular analysis of the NbDEF -silenced plants revealed a dramatic reduction of the levels of NbDEF mRNA and protein in flowers. NbDEF silencing was specific and has no effect on the mRNA levels of NbTM6, the closest paralog of NbDEF. A dramatic reduction of the levels of N. benthamiana GLOBOSA (NbGLO) mRNA and protein was also observed in flowers of NbDEF-silenced plants, suggesting that cross-regulation of this GLO-like gene by NbDEF. Taken together, our results suggest that NbDEF is a functional homolog of Antirrhinum DEF. Our results are significant in that they show that TRV efficiently induces gene silencing in young and differentiating flowers and that VIGS is a promising new tool for analyses of developmental gene function in non-model organisms.

DEFICIENS Protein↗

PubMed2004

Involvement of MEK1 MAPKK, NTF6 MAPK, WRKY/MYB transcription factors, COI1 and CTR1 in N-mediated resistance to tobacco mosaic virus.

The tobacco N gene, a member of the Toll-interleukin 1 homology region/nucleotide binding site/leucine-rich repeat (TIR-NBS-LRR) class of resistance (R) genes, confers resistance to tobacco mosaic virus (TMV). We used a candidate gene approach to identify known defense genes that were also involved in N signaling. The requirement for these genes was determined by downregulating their expression using the well-established tobacco rattle virus (TRV)-based virus-induced gene silencing (VIGS). Silencing of genes encoding a mitogen-activated protein kinase (MAPK) NTF6/NRK1, or an MAPK kinase (MAPKK) MEK1/NQK1, attenuated N-mediated resistance to TMV. We also found that N resistance is compromised in plants in which expression of WRKY1-WRKY3 and MYB1 transcription factors were downregulated. In addition, suppression of jasmonic acid (JA) signaling component COI1 ortholog affected N function. However, downregulation of expression of CTR1 ortholog leads to more rapid hypersensitive response (HR). The involvement of these genes in N- and other R-gene-mediated defense provides further evidence for the convergence of downstream signaling pathways of different R genes.

Gene Silencing↗

PubMed2004

Comparison of the analgesic efficacy and safety of nonprescription doses of naproxen sodium and Ibuprofen in the treatment of osteoarthritis of the knee.

OBJECTIVE: To compare the analgesic efficacy and safety of nonprescription doses of naproxen sodium, ibuprofen, and placebo in patients with osteoarthritis (OA) of the knee. METHODS: In 2 identical multicenter, randomized, double-blind, placebo-controlled, multidose, parallel-design studies, patients aged > or = 25 years with OA were randomized to daily doses of naproxen sodium 660 mg, naproxen sodium 440 mg (patients > or = 65 years), ibuprofen 1200 mg, or placebo, for 7 days. RESULTS: For investigator and patient assessment of knee joint pain, naproxen sodium (440/660 mg) and ibuprofen were clinically effective at relieving pain compared with placebo (n = 444); both treatments reduced the mean symptom score by 30-45%, compared with a 20-25% reduction with placebo. Naproxen sodium (440/660 mg) significantly improved all 7 symptoms from baseline compared with placebo, while ibuprofen significantly improved 5 of the symptoms. For the subgroup of patients aged > or = 65 years (n = 183), naproxen sodium 440 mg was significantly superior to placebo in all symptoms except pain on weight-bearing; ibuprofen only significantly reduced day pain. For daily diary evaluations, naproxen sodium and ibuprofen were effective in reducing all 6 symptoms; there was a trend toward higher efficacy for night-time pain with naproxen sodium 440/660 mg compared with ibuprofen. There were no significant differences in adverse event reporting between groups. CONCLUSION: Over-the-counter doses of naproxen sodium (440/660 mg) and ibuprofen (1200 mg) effectively relieve pain in patients with mild to moderate OA of the knee. Naproxen sodium provided more effective pain relief for most variables compared with placebo, and for night pain compared with ibuprofen. Efficacy was combined with good safety and tolerability.

Aged↗

PubMed2003

Molecular chaperone Hsp90 associates with resistance protein N and its signaling proteins SGT1 and Rar1 to modulate an innate immune response in plants.

SGT1 and Rar1 are important signaling components of resistance (R) gene-mediated plant innate immune responses. Here we report that SGT1 and Rar1 associate with the molecular chaperone Hsp90. In addition, we show that Hsp90 associates with the resistance protein N that confers resistance to tobacco mosaic virus. This suggests that Hsp90-SGT1-Rar1 and R proteins might exist in one complex. Suppression of Hsp90 in Nicotiana benthamiana plants shows that it plays an important role in plant growth and development. In addition, Hsp90 suppression in NN plants compromises N-mediated resistance to tobacco mosaic virus. Our results reveal a new role for SGT1- and Rar1-associated chaperone machinery in R gene-mediated defense signaling.

Amino Acid Sequence↗

PubMed2003

A rationale for the use of summary measurements for the assessment of the effects of rheumatoid arthritis therapies.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic disease with diverse and fluctuating manifestations. Because no single variable fully captures disease activity or severity, clinical trials of antirheumatic drugs typically employ composite indices, such as the American College of Rheumatology (ACR) core criteria, to assess disease status. Drug effects (as demonstrated with these indices) are usually assessed at discrete time points, which may obscure information about the time of onset or duration of improvements. An alternative methodology is the use of summary measurements based on area under the curve (AUC) analyses of disease activity. For these analyses, response is plotted over time, and the area under the response curve is calculated. Because disease variables are quantified over time, AUC measures summarize the therapeutic effects during the entire course of the trial or treatment course. Trials of RA agents have used AUC-based calculations in data analyses. OBJECTIVE: We examined the use of summary AUC measurements for the assessment of the effects of antirheumatic therapies. METHODS: Results provided by summary measurements from studies identified by a MEDLINE search (years, 1990-2002; search terms, rheumatoid arthritis, clinical trial, American College of Rheumatology, disease activity, and radiographic progression) were evaluated to assess the relevance of AUC analyses in the determination of disease activity. RESULTS: Results from these trials suggest that summary AUC measurements produce more precise treatment-effect estimates and are more sensitive than end-of-study data to differences between slower and more rapidly acting agents. Some research suggests that AUC analyses may be more stable and more sensitive to interpatient differences than other measures. AUC measures based on numeric ACR scores have been used successfully to determine treatment effects over time. CONCLUSIONS: Summary measurements are more sensitive to treatment differences than single-time-point assessments and should be considered for use in future RA clinical trials.

Antirheumatic Agents↗

PubMed2003

P58(IPK), a plant ortholog of double-stranded RNA-dependent protein kinase PKR inhibitor, functions in viral pathogenesis.

P58(IPK) is a cellular inhibitor of the mammalian double-stranded RNA-activated protein kinase (PKR). Here we provide evidence for the existence of its homolog in plants and its role in viral infection at the organism level. Viral infection of P58(IPK)-silenced Nicotiana benthamiana and Arabidopsis knockouts leads to host death. This host cell death is associated with phosphorylation of the alpha subunit of eukaryotic translation initiation factor (eIF-2alpha). Loss of P58(IPK) leads to reduced virus titer, suggesting that wild-type P58(IPK) protein plays an important role in viral pathogenesis. Although our complementation results using mammalian P58(IPK) suggest conservation of the P58(IPK) pathway in plants and animals, its biological significance seems to be different in these two systems. In animals, P58(IPK) is recruited by the influenza virus to limit PKR-mediated innate antiviral response. In plants, P58(IPK) is required by viruses for virulence and therefore functions as a susceptibility factor.

Amino Acid Sequence↗

PubMed2003

Fatal cholestatic liver failure associated with gemcitabine therapy.

Drug-induced hepatotoxicity accounts for more than a third of the cases of acute liver failure in the United States. In complex medical conditions, the diagnosis of drug-induced liver injury may be confounding and, specifically, the potential hepatotoxicity of chemotherapeutic agents may be easily overlooked. Two fatal cases of cholestatic hepatotoxicity have been previously reported, clearly implicating gemcitabine therapy. We report a third fatal case of cholestatic liver failure that we think is strongly linked to the use of gemcitabine. This chemotherapeutic agent is a fluorine analog with broad-spectrum antitumor activity commonly used in the treatment of breast, lung, prostate, and cervical cancer. The case we report is of a 45-year-old woman with a history of metastatic breast cancer to her spine. The patient was in remission for two years before she presented with a compensated mixed hepatitis of mild to moderate severity. Inpatient work-up found metastases to the right humerus and inferior pubic ramus, but none in the liver. Gemcitabine and carboplatin therapy was initiated for relapse of breast cancer. The patient's liver enzyme elevation diminished, but did not normalize before the start of chemotherapy. She received four courses of gemcitabine/carboplatin and subsequently presented with decompensated, severe cholestatic hepatitis. Transjugular liver biopsy displayed marked cholestasis and hepatocellular injury consistent with drug-induced hepatoxicity. Gemcitabine has been extensively studied in the oncology literature and at this time is thought to be a low-risk hepatotoxin causing hepatic adaptation and transient, reversible liver enzyme elevation, rarely leading to termination of gemcitabine therapy for solid tumors. We believe that gemcitabine therapy, particularly in the setting of preexisting liver injury or metastases to the liver, increases the relative risk of severe and potentially fatal hepatic injury possibly by idiosyncratic and dose-dependent mechanisms. We recommend careful monitoring and dose adjustment of gemcitabine in patients with abnormal liver function tests or evidence of hepatic metastases until further study clarifies this issue.

Adenocarcinoma↗