A comparative study of etanercept plus methotrexate and methotrexate alone in Taiwanese patients with active rheumatoid arthritis: a 12-week, double-blind, randomized, placebo-controlled study.

BACKGROUND AND PURPOSE: Etanercept (Enbrel), a recombinant tumor necrosis factor receptor fusion protein, has been shown to be effective in the treatment of patients with rheumatoid arthritis (RA). The purpose of this study was to compare the efficacy and safety of etanercept in combination with methotrexate (MTX) and MTX alone in Taiwanese patients with active RA. METHODS: In this double-blind study, 58 patients with active RA who were maintained on MTX therapy at a stable dose of 12.5 to 20 mg per week for 4 weeks were randomized to receive either etanercept 25 mg (n = 29) or placebo (n = 29) by subcutaneous injection twice weekly over a period of 12 weeks. The primary endpoint was the reduction of tender and swollen joint counts by 20% (ACR 20), 50% (ACR 50), and 70% (ACR 70) as determined by the American College of Rheumatology criteria at the 12th week. RESULTS: The addition of etanercept to MTX resulted in a greater reduction in the number of tender (7.00 vs 2.45, p = 0.012) and swollen joints (8.55 vs 3.86, p = 0.017), and in serum levels of C-reactive protein (1.26 mg/dL vs 0.45 mg/dL, p = 0.014) compared to MTX alone after 12 weeks of therapy. In addition, the global assessment of disease activity by both physicians and patients, duration of morning stiffness, pain visual analog scale score, and Health Assessment Questionnaire were all improved by etanercept plus MTX therapy. Results for the overall improvement in disease activity assessed by ACR 20 (90% vs 34%), ACR 50 (66% vs 10%) and ACR 70 (24% vs 0%) all favored the etanercept plus MTX group. However, the adverse events were comparable between the 2 treatment groups. CONCLUSION: Etanercept in combination with MTX was well tolerated and provided significantly more clinical benefit than MTX alone in Taiwanese patients with active RA.     

Hepatocyte paraffin 1 antibody does not distinguish primary ovarian tumors with hepatoid differentiation from metastatic hepatocellular carcinoma.

Anti-hepatocyte antibody, hepatocyte paraffin 1, is a monoclonal antibody that is highly specific for normal and neoplastic hepatocytes and that can differentiate hepatocytic from nonhepatocytic tumors. This marker has been rarely studied in extra-hepatic tumors and to our knowledge has not been investigated in ovarian tumors with hepatoid differentiation. We studied hepatocyte paraffin 1 immunoreactivity in a series of ovarian hepatoid carcinomas, ovarian hepatoid yolk sac tumors (YSTs), and hepatocellular carcinomas metastatic to the ovary to assess the potential utility of hepatocyte paraffin 1 in differential diagnosis. Hepatocyte paraffin 1 positivity was seen in three of seven ovarian hepatoid carcinomas, five of eight hepatoid yolk sac tumors, and six of eight metastatic hepatocellular carcinomas. The extent of positivity ranged from <25% to >50% of the tumor cells. There was strong coarsely granular cytoplasmic staining in all three tumor types without a distinctive staining pattern in any group. The degree of hepatic differentiation correlated with hepatocyte paraffin 1 positivity in the three groups: 83% of the well differentiated tumors, 50% of the moderately differentiated tumors, and none of the poorly differentiated tumors were positive. All ovarian hepatoid carcinomas were either immunoreactive for alpha-fetoprotein or had an elevated serum alpha-fetoprotein level; more than half of these tumors were hepatocyte paraffin 1 negative. All but one hepatocyte paraffin 1 negative hepatoid yolk sac tumor and ovarian hepatocellular carcinoma were also negative for alpha-fetoprotein. In conclusion, hepatocyte paraffin 1 is positive in primary ovarian tumors with hepatoid differentiation, with the degree of hepatocyte paraffin 1 positivity correlating with the degree of hepatoid differentiation. Hepatocyte paraffin 1, however, is not useful in distinguishing metastatic hepatocellular carcinoma from primary ovarian hepatoid carcinoma or hepatoid yolk sac tumor.     

Interactions between membrane IgM and the cytoskeleton involve the cytoplasmic domain of the immunoglobulin receptor

Cross-linking induced interactions between the membrane form of immunoglobulin (mIg) and the cytoskeletal matrix have been described by several groups. To date, the function of mIgM association with the cytoskeleton is not yet understood. Delineation of the molecular basis of these interactions will be instrumental in elucidating their function. We have previously shown that the Igα/β heterodimer is not required for ligand-induced mIgM binding to the cytoskeleton. In this study, we have investigated the role of other B cell-specific proteins in mediating these interactions. For this, we expressed mIgM in the non-hematopoietic human cervical carcinoma cell line HeLa S3 and verified the capacity of the surface-expressed IgM to interact with the cytoskeletal matrix upon cross-linking with anti-μ chain antibodies. We show here that only the mIgM molecule itself and no other B cell-specific protein(s) is required in mediating mIgM interactions with actin filaments. In an attempt to determine the cytoskeleton-binding site of mIgM we investigated the role of the cytoplasmic tail of mIgM (KVK) in binding the receptor to actin-based microfilaments. Using mutated forms of mIgM expressed in J558L cells, we show here that KVK plays a role in mediating these interactions. The absence of KVK did not, however, completely abrogate mIgM-cytoskeletal interactions, suggesting that there are additional molecular requirements for the ligand-induced mIgM binding to the cytoskeletal matrix.     

Estrogen and the etiology of anorexia nervosa

Most patients suffering from anorexia nervosa are women, but the types and relative contributions of social, psychological, or organic characteristics of women that make women more likely to develop this feeding disorder are uncertain. In this theoretical review, evidence that the female sex hormone, estrogen, contributes to the symptoms seen in anorexia and underlies the sex difference in incidence is discussed. Current data on the anorexic potency of estrogen in experimental animals, humans, and in anorexic patients is presented, along with a suggestion that treatment of anorexics with progesterone, a hormone that blocks these effects of estrogen, might have a beneficial influence upon the outcome of anorexia nervosa.     

Acute vascular rejection is associated with up-regulation of vitronectin receptor (alphavbeta3), increased expression of tissue factor, and activation of the extracellular matrix metalloproteinase induction system.

BACKGROUND: A cascade of inflammatory reactions characterize acute vascular rejection after heart transplantation. This study was undertaken to test the hypothesis that acute vascular rejection is associated with up-regulation of vitronectin receptor (alphavbeta3), increased expression of tissue factor, and activation of the extracellular matrix metalloproteinase induction system. METHODS: Acute vascular rejection developed in 14 heart transplant recipients within 2 weeks of transplantation, confirmed by immunofluorescence (AVR group). We compared these patients with 10 transplant recipients who had no evidence of acute vascular rejection or peritransplant ischemic injury (control group). We evaluated endomyocardial biopsy specimens for alphavbeta3, tissue factor, and extracellular matrix metalloproteinase inducer (EMMPRIN). RESULTS: Compared with the control group, the AVR group demonstrated evidence of significantly increased expression of alphavbeta3 (1.9-fold, p < 0.001), tissue factor (1.8-fold, p < 0.001), and EMMPRIN (1.5-fold, p < 0.001). All patients in the AVR group received plasmapheresis; 11 of 14 patients had evidence of ischemic necrosis on biopsy specimens, and 3 of 14 patients experienced hemodynamic compromise and graft dysfunction and died within 3 weeks of transplant. Another patient died at 10 months after transplant. CONCLUSIONS: Acute vascular rejection is associated with up-regulation of alphavbeta3, tissue factor, and activation of the matrix metalloproteinase induction system, which may contribute to the lethal morbidity associated with this disease.     

The assessment of pain in rheumatoid arthritis: disease differentiation and temporal stability of a behavioral observation method

An observation method for the assessment of pain behaviors in patients with rheumatoid arthritis (RA) has been developed. We investigated the extent to which the frequencies of pain behaviors differentiated patients with RA and patients with chronic low back pain from depressed and nondepressed, pain free, control subjects. The reliability of the pain behavior frequencies of patients with RA across 2 observation sessions also was determined. Total pain behavior scores clearly differentiated patients with RA and low back pain from depressed and nondepressed, pain free, control subjects. Pain behavior observed in patients with RA showed a high degree of stability over time. The results of our study suggest that the behavioral observation method will prove useful in the assessment of RA pain in clinical and research settings.     

Cloned human T lymphocytes reactive with Dermatophagoides farinae (house dust mite): a comparison of T- and B-cell antigen recognition.

In this report, T-cell and B-cell recognition of the house dust mite Dermatophagoides farinae (D. far.) is compared. Nitrocellulose immunoblots of polyacrylamide gel electrophoresis (SDS-PAGE)-fractionated D. far. were added to proliferation assays to map the antigen specificity of cloned human helper T cells and a long-term line induced with D. far. T-cell recognition was of a polypeptide of molecular weight 9000-13,000, that migrates with the serologically defined allergen Der fII (12,500 MW). Since the cloned T cells, unlike the polyclonal response, failed to respond to Dermatophagoides pteronyssinus (D. pter.), this suggests that they recognize a species-specific epitope. In contrast, analysis of the B-cell response using Western blotting demonstrated that, in addition to Der fII, antibodies reactive with the major allergens Der fI (26,000 MW) and Der fIII (29,000 MW) were present in the serum. Similar specificities were seen in the antibody response to D. pter., and while it has been reported that the B-cell response to D. far. and D. pter. are predominantly cross-reactive, our observations suggest that species-specific CD4-positive T cells are present in the overall cellular response to D. far.     

Kinetics and specificity at the clonal level of the cytotoxic T lymphocyte response to influenza pneumonia

We have studied the kinetics and specificity of the cytotoxic T lymphocyte (CTL) response to influenza A/PR/8 (H1N1) virus pulmonary infection in the mouse detected using spleen cells from infected mice which were stimulated in bulk and limiting dilution cultures. A hybrid protein designated D-peptide, which contains the terminal 157 amino acids of the HA2 subunit of A/PR/8 virus, was used to stimulate influenza virus subtype-specific secondary CTL in vitro. Infection induced two specificities of precursor CTL, cross-reactive and subtype-specific. The kinetics of the subtype-specific CTL response detected by the D-peptide were similar to the cross-reactive CTL response detected by stimulation with live virus. The majority of the precursor CTL (CTL-p) are able to lyse virus-infected target cells in a cross-reactive fashion. The number of memory subtype-specific and cross-reactive CTL increased by approximately 2.5 logs10 during the first 3 weeks after infection.