Therapeutic depletion of myeloid lineage leukocytes by adsorptive apheresis for psoriatic arthritis: Efficacy of a non-drug intervention for patients refractory to pharmacologics.

Psoriatic arthritis (PsA), a chronic inflammatory arthropathy associated with psoriasis, is an intractable immune disorder and refractory to pharmacological intervention. We assessed efficacy of selective depletion of myeloid lineage leukocytes in patients with PsA in a multicenter setting. A total of 20 patients with moderate to severe PsA refractory to conventional and biological disease-modifying antirheumatic drugs were included. Eligible patients had 3 points or more in the classification criteria for PsA. Each patient received five sessions, once a week, of adsorptive granulocyte and monocyte apheresis (GMA) with the Adacolumn® . The primary efficacy outcome was 20% or more decrease in the American College of Rheumatology score 20 (ACR20). Partial responders could receive an additional five GMA sessions. Of 20 patients, two did not complete the study, nine responded to five GMA sessions and nine received 10 sessions. At the first evaluation 2 weeks after the last GMA session, 13 of the 20 (65.0%) patients achieved ACR20. ACR20 was maintained in seven of 10 (70%) and five of 10 (50%) patients at the follow-up evaluation points 8 and 20 weeks after the last GMA session, respectively. GMA was well tolerated without any safety concern. This study demonstrates that GMA with the Adacolumn was effective with good safety profile in patients with PsA refractory to pharmacologicals. The results indicate a major role for myeloid leukocytes in the immunopathogenesis of PsA. A large controlled study is warranted to fully evaluate the efficacy of Adacolumn GMA in patients with PsA.

Mentoring doctoral students for qualitative research: interviews with experienced nursing faculty in Japan.

This study aimed to describe the process of mentoring doctoral students for qualitative research in Japanese graduate programs in nursing. Nine experienced faculty-seven nurse researchers and two sociologists-were interviewed. Participants were asked about their process of mentoring students for qualitative nursing dissertations. Data analysis was conducted using a qualitative descriptive method. Participants' age ranged from 48 to 60 years. The first theme in the mentoring process is about the individualized, one-on-one mentorship process. The second theme occurs in a group process. The third theme is coordinating mentors and establishing a network to support the evaluation system. The mentoring processes identified in this study will be useful for future faculty development. The study elucidated much room for improvement in doctoral education programs for qualitative research methods in nursing science.

Therapeutic depletion of myeloid lineage leukocytes in patients with generalized pustular psoriasis indicates a major role for neutrophils in the immunopathogenesis of psoriasis.

BACKGROUND: Generalized pustular psoriasis (GPP) is a chronic autoimmune disease characterized by fever, erythema, and neutrophilic pustules over large areas of the skin. GPP does not respond well to pharmacologic intervention. OBJECTIVE: We sought to assess efficacy of selectively depleting the myeloid lineage leukocytes in patients with GPP. METHODS: Fifteen patients with persistent moderate to severe GPP despite conventional therapy were included. Eligible patients had more than 10% of their skin area covered by pustules. Treatment with oral etretinate, cyclosporine, methotrexate, prednisolone, and topical prednisolone/vitamin D3 was continued if had been initiated well in advance of study entry. Five sessions of adsorptive granulocyte and monocyte apheresis (GMA) with the Adacolumn (JIMRO Co Ltd, Takasaki, Japan) were administered (1 session/wk over 5 weeks) to selectively deplete Fcγ receptor and complement receptor bearing leukocytes. Efficacy was assessed by measuring the skin areas covered by pustules at baseline and 2 weeks after the last GMA session. RESULTS: One patient did not complete the first GMA session. Based on the GPP severity scores relative to entry, the overall scores improved (n = 14, P = .0027), and the area of erythroderma (P = .0042), pustules (P = .0031), and edema (P = .0014) decreased. Likewise, Dermatology Life Quality Index improved (P = .0016), reflecting better daily function and quality of life. Twelve patients were judged as responders (85.7%), and 10 patients maintained the clinical response for 10 weeks after the last GMA session without any change in medication. LIMITATIONS: This study was unblinded and without a placebo arm. CONCLUSION: GMA in this clinical setting was safe and effective, suggested a major role for granulocytes/monocytes in the immunopathogenesis of GPP.

Granulocyte and monocyte adsorption apheresis for generalized pustular psoriasis.

Granulocyte and monocyte adsorption apheresis (GCAP) is an extracorporeal circulation therapy that removes activated granulocytes and monocytes. GCAP was initially approved for the treatment of ulcerative colitis, which is attributed to activated granulocytes and macrophages that infiltrate the target tissues. Generalized pustular psoriasis (GPP) is also supposed to be caused by activated neutrophils. In this study, we treated two patients with refractory GPP by using GCAP. Patient 1, a 68-year-old woman who had liver cirrhosis, underwent seven GCAP sessions. Patient 2, a 26-year-old woman who had systemic lupus erythematosus and had been treated with systemic corticosteroids, underwent eight GCAP sessions. In both patients, GCAP resulted in an immediate improvement in skin lesions and fever reduction, without any adverse effects. We suggest that GCAP is an effective therapy for refractory GPP.

A case report of steroid and immunosuppressant-resistant pyoderma gangrenosum successfully treated by granulocytapheresis.

Granulocytapheresis (GCAP) therapy is a newly developed therapeutic modality for inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. Pyoderma gangrenosum (PG) is a chronic inflammatory skin disease characterized by the appearance of erythematous macules and plaques with pustules or nodules that rapidly progress to ragged, undermined multiple ulcers. We attempted GCAP therapy in a patient with PG resistant to prednisolone and various other immunosuppressants. GCAP therapy was initiated at three- to four-day intervals and a good response from all skin lesions, with eventual total epithelialization, was observed after 10 sessions of this therapy. Furthermore, circulating levels of inflammatory cytokines such as interleukin-8 (IL-8) and granulocyte colony stimulating factor (G-CSF) also decreased after the GCAP therapy. Our results suggest that GCAP is a safe and useful tool for the treatment of intractable PG, and that IL-8 and G-CSF are likely to be involved in the pathogenesis of PG.

[Community-associated methicillin-resistant Staphylococcus aureus: current status and molecular epidemiological perspective].

MRSA has been a major causative agent of nosocomial infection. However, recently MRSA has become increasingly isolated from community-associated infections. We summarized here up to date information about community-associated MRSA (C-MRSA) infections and characteristics of C-MRSA strains based on molecular analysis. By using the SCCmec typing, strong evidence was provided for the independent derivation of healthcare-associated MRSA and C-MRSA clones.

Novel type V staphylococcal cassette chromosome mec driven by a novel cassette chromosome recombinase, ccrC.

Staphylococcal cassette chromosome mec (SCCmec) is a mobile genetic element composed of the mec gene complex, which encodes methicillin resistance, and the ccr gene complex, which encodes the recombinases responsible for its mobility. The mec gene complex has been classified into four classes, and the ccr gene complex has been classified into three allotypes. Different combinations of mec gene complex classes and ccr gene complex types have so far defined four types of SCCmec elements. Now we introduce the fifth allotype of SCCmec, which was found on the chromosome of a community-acquired methicillin-resistant Staphylococcus aureus strain (strain WIS [WBG8318]) isolated in Australia. The element shared the same chromosomal integration site with the four extant types of SCCmec and the characteristic nucleotide sequences at the chromosome-SCCmec junction regions. The novel SCCmec carried mecA bracketed by IS431 (IS431-mecA-DeltamecR1-IS431), which is designated the class C2 mec gene complex; and instead of ccrA and ccrB genes, it carried a single copy of a gene homologue that encoded cassette chromosome recombinase. Since the open reading frame (ORF) was found to encode an enzyme which catalyzes the precise excision as well as site- and orientation-specific integration of the element, we designated the ORF cassette chromosome recombinase C (ccrC), and we designated the element type V SCCmec. Type V SCCmec is a small SCCmec element (28 kb) and does not carry any antibiotic resistance genes besides mecA. Unlike the extant SCCmec types, it carries a set of foreign genes encoding a restriction-modification system that might play a role in the stabilization of the element on the chromosome.

Insights on antibiotic resistance of Staphylococcus aureus from its whole genome: genomic island SCC.

Staphylococci are ubiquitous colonizers of the skin and mucous membranes and Staphylococcus aureus is the most pathogenic species. The spread of antibiotic resistance among S. aureus strains is a major concern in the treatment of staphylococcal infections. Acquisition of resistance may involve mutation of a bacterial gene on the chromosome or transfer of a resistance gene from other organisms by some form of genetic exchange (conjugation, transduction, or transformation). Completion of whole genome sequences of three methicillin-resistant S. aureus (MRSA) strains has provided us a bird's-eye view of the distribution of the mobile genetic elements in the bacterial chromosome that encode antibiotic resistance as well as pathogenicity in S. aureus.

Cell wall thickening is a common feature of vancomycin resistance in Staphylococcus aureus.

We have previously shown that a thickened cell wall is responsible for the vancomycin resistance of vancomycin-resistant Staphylococcus aureus (VRSA) (equivalent to vancomycin-intermediate S. aureus and glycopeptide-intermediate S. aureus) strain Mu50 (L. Cui, H. Murakami, K. Kuwahara-Arai, H. Hanaki, and K. Hiramatsu, Antimicrob. Agents Chemother. 44:2276-2285, 2000). However, the mechanism of vancomycin resistance in other VRSA strains remained unclear. In this study, 16 clinical VRSA strains from seven countries were subjected to serial daily passage in drug-free medium. After 10 to 84 days of passage in the nonselective medium, passage-derived strains with decreased MICs of vancomycin (MIC, <4 mg/liter) were obtained. However, all of the passage-derived strains except one (15 of 16) still possessed subpopulations that were resistant to vancomycin as judged by population analysis, and vancomycin-resistant mutant strains were selected from the passage-derived strains by one-step vancomycin selection with a frequency of 4.25 x 10(-6) to 1.64 x 10(-3). The data indicated that vancomycin-resistant cells are frequently generated from the passage-derived strains even after vancomycin selective pressure is lifted. Cell wall thicknesses and MICs of glycopeptides (vancomycin and teicoplanin) and beta-lactams (imipenem and oxacillin) were determined for a total of 48 strains, including 15 sets of three strains: the clinical VRSA strain, the passage-derived strain, and the vancomycin-resistant mutant strain obtained from the passage-derived strain. No simple correlation between glycopeptide and beta-lactam MICs was seen, while significant correlations between MICs of vancomycin and teicoplanin (r = 0.679; P < 0.001) and between MICs of imipenem and oxacillin (r = 0.787; P < 0.001) were recognized. Moreover, all of the VRSA strains had significantly thickened cell walls, which became thinner with the loss of vancomycin resistance during drug-free passages and again became thick in the resistant mutant strains. The data showed that cell wall thickness had high correlation with the MICs of the two glycopeptides (correlation coefficients, 0.908 for vancomycin and 0.655 for teicoplanin) but not with those of the beta-lactam antibiotics tested. These results together with coupled changes of cell wall thickness and vancomycin MICs in 16 isogenic sets of strains indicate that thickening of the cell wall is a common phenotype of clinical VRSA strains and may be a phenotypic determinant for vancomycin resistance in S. aureus.

Dissemination of new methicillin-resistant Staphylococcus aureus clones in the community.

Multiple methicillin-resistant Staphylococcus aureus (MRSA) clones carrying type IV staphylococcal cassette chromosome mec were identified in the community-acquired MRSA strains of both the United States and Australia. They multiplied much faster than health-care-associated MRSA and were resistant to fewer non-beta-lactam antibiotics. They seem to have been derived from more diverse S. aureus populations than health-care-associated MRSA strains.

New trends in Staphylococcus aureus infections: glycopeptide resistance in hospital and methicillin resistance in the community.

PURPOSE OF REVIEW: Methicillin-resistant Staphylococcus aureus is prevalent in hospitals throughout the world, and we have got used to its presence in daily clinical practice. However, methicillin-resistant S. aureus has not remained static over the past four decades, but seems to be evolving in unfamiliar directions. This review focuses on recent findings on two directions of methicillin-resistant S. aureus evolution: the acquisition of multiple antibiotic resistance in the hospital and the trend towards methicillin-resistant S. aureus as a community pathogen. RECENT FINDINGS: We looked at reports on glycopeptide resistance in S. aureus and those on community-acquired methicillin-resistant S. aureus strains, with some references of historical value to explain the entire picture of this 'new field' of the methicillin-resistant S. aureus problem. SUMMARY: The references given here (excluding some of low credibility) attest the increasing awareness of the two conspicuous problems concerning methicillin-resistant S. aureus infection. One is the increasing trend of glycopeptide-resistance, making difficult the successful treatment of multi-drug-resistant methicillin-resistant S. aureus infection in the hospital. On the other hand, non-multi-drug-resistant methicillin-resistant S. aureus strains are emerging as novel threats in the community, the genetic analysis of which indicates that they are independent clones from those found in hospitals.