Cultural Consensus Analysis as a Tool for Clinic Improvements

Some problems in clinic function recur because of unexpected value differences between patients, faculty, and residents. Cultural consensus analysis (CCA) is a method used by anthropologists to identify groups with shared values. After conducting an ethnographic study and using focus groups, we developed and validated a CCA tool for use in clinics. Using this instrument, we identified distinct groups with 6 important value differences between those groups. An analysis of these value differences suggested specific and pragmatic interventions to improve clinic functioning. The instrument has also performed well in preliminary tests at another clinic.     

IL-10 fails to abrogate experimental autoimmune encephalomyelitis

Mice adoptively-sensitized to develop chronic relapsing experimental autoimmune encephalomyelitis (EAE), a model for the human demyelinating condition, multiple sclerosis (MS), were given injections of recombinant human IL-10 at various timepoints post-sensitization in an attempt to abrogate disease development. IL-10 is a Th2 immunomodulatory cytokine with known down-regulatory effects upon Th1 responses and macrophages. Contrary to a previous report on EAE and the predicted outcome, after repeated experiments, IL-10 was found to elicit a worsening or no effect upon EAE in the mouse. Animals were studied clinically, histopathologically and immunocytochemically. On no occasion was disease ameliorated by IL-10. Pretreatment with IL-10 of lymph node cells used to transfer EAE had no effect upon disease outcome, indicating that the cells were already committed effectors. Administration of anti-IL-10 monoclonal antibody before onset of signs had no effect when given early post-sensitization and caused marked worsening when given immediately before onset of signs. In the context of this autoimmune demyelinating model, these results suggest that IL-10 alone is insufficient to reverse the effector response and indeed may serve to enhance the cascade of events in EAE. © 1996 Wiley-Liss, Inc.     

Caveolin-1 Expression Determines the Route of Neutrophil Extravasation through Skin Microvasculature

Interleukin-8 plays a key role in the acute inflammatory response by mediating recruitment of neutrophils through vessel walls into affected tissues. During this process, molecular signals guide circulating blood neutrophils to target specific vessels for extravasation and to migrate through such vessels via particular routes. Our results show that levels of endothelial caveolin-1, the protein responsible for the induction of the membrane domains known as caveolae, are critical to each of these processes. We demonstrate that, in response to the intradermal injection of interleukin-8, neutrophils are preferentially recruited to a unique subset of venules that express high levels of intercellular adhesion molecule-1 and low levels of caveolin-1. Our results show that neutrophils traverse human dermal microvascular endothelial cells using one of two pathways: a transcellular route directly through the cell or a paracellular route through cellular junctions. Caveolin-1 expression appears to favor the transcellular path while down-regulation of caveolin-1 promotes the paracellular route.Wounding of the epithelium and entry of a foreign body elicit a series of responses from the innate immune system. One of the main hallmarks of acute inflammation is neutrophil infiltration at the affected site.^1,2 In response to injury or infection, resident phagocytic cells become activated and release inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-8. TNF-α activates the vascular endothelium causing vasodilation and cellular infiltration.³ IL-8 functions as a critical chemotactic factor attracting neutrophils from the blood to the affected area.^1,4It is currently thought that leukocyte recruitment and migration through the vasculature is an active process not only for migrating blood cells but also for endothelial cells lining the vessels. Initially, inflammatory cytokines or bacterial endotoxins induce expression of P- and E-selectin on the surface of microvascular endothelial cells.^5,6 These molecules recognize carbohydrate counterligands on the surface of circulating leukocytes and mediate the tethering and rolling of these cells along vessel walls.^5,6,7 Firm adhesion is then initiated through the upregulation of endothelial adhesion molecules such as intercellular adhesion molecule (ICAM)-1 and vascular adhesion molecule (VCAM)-1, which bind to integrins expressed on the leukocyte surface.^5,7,8 Finally, the leukocyte is induced to migrate through the vessel in a process known as diapedesis.^5,6,7Among the many proteins implicated in the process of diapedesis, the adhesion molecule ICAM-1, which is up-regulated on activated endothelium, and caveolin-1, which is expressed on most terminally differentiated cell types but is largely undetectable in white blood cells, have been most closely associated with the route of transendothelial migration in in vitro systems.^7,9,10 A recent study by Millan et al clearly demonstrates that ICAM-1 and caveolin-1 are involved in directing the path of T lymphoblast migration through human umbilical vein endothelial cells (HUVECs).⁷Although both caveolin-1 and ICAM-1 have been associated with leukocyte transendothelial migration in vitro, the distribution of these proteins in vessels used by migrating leukocytes in vivo remain unclear. While all endothelial cells (ECs) share common features, the vascular tree is known to be extremely heterogeneous. As a result, the precise molecular profile of selectins and adhesion molecules defining vessels targeted for extravasation by circulating leukocytes is unknown. Furthermore, since the phenotype of vessel ECs is determined in large part by their unique in vivo microenvironment, site specific and regional differences in the expression of molecules contributing to the regulation of leukocyte transmigration have yet to be thoroughly characterized.^11,12 In this study, we have examined the in vivo molecular profile of vessels targeted by circulating neutrophils in response to IL-8 in the skin and have determined the effect of the expression of these factors on the route of neutrophil transmigration in vitro.     

Heat shock protein 70 associations with myelin basic protein and proteolipid protein in multiple sclerosis brains

Heat shock proteins (hsp) are known to facilitate the generation of specific immune responses by chaperoning proteins and peptides involved in T cell activation. Hsp have been shown to be strikingly elevated in multiple sclerosis (MS) lesions. The unique chaperonin properties of hsp70 have allowed identification of immunogenic proteins bound to it by the ex vivo demonstration of hsp associations with proteins implicated in the immune response. We have investigated the association of hsp70 with myelin basic protein (MBP), myelin proteolipid protein (PLP) and myelin oligodendrocyte protein (MOG) in MS and control brain tissue. In co-immunoprecipitation experiments, in all samples of MS brains examined (n = 3), but not control brain tissue (n = 3), direct association of MBP with hsp70, but not with hsp90, was found. In some MS brain samples, association between PLP and hsp70 was also seen. In similar co-immunoprecipitation experiments on brain tissue obtained from mice with experimental autoimmune encephalomyelitis (n = 5) induced by immunization with PLP peptide, specific association of hsp70 with PLP and MBP was found. Using surface plasmon resonance we demonstrated specific binding of hsp70 with MBP in vitro. Analysis of the amounts of MBP bound to hsp70 yielded a molecular ratio of MBP binding to hsp70 at 6.5:1. MBP complexed with hsp70 was taken up at significantly higher rates by antigen-presenting cells than MBP alone and enhanced MBP-specific immune responses. These results indicate that hsp70 specifically associates with MBP in MS brain tissue. This association might be relevant to the enhanced immune recognition of MBP in MS.     

Clinical and genetic analysis of Korean patients with Marfan syndrome: possible ethnic differences in clinical manifestation

Yoo E‐H, Woo H, Ki C‐S, Lee HJ, Kim D‐K, Kang I‐S, Park P, Sung K, Lee CS, Chung T‐Y, Moon JR, Han H, Lee S‐T, Kim J‐W. Clinical and genetic analysis of Korean patients with Marfan syndrome: possible ethnic differences in clinical manifestation. Marfan syndrome (MFS) is an autosomal dominant disorder of the fibrous connective tissue caused by mutations in the fibrillin‐1 (FBN1) gene. Although clinical and genetic analyses have been performed in various populations, there have been few studies in Korea. The aim of this study was to investigate the clinical characteristics and genetic background of Korean patients with MFS. In 39 Korean patients with MFS who met the Ghent criteria, the most common clinical finding was aortic dilatation and/or dissection (94.9%), whereas only 35.9% of patients had ectopia lentis. The majority of MFS patients had fewer than four of the skeletal findings required to fulfill the major skeletal Ghent criterion for MFS. Only 21% of Korean patients had major skeletal abnormalities and most cases showed only minor skeletal involvement. FBN1 gene mutations were detected in 35 out of 39 patients (89.7%), which is similar to rates presented in the previous reports. These results suggest that some clinical features in Korean patients with MFS differed from those reported in Western MFS patients.     

Managing uncertainty about treatment decision making in early stage prostate cancer: A randomized clinical trial

Objectives

Several new methods are available, but we know little about successful integration of contraceptive technologies into services. We investigated provider factors associated with the initiation of new hormonal methods among women at high risk of unintended pregnancy.

Methods

This cohort study enrolled 1387 women aged 15-24 starting hormonal contraception (vaginal ring, transdermal patch, oral contraceptive, or injectable) at four family planning clinics in low-income communities. We measured provider factors associated with method choice, using multinomial logistic regression.

Results

Ring and patch initiators were more likely than women starting oral contraceptives to report that they chose their method due to provider counseling (p < 0.001). Contraceptive knowledge in general was low, but initiation of a new method, the ring, was associated with higher knowledge about all methods after seeing the provider (p < 0.001). Method initiated varied with provider site (p < 0.001). These associations remained significant, controlling for demographics and factors describing the provider-patient relationship, including trust in provider and continuity of care.

Conclusion

Women's reports of provider counseling and of their own contraceptive knowledge after the visit was significantly associated with hormonal method initiated.

Practice implications

More extensive counseling and patient education should be expected for successful integration of new hormonal methods into clinical practice.     

Upregulation of group 1 CD1 antigen presenting molecules in guinea pigs with experimental autoimmune encephalomyelitis: an immunohistochemical study

In humans, group 1 CD1 glycoproteins present foreign and self lipid and glycolipid antigens to T-cells. Homologues of these molecules are not found in mice or rats but are present in guinea pigs (GPs). We examined CD1 and MHC class II expression in the central nervous system (CNS) of GPs sensitized for experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. In normal GPs and the uninflamed CNS, low-level MHC class II (MHC II) immunoreactivity occurred on vascular elements, meningeal macrophages and parenchymal microglial cells, whereas immunoreactivity for CD1 was absent. In the inflamed CNS, the majority of infiltrating cells were MHC II+ and microglia showed increased expression. CD1 immunoreactivity was detected on astrocytes and subsets of inflammatory cells Including B cells and macrophages. Minimal CD1 and MHC II co-expression was noted on inflammatory cells or glia. We conclude that group 1 CD1 molecules are strongly upregulated in the inflamed CNS on subsets of cells distinct from the majority of MHC II bearing cells. The expression of CD1 proteins in such lesions broadens the potential repertoire of antigens recognized at these sites and highlights the value of the GP as a model for studies of the relevance of CD1 molecules in host defense and autoimmune diseases.