Analysis of anti-tumour necrosis factor-induced skin lesions reveals strong T helper 1 activation with some distinct immunological characteristics.

BACKGROUND: Psoriasiform and eczematous eruptions are the most common dermatological adverse reactions linked to anti-tumour necrosis factor (TNF)-α therapy. Yet, a detailed characterization of their immune phenotype is lacking. OBJECTIVES: To characterize anti-TNF-α-induced inflammatory skin lesions at a histopathological, cellular and molecular level, compared with psoriasis, eczema (atopic dermatitis) and healthy control skin. METHODS: Histopathological evaluation, gene expression (quantitative real-time polymerase chain reaction) and computer-assisted immunohistological studies (TissueFAXS) were performed on 19 skin biopsies from patients with inflammatory bowel disease (n = 17) and rheumatoid arthritis (n = 2) with new-onset inflammatory skin lesions during anti-TNF-α-therapy. RESULTS: Although most biopsies showed a psoriasiform and/or spongiotic (eczematous) histopathological architecture, these lesions were inconsistent with either psoriasis or eczema on a molecular level using an established chemokine (C-C motif) ligand 27/inducible nitric oxide synthase classifier. Despite some differences in immune skewing depending on the specific histopathological reaction pattern, all anti-TNF-α-induced lesions showed strong interferon (IFN)-γ activation, at higher levels than in psoriasis or eczema. IFN-γ was most likely produced by CD3/CD4/Tbet-positive T helper 1 lymphocytes. CONCLUSIONS: New-onset anti-TNF-α-induced eruptions previously classified as psoriasis or spongiotic dermatitis (eczema) exhibit a molecular profile that is different from either of these disorders.

Effect of intravenous immunoglobulin administration on erythrocyte and leucocyte parameters.

BACKGROUND: Intravenous immunoglobulins (IVIG) are an attractive therapeutic tool for therapy of toxic epidermal necrolysis and severe forms of certain autoimmune diseases, including dermatomyositis, autoimmune blistering diseases, systemic vasculitis and lupus erythematodes. OBJECTIVES: Prompted by a case of IVIG-associated haemolytic anaemia, the effects of IVIG administrations on haematological parameters in patients with dermatological conditions were investigated. METHODS: Erythrocyte and leucocyte parameters were retrospectively analysed in 16 patients who had received IVIG at doses from 1 to 3 g/kg bodyweight (n = 35 cycles). The influence of IVIG on leucocyte survival was determined in vitro. RESULTS: Decreased absolute erythrocyte numbers, haemoglobin and haematocrit levels and a case of haemolytic anaemia were linked to transfusion of high-, but not low-dose IVIG. In contrast, leucopenia post-IVIG occurred in the vast majority of the recipients, unrelated to the administered IVIG amounts. In vitro investigations revealed a dose-dependent impairment of cell survival by IVIG in the neutrophil and monocyte, but not in the lymphocyte subpopulations. In several IVIG preparations, substantial amounts of blood group anti-A/anti-B antibodies were detected which could have accounted for the observed changes in the haematological parameters in our study cohort. CONCLUSIONS: IVIG products should be administered strictly according to indications. Commercially available IVIG products can contain blood group-specific antibodies that may induce haemolysis in some recipients. Monitoring of blood counts during applied IVIG therapy, especially when high doses are administered, is recommended.

Addressing high cervical cancer rates in the Rio Grande Valley along the Texas-Mexico border: a community-based initiative focused on education, patient navigation, and medical provider training/telementoring.

AIMS: Cervical cancer incidence and mortality rates are approximately 55% higher in the Rio Grande Valley (RGV) along the Texas-Mexico border compared with the average rates in the US. Our aim was to improve cervical cancer prevention efforts in the RGV through a comprehensive multilevel intervention initiative focused on community education, patient navigation, and training of local providers. METHODS: We initiated a program in the RGV which consisted of (1) community education, (2) patient navigation, and (3) a training/mentoring program for local medical providers including hands-on training courses coupled with telementoring using Project ECHO® (Extension for Community Health Outcomes). We assessed the number of women undergoing cervical cancer screening, diagnosis, and treatment at three participating clinics caring for underserved women in the region. RESULTS: From November 2014 to October 2018, 14,846 women underwent cervical cancer screening. A total of 2030 (13.7%) women underwent colposcopy for abnormal results (179% increase over baseline) and 453 women underwent loop electrosurgical excision procedures (LEEPs) for treatment of cervical dysplasia. Invasive cancer was diagnosed in 39 women who were navigated to a gynecologic oncologist for treatment. Seven local medical providers were trained to perform colposcopy and/or LEEP. Project ECHO telementoring videoconferences were held every 2 weeks for a total 101 sessions with an average of 22 participants per session and a total of 180 patient cases presented and discussed. CONCLUSIONS: Our program led to a large number of women undergoing diagnosis and treatment of cervical dysplasia in the RGV. If sustained, we anticipate these efforts will decrease cervical cancer rates in the region. The program is currently being expanded to additional underserved areas of Texas and globally to low- and middle-income countries.

Expression of functional high affinity immunoglobulin E receptors (Fc epsilon RI) on monocytes of atopic individuals.

Suggestive evidence indicates that immunoglobulin E (IgE)-dependent activation of mononuclear phagocytes plays an important pathogenic role in allergic tissue inflammation. Prevailing opinion holds that low affinity IgE receptors are the relevant IgE-binding structures on monocytes/macrophages and that functional events occurring after cross-linking of membrane-bound IgE on these cells are mediated by these receptors. Here we demonstrate that peripheral blood monocytes can bind monomeric IgE via the high affinity IgE receptor (Fc epsilon RI) and that Fc epsilon RI expression on these cells is upregulated in atopic persons. Further, we demonstrate that, upon monocyte adherence to substrate, bridging of monocyte Fc epsilon RI is followed by cell activation. We propose that direct interaction of multivalent allergen with Fc epsilon RI(+)-bound IgE on mononuclear phagocytes results in cell signaling via Fc epsilon RI and that the biological consequences of this event may critically influence the outcome of allergic reactions.

Serum IgG autoantibodies directed against the alpha chain of Fc epsilon RI: a selective marker and pathogenetic factor for a distinct subset of chronic urticaria patients?

While it is well established that acute allergic urticaria is caused by degranulation of skin mast cells occurring after allergen/IgE-dependent cross-linking of high affinity IgE receptors (FcepsilonRI), the pathophysiologic mechanisms operative in chronic urticaria (CU) are less well understood. Some evidence points to the existence of histamine-releasing activity in the serum of CU patients which possibly acts via triggering of FcepsilonRI. In this study, we aimed to better characterize this anti-FcepsilonRIalpha reactivity of CU patients using affinity-purified, IgE-depleted IgG fractions of such individuals (CU-IgG). Using immobilized, recombinant soluble FcepsilonRIalpha as a a reaction target for Western blot studies, we found that 12/32 (37%) CU-IgG serum samples exhibited IgG autoreactivity against FcepsilonRI- alpha. These findings were confirmed by experiments demonstrating that immunoblot-reactive, but not immunoblot-nonreactive, CU-IgG preparations precipitated the FcepsilonRIalpha from FcepsilonRI- alphagamma-transfected cells. No anti-FcepsilonRIalpha reactivity was observed in IgG fractions from atopic dermatitis (AD) patients (0/15) or healthy control individuals (CO:0/15). As opposed to the selective occurrence of IgG anti-Fc epsilon RI alpha autoantibodies in CU patients, IgG anti-IgE antibodies were detected in all groups investigated (CU: 69%; AD: 73%; CO: 26%). While both types of autoantibodies can exhibit histamine-releasing properties, not all of the autoantibodies proved to be functional in vitro. Our results indicate that the occurrence of IgG anti-FcepsilonRIalpha reactivity defines an autoimmune-mediated subentity of CU and provide a basis for the development of new diagnostic procedures and, perhaps, therapeutic strategies for this disease.

Aspects of motivation of a volunteer AIDS care team program.

The South Carolina AIDS Care Team Program, directed by The Ecumenical AIDS Ministry, a component of the South Carolina Christian Action Council, provides emotional and supportive services to people living with HIV and AIDS. A sample of volunteer care team members participated in five focus groups as part of a process evaluation. Care teams were asked to participate based on years since training (new vs. experienced), race (white vs. African American), and location (urban vs. rural). Volunteers were motivated to become involved in a care team through previous contact with a person with AIDS, a general sense of altruism, and influences from their faith community. Due to the emotionally demanding nature of the work, motivation to remain a volunteer was also examined. It was discovered that a support system, the expression of faith, support of their faith community, and coping with the death of a care partner were essential elements for sustaining care team involvement. The implications of this study are useful to volunteer programs through faith communities to meet the growing need of people living with HIV and AIDS.

Support for instruction about homosexuality in South Carolina public schools.

Research has demonstrated that recognition of sexual orientation begins in adolescence. However, students who identify as gay or lesbian report that the subject of homosexuality is virtually absent from classroom instruction. In South Carolina public schools, the subject of homosexuality may not be discussed except during instruction about sexually transmitted diseases. In 1997, survey data were obtained from 534 South Carolina registered voters to determine level of support for school-based sexuality education, including support for instruction about homosexuality. Overall, support for sexuality education was strong, however, homosexuality was the least-supported subject in the survey. In addition, registered voters were less sure as to what grade level instruction about homosexuality should begin. Characteristics of voters who supported and opposed instruction about homosexuality in the public schools were examined and compared. These data may be useful in building support for sexuality education programs that address this controversial topic.

Support for school-based reproductive health services among South Carolina voters.

In 1997 a statewide random digit-dialed telephone survey of 534 South Carolina registered voters was conducted to determine level of support for school-based reproductive health services. Results indicated most voters supported services in secondary schools that would provide students with information and counseling about contraceptive methods and refer students to community-based agencies for abstinence education and counseling. Voters were less supportive of reproductive health services that would diagnose or treat sexually transmitted diseases, test for pregnancy, refer students to community-based agencies for contraceptives, or make contraceptives available to students at school. Significant associations in support for school-based reproductive health services were reported based on income, personal beliefs, intentions, and outcome expectations regarding sexuality education and contraceptive availability. These data reinforce the need for school-aged youth in South Carolina to have access to reproductive health services within their communities, outside of the school setting.

Comparison of selected health risk behaviors between adolescents in public and private high schools in South Carolina.

This study examined differences in selected health risk behaviors among 5,517 students attending public high schools (PUBHS) and 1,089 students attending private high schools (PVTHS) in South Carolina. The 1995 CDC Youth Risk Behavior Survey was used to collect self-report information on adolescent risk behaviors. Chi-square analyses were performed for comparing public and private students on selected risk behaviors. Both PUBHS and PVTHS students reported substantial involvement in most of the risk-taking behaviors examined. PUBHS students, in general, were more likely to report higher prevalence rates than PVTHS students for most of the selected health risk behaviors. However, PVTHS students reported even higher prevalence rates than PUBHS students for alcohol use, driving after drinking, and binge drinking; smoking cigarettes (past 30 days); chewing tobacco (males only); marijuana use during the past 30 days (females only); and use of alcohol or other drugs before last act of sexual intercourse. Results suggest attendance at a private high school is not a panacea for protection against adolescent risk behaviors, and that all high school students could benefit from a coordinated school health program.

Support for school-based sexuality education among South Carolina voters.

A random-digit dialed telephone survey was conducted in a traditionally conservative southern state to determine the level of support for sexuality education in the public schools including support for specific sexuality education topics, the earliest grade level at which each topic should be taught, and the amount of instruction time required for sexuality education in the high schools. Survey data were obtained from 534 South Carolina registered voters in late January/early February 1997. Results demonstrated that most South Carolina registered voters: 1) supported sexuality education in the public schools; 2) supported instruction on a variety of sexuality education topics; 3) supported instruction at all grade levels, especially beginning in middle school; and 4) believed instruction time for sexuality education in the high schools should either remain the same or be increased. In addition, a significant increase in support for sexuality education occurred from the beginning of the survey to the end, suggesting that the instrument itself may have served as an educational tool for respondents. The characteristics of registered voters who supported sexuality education at the beginning of the survey and at the end were examined and compared. These results may assist in the development of educational and marketing strategies designed to build support for school-based sexuality education programs in South Carolina and elsewhere.

Development of multidimensional scales to measure key leaders' perceptions of community capacity and organizational capacity for teen pregnancy prevention.

This study discusses the development of scales to measure key leaders' self-reported involvement in community capacity building, perceptions of organizational capacity for teen pregnancy prevention, and the relationship between capacity and teen pregnancy rates. Data were collected from 1,516 key leaders across a rural southern state. Findings indicate that key leaders' perceptions of organizational capacity are related to their involvement in community capacity building efforts and community capacity is associated with teen pregnancy rates. This research represents progress toward measuring community and organizational capacity and may be used to inform future work focusing on developing quantitative measures of community capacity.

Associations between self-reported and objective physical environmental factors and use of a community rail-trail.

BACKGROUND: To effectively promote physical activIty, researchers and policy makers have advocated for greater use of environmental approaches, such as the construction of community paths and trails. However, research on the use of these facilities is limited. METHODS: In this cross-sectional community study, we examined associations between self-reported and objective physical environmental variables and use of the Minuteman Bikeway (Arlington, MA) in a random sample of 413 adults. Sociodemographic and perceived environmental variables were measured with a mail survey during September 1998. Geographic information system (GIS) data were used to geocode survey respondents' homes and create three objective environmental variables: distance to the Bikeway, steep hill barrier, and a busy street barrier. RESULTS: In logistic models, age and female gender showed statistically significant inverse associations with Bikeway use over the previous 4-week period. Increases in self-reported (OR = 0.65) and GIS distance (OR = 0.57) were associated with decreased likelihood of Bikeway use. Absence of self-reported busy street (OR = 2.01) and GIS steep hill barriers (OR = 1.84) were associated with Bikeway use. CONCLUSIONS: Environmental barriers such as travel distance and hilly terrain should be considered when planning community trails. A better understanding of such factors may lead to more effective promotion of trail use.

The high affinity IgE receptor (Fc epsilon RI) mediates IgE-dependent allergen presentation.

The discovery that the high affinity IgE receptor (Fc epsilon RI) is expressed on APCs of patients with atopic diseases raised the possibility that the functional importance of Fc epsilon RI in the pathogenesis of atopy may extend beyond its role in type I allergic reactions. Here we show that, following removal of in vivo-bound IgE by lactic acid treatment, targeting of allergens to monocytes by Ag-specific IgE critically depends on Fc epsilon RI expression. Even more importantly, lactic acid-treated, monocyte-enriched PBMCs present allergen to T cells 100- to 1000-fold more effectively if the allergen has been targeted to Fc epsilon RI on these cells via allergen-specific IgE. This mechanism may critically lower the atopic individual's threshold to mount allergen-specific T cell responses capable of promoting IgE production and delayed-type hypersensitivity reactions.

Fc epsilon receptor I on dendritic cells delivers IgE-bound multivalent antigens into a cathepsin S-dependent pathway of MHC class II presentation.

In this study, we elucidate the Fc epsilon RI-mediated Ag uptake and presentation mechanisms of dendritic cells (DC). We found that Fc epsilon RI-bound IgE, after polyvalent but not after monovalent ligation, is efficiently internalized into acidic, proteolytic compartments, degraded, and delivered into organelles containing MHC class II, HLA-DM, and lysosomal proteins. To follow the fate of the fragmented ligand, we sought to interfere with invariant chain (Ii) degradation, a process critical for peptide loading of nascent MHC class II molecules. We found DC to express cathepsin (Cat) S, a cysteine protease involved in Ii processing by B cells. Exposure of DC to a specific, active-site inhibitor of Cat S resulted in the loss of anti-Cat S immunoreactivity, led to the appearance of an N-terminal Ii remnant, and decreased the export of newly synthesized MHC class II to the DC surface. Furthermore, inactivation of Cat S as well as blockade of protein neosynthesis by cycloheximide strongly reduced IgE/Fc epsilon RI-mediated Ag presentation by DC. Thus, multimeric ligands of Fc epsilon RI, instead of being delivered into a recycling MHC class H pathway, are channeled efficiently into MIIC (MHC class II compartment)-like organelles of DC, in which Cat S-dependent Ii processing and peptide loading of newly synthesized MHC class II molecules occur. This IgE/Fc epsilon RI-dependent signaling pathway in DC may be a particularly effective route for immunization and a promising target for interfering with the early steps of allergen presentation.

Assessing the HIV prevention capacity building needs of community-based organizations.

Community-based organizations (CBOs) have been providing HIV prevention services to priority populations for many years. Recent research suggests that CBOs could benefit from capacity building to strengthen their public health prevention knowledge and skills, including ability to access and use behavioral science to guide prevention efforts. A cross-sectional survey of 316 CBOs was conducted to assess desire and preferences for training, support for training at the organizational level, motivation for training at the individual level, barriers to training, and factors associated with the perceived need for training. Results suggest the need for a national training initiative to increase CBO capacity.

Development of a youth survey to measure risk behaviors, attitudes and assets: examining multiple influences.

Currently, most surveys assessing adolescent health concerns focus primarily on risk behaviors and negative influences rather than positive influences such as assets. The purpose of this paper is to describe the development and validation of the Adolescent Health Attitude and Behavior Survey (AHABS). This instrument was developed to measure the prevalence of youth health risk behaviors, attitudes towards adolescent sexual behavior and youth assets in a statewide evaluation effort. The questionnaire was completed by 4368 public high school students in Grades 9-12. Content validity was established through an extensive review of literature, a group process and factor analyses. Reliability was established through Cronbach's alpha coefficients. Factor loadings ranged from 0.48 to 0.84 for scales measuring attitudes towards adolescent sexual behavior and alpha coefficients ranged from 0.61 to 0.81. Factor loadings ranged from 0.34 to 0.90 for scales measuring youth assets and alpha coefficients ranged from 0.69 to 0.85. Because of several limitations (e.g. construct validity was not measured), additional development work is needed. Therefore, the AHABS is still in a developing, but promising, state. Additional psychometric work will provide program practitioners and evaluators with a psychometrically sound tool to measure behaviors, attitudes and assets.

Peripheral blood dendritic cells express Fc epsilon RI as a complex composed of Fc epsilon RI alpha- and Fc epsilon RI gamma-chains and can use this receptor for IgE-mediated allergen presentation.

Originally limited to basophils and mast cells, the spectrum of high affinity IgE receptor (Fc epsilon RI-bearing cells has expanded recently to include Langerhans cells, dermal dendritic cells (DC), monocytes, and eosinophils. As a result of studies on the distribution, structure, and function of Fc epsilon RI on APCs, we discovered a minor nonbasophil, nonmonocyte PBMC population that can bind IgE via Fc epsilon RI. This receptor occurs on the surface of these cells as a multimeric structure containing Fc epsilon RI alpha- and Fc epsilon RI gamma-chains but, unlike its counterpart on basophils, lacking Fc epsilon RI beta. Further experiments revealed that these Fc epsilon RI alpha gamma-expressing cells closely resemble peripheral blood DC by immunophenotype (HLA-DRhigh, HLA-DQhhigh; CD4+, CD11a+, CD32+, CD33+, B7/2 (CD86)+; CD11blow, CD14low, CD40low, CD54low, CD64low) and cell morphology. These features allowed us to isolate Fc epsilon RI-expressing DC from the peripheral blood and to investigate their immunostimulatory properties. We found Fc epsilon RI-positive DC to be efficient stimulators of both primary (allogeneic MLR) and Fc epsilon RI/IgE-dependent, secondary T cell responses at low cell numbers. Thus, Fc epsilon RI-expressing DC may not only amplify established type I allergic immune reactions but, unlike Fc epsilon RI-positive semiprofessional APCs, may be able to prime naive T cells to common and/or cryptic epitopes of IgE-reactive Ags.