Objective. Adalimumab, a fully human, antitumor necrosis factor monoclonal antibody, was evaluated for its safety and efficacy compared with placebo in the treatment of active psoriatic arthritis (PsA).Methods. Patients with moderately to severely active PsA and a history of inadequate response to nonsteroidal antiinflammatory drugs were randomized to receive 40 mg adalimumab or placebo subcutaneously every other week for 24 weeks. Study visits were at baseline, weeks 2 and 4, and every 4 weeks thereafter. The primary efficacy end points were the American College of Rheumatology 20% improvement (ACR20) response at week 12 and the change in the modified total Sharp score of structural damage at week 24. Secondary end points were measures of joint disease, disability, and quality of life in all patients, as well as the severity of skin disease in those patients with psoriasis involving at least 3% of body surface area.Results. At week 12, 58% of the adalimumabtreated patients (87 of 151) achieved an ACR20 response, compared with 14% of the placebo-treated patients (23 of 162) (P < 0.001). At week 24, similar ACR20 response rates were maintained and the mean change in the modified total Sharp score was ؊0.2 in patients receiving adalimumab and 1.0 in those receiving placebo (P < 0.001). Among the 69 adalimumabtreated patients evaluated with the Psoriasis Area and Severity Index (PASI), 59% achieved a 75% PASI improvement response at 24 weeks, compared with 1% of the 69 placebo-treated patients evaluated (P < 0.001). Disability and quality of life measures were also significantly improved with adalimumab treatment compared with placebo. Adalimumab was generally safe and welltolerated.Conclusion. Adalimumab significantly improved joint and skin manifestations, inhibited structural changes on radiographs, lessened disability due to joint damage, and improved quality of life in patients with moderately to severely active PsA.Psoriatic arthritis (PsA) is a chronic, inflammatory arthritis occurring in individuals with psoriasis. Psoriasis occurs in 2-3% of the US population (1). The reported range of prevalence of PsA in patients with psoriasis is 6-39%, depending on the population studied

The reduction of iron is an essential step in the transferrin (Tf) cycle, which is the dominant pathway for iron uptake by red blood cell (RBC) precursors. A deficiency in RBC iron acquisition leads to a hypochromic, microcytic anemia. Using a positional cloning strategy, we have identified a gene, sixtransmembrane epithelial antigen of the prostate 3 (Steap3), which is responsible for the iron deficiency anemia in the murine mutant nm1054. Steap3 is expressed highly in hematopoietic tissues, co-localizes with the Tf cycle endosome, and facilitates Tf-bound iron uptake. Steap3 shares homology with F 420 H 2 :NADP + oxidoreductases found in archaea and bacteria, as well as with the yeast FRE family of metalloreductases. Overexpression of Steap3 stimulates the reduction of iron, and mice lacking Steap3 are deficient in erythroid ferrireductase activity. Altogether, these findings demonstrate that Steap3 is an endosomal ferrireductase required for efficient Tf-dependent iron uptake in erythroid cells.Red blood cell precursors are uniquely dependent upon the transferrin (Tf) cycle to acquire iron in order to synthesize heme in amounts sufficient for hemoglobin production 1 . In the transferrin cycle, iron bound to transferrin (Tf) binds to the transferrin receptor (Tfr1), the complex is taken up by receptor-mediated endocytosis, and iron is released from Tf by endosomal acidification to be delivered to the cytoplasm by the divalent metal transporter 1 (Dmt1) 2-4 . Tf carries ferric iron (Fe 3+ ), whereas Dmt1 is selective for ferrous iron (Fe 2+ ) 4 . Therefore, iron must be reduced in the Tf cycle endosome. Despite functional evidence of such an activity, the molecular identity of this reductase is unknown. Recently, an ascorbatedependent b-type cytochrome ferrireductase, Dcytb (Cybrd1), expressed predominantly in the duodenum, was described 5 . However, Dcytb is not expressed highly in erythroid precursors, and Dcytb null mice have normal iron metabolism and normal hematologic parameters 6 . Such

Targeted mutagenesis in mice, a powerful tool for the analysis of gene function and human disease, makes extensive use of 129 mouse substrains. Although all are named 129, we document that outcrossing of these substrains, both deliberate and accidental, has lead to extensive genetic variability among substrains and embryonic stem cells derived from them. This clearer understanding of 129 substrain variability allows consideration of its negative impact on targeting technology, including: homologous recombination frequencies, preparation of inbred animals, and availability of appropriate controls. Based on these considerations we suggest a number of recommendations for future experimental design.

We have recently found that the erythroid ankyrin gene, Ank1, expresses isoforms in mouse skeletal muscle, several of which share COOH-terminal sequence with previously known Ank1 isoforms but have a novel, highly hydrophobic 72–amino acid segment at their NH2 termini. Here, through the use of domainspecific peptide antibodies, we report the presence of the small ankyrins in rat and rabbit skeletal muscle and demonstrate their selective association with the sarcoplasmic reticulum. In frozen sections of rat skeletal muscle, antibodies to the spectrin-binding domain (anti-p65) react only with a 210-kD Ank1 and label the sarcolemma and nuclei, while antibodies to the COOH terminus of the small ankyrin (anti-p6) react with peptides of 20 to 26 kD on immunoblots and decorate the myoplasm in a reticular pattern. Mice homozygous for the normoblastosis mutation (gene symbol nb) are deficient in the 210-kD ankyrin but contain normal levels of the small ankyrins in the myoplasm. In nb/nb skeletal muscle, anti-p65 label is absent from the sarcolemma, whereas anti-p6 label shows the same distribution as in control skeletal muscle. In normal skeletal muscle of the rat, anti-p6 decorates Z lines, as defined by antidesmin distribution, and is also present at M lines where it surrounds the thick myosin filaments. Immunoblots of the proteins isolated with rabbit sarcoplasmic reticulum indicate that the small ankyrins are highly enriched in this fraction. When expressed in transfected HEK 293 cells, the small ankyrins are distributed in a reticular pattern resembling the ER if the NH2-terminal hydrophobic domain is present, but they are uniformly distributed in the cytosol if this domain is absent. These results suggest that the small ankyrins are integral membrane proteins of the sarcoplasmic reticulum. We propose that, unlike the 210-kD form of Ank1, previously localized to the sarcolemma and believed to be a part of the supporting cytoskeleton, the small Ank1 isoforms may stabilize the sarcoplasmic reticulum by linking it to the contractile apparatus.