Staphylococcal-derived superantigen enhances peanut induced Th2 responses in the skin.

BACKGROUND: The allergen-induced activation and expansion of IL-4 producing T helper type 2 (Th2) cells is a key event in the initiation and progression of allergic disease. Intriguingly, concomitant early childhood staphylococcal skin infections are being increasingly implicated in the allergen-induced switch of primary T cell responses towards the Th2 phenotype. OBJECTIVE: We sought to identify whether or not staphylococcal-derived superantigen can influence the primary T cell response in the skin to food allergens with a view to determining whether such exposures create the immune pathology that predisposes to the development of food allergy. METHODS: Using a novel Th2 reporter model, we determined the ability of the staphylococcal superantigen (SEB) to influence priming in the skin of IL-4 expressing Th2 cells by peanut extract (PE). Factors including the effect of SEB on the magnitude of the Th2 response in the skin draining lymph nodes, T cell receptor V region usage and the influence of endotoxin were evaluated. RESULTS: Primary exposure to PE and SEB lead to significantly enhanced PE specific Th2 responses when the mice were subsequently exposed to PE alone. The enhancement of the Th2 response was dependent on the Vß-binding properties of the SEB, but was not affected by endotoxin-mediated TLR-4 effects or strain differences in the mice. CONCLUSIONS AND CLINICAL RELEVANCE: These results identify that in the skin environment, the presence of SEB can significantly increase the numbers of allergen-induced Th2 cells which develop in response to subsequent allergen exposure. These data highlight the process by which individuals may become pathologically sensitized to food allergens in early life.

Attitudes of primary care physicians toward cancer-prevention trials: a focus group analysis.

PURPOSE: Recruitment of low-income and minority women to cancer-prevention trials requires a joint effort from specialists and primary care providers. We sought to assess primary care providers' attitudes toward participating in cancer-prevention trial recruitment. PROCEDURES: We conducted a focus group with seven Boston-based primary care providers serving low-income and minority women. Providers discussed knowledge, attitudes, and beliefs regarding their role in recruitment to prevention trials. FINDINGS: A qualitative analysis of the focus group transcript revealed nine categories. Three categories related specifically to the primary care physician: 1) the dual role physicians play as advocates for both patient and research; 2) threats to maintaining the primary care relationship; and 3) general philosophy toward prevention. An additional six categories could be subdivided as they apply to the primary care physician, the patient, and the community: 4) trust/commitment; 5) benefits of the research; 6) access to the research; 7) knowledge and recall of the research; 8) influences of media coverage about the research; and 9) cultural sensitivity. CONCLUSIONS: Investigators conducting cancer-prevention trials must address the concerns of primary care physicians to optimize recruitment of subjects- especially low-income and minority women-into trials.

Participation of women in clinical trials of drug therapies: a context for the controversies.

Women's participation in clinical trials, particularly those involving drugs, has been said to be both overrepresented and underrepresented. How can this be? Studies of participation are compared and contrasted to elucidate some reasons for this contradiction. The history of women's participation in clinical trials is chronicled through policies and regulations filled with restrictions. Since 1993, however, the National Institutes of Health has mandated, and the Food and Drug Administration has emphasized, inclusion of women in clinical trials, only to be thwarted by other regulations excluding many women. Gender-specific analyses are required to detect gender differences in effects of pharmaceutical and nonpharmaceutical interventions, but they are seldom performed. The exclusion of women from clinical trials means that women's healthcare is compromised by lack of sex-specific information about dosing of drugs and unique uses of drugs. A database, although currently quite limited, tracks the participation of women in clinical trials funded by federal agencies, industries, and nonprofit groups. Federal regulations have recently changed. Additional changes in access to all phases of clinical trials and enhanced monitoring of clinical trials are recommended.

CD80 costimulation is required for Th2 cell cytokine production but not for antigen-specific accumulation and migration into the lung.

The CD28 ligands CD80 and CD86 are expressed on APC, and both provide costimulatory function. However, the reason for the expression of two separate CD28 ligands remains unclear. We have previously shown that blockade of CD80 costimulation by Y100F-Ig, a CTL-associated Ag-4 (CTLA4)-Ig mutant that does not bind CD86, inhibits the development of lung inflammatory immune responses, but does not affect blood eosinophilia or Ab production. Each of those responses was inhibited by treatment with CTLA4-Ig, which binds both CD80 and CD86. To clarify the mechanism underlying these observations we have developed a model of lung inflammation using adoptively transferred CD4(+) T cells expressing a Valpha11(+)Vbeta3(+) transgenic TCR specific for I-E(k) and moth cytochrome c. Treatment with Y100F-Ig inhibited the induction of lung eosinophilia in adoptively transferred mice. However, Y100F-Ig did not detectably affect the accumulation of Ag-specific T cells at the site of peptide deposit or in the draining lymphoid tissues. Acquisition of an activated phenotype and expression of adhesion molecules required for migration into the lung were modestly affected. Importantly, treatment with Y100F-Ig diminished the ability of T cells to produce the cytokines IL-4 and IL-5 following intranasal challenge with Ag. All the responses examined were severely inhibited by treatment with CTLA4-Ig. We conclude that T cells require CD80 costimulation for the optimal production of IL-5 following intranasal administration of Ag. Decreased IL-5 production is the most likely explanation for the diminished airway eosinophilia observed.

The New England division Tell A Friend program implementation evaluation.

Tell A Friend (TAF) is the nationwide program of the American Cancer Society that aims to decrease breast cancer mortality by encouraging unscreened women to have mammograms using a peer-to-peer approach. An evaluation via the Collaborative Evaluation Fellows Project attempted to identify barriers and facilitators to successful implementation of TAF in the New England division. The proposed method included three surveys; this was revised because of a low response rate to the initial e-mailed survey. The actual method included one shortened survey and one follow-up survey. Results are presented for an initial and shortened survey for staff and a follow-up survey of respondents. Initial TAF implementation timelines were unrealistic, and the field staff encountered many barriers to implementation of TAF in the targeted communities. Changes are being made in training, management, and resources to ensure successful implementation. Continuous re-evaluation is planned to ensure the successful implementation and conduct of the program.

Breast cancer risk reduction: what do we know and where should we go?

Clinicians should be aware of the advances in breast cancer risk assessment and risk-reduction therapy. The modified Gail model is appropriate for predicting the risk of developing breast cancer within the next 5 years for most women between ages 35 and 75. Tamoxifen has been approved by the U.S. Food and Drug Administration (FDA) for reduction of breast cancer risk in women aged 35 and older who meet the threshold risk for breast cancer. Raloxifene is being compared with tamoxifen in the clinical trial, STAR (a Study of Tamoxifen and Raloxifene), which is now enrolling postmenopausal women aged 35 or older. The risks and benefits of therapy to reduce breast cancer risk are reviewed here. Processes for comparison of risks and benefits and for shared decision making are outlined.

Th2-dependent airway eosinophilia is regulated by preproenkephalin.

We have used preproenkephalin (PPNK)-deficient mice to study the role of PPNK in the development of airway inflammation. Airway eosinophilia was established by either sensitization followed by airway challenge with OVA or by infection with Nippostrongylus brasiliensis. Both models induce a strong Th2 immune response, characterized by an IL-5-dependent airway eosinophilia. We observed that although the accumulation of lymphocytes in the airways of PPNK-deficient mice was similar to that induced in control mice, IL-5 production and eosinophil infiltration were reduced. We conclude from this work that PPNK has a role in enhancing Th2 cell function and that this molecule may be an important target in asthma immunotherapy.

Involving minority and underrepresented women in clinical trials: the National Centers of Excellence in Women's Health.

Recent attention to reducing health disparities among population groups has focused on the need to include in clinical studies, especially clinical trials, participants who represent the diversity of the populations to which study results will be applied. While scientists generally applaud the goal of broadening the characteristics of participants in clinical trials, they are faced with multiple challenges as they seek to include historically underrepresented populations in their research. This article examines the historical and sociocultural context of participation by underrepresented groups, especially women and minorities, in clinical trials, identifies major barriers and challenges facing researchers, and suggests strategies for meeting these challenges. The article draws upon the experiences of the investigators affiliated with the National Centers of Excellence of Women's Health (CoEs).

Cancer skills laboratories for medical students: a promising approach for cancer education.

BACKGROUND: Most medical students graduate without the skills necessary to assist patients in cancer control. To address this problem, the authors developed a cancer skills laboratory for second-year medical students. METHODS: The skills laboratory consists of two hours of training, with 15 minutes allotted per station (six to eight students assigned per station). Faculty and fellows lead the stations on prostate cancer, breast cancer, colorectal cancer, skin cancer, counseling for smoking cessation, and a discussion of anti-tobacco advertisements. Students completed pre- and post-laboratory surveys consisting of ten brief questions. RESULTS: Overall, 94% of eligible students in 1997 and 1998 completed the surveys. Using a five-point scale, self-rated skill level increased from 2.12 to 3.83 when all modalities were averaged (p < .001). CONCLUSIONS: Cancer skills laboratories are a promising new means for cancer education.

Preproenkephalin is a Th2 cytokine but is not required for Th2 differentiation in vitro.

Preproenkephalin (PPNK) mRNA expression has been detected in many cells of the immune system, including monocytes and lymphocytes. In the present paper, the expression of PPNK mRNA in purified CD4+ Th1 and Th2 lymphocyte subpopulations is investigated and correlated with the presence of the opioid neuropeptides leu- and met-enkephalin. We found that PPNK mRNA and met-enkephalin were present at higher levels in the Th2 cultures compared with the Th1 cultures. Lymphocytes from PPNK-deficient mice were then used to look at the role of PPNK in Th2 lymphocyte differentiation. Lymphocytes from these mice could be driven into a Th2 phenotype, suggesting that cultures containing IL-4 do not require PPNK for Th2 differentiation.

Implementation of on-site screening sigmoidoscopy positively influences utilization by primary care providers.

BACKGROUND & AIMS: Sigmoidoscopy is an effective screening strategy for colorectal cancer that is not widely used by primary care providers. The aim of this study was to assess the impact of "academic detailing" in the form of an outreach educational seminar combined with implementation of on-site sigmoidoscopy services performed by university-based gastroenterologists on provider compliance. METHODS: A controlled trial was initiated at 9 urban neighborhood health centers, including 4 intervention and 5 comparison sites. Baseline data on provider attitudes and practice patterns were collected using a validated questionnaire. Outcome measures included a year 1 follow-up survey of provider attitudes and quarterly review of screening sigmoidoscopy referrals using appointment logs to assess utilization. RESULTS: Overall self-reported compliance rates for screening sigmoidoscopy increased by 36% (baseline, 24%; year 1, 60%) for the intervention group vs. only 7% (baseline, 19%; year 1, 26%) for the comparison group (P = 0. 001). When stratified by site, compliance rates increased at each intervention site (range, 7%-92%) but at only 2 control sites. Use of screening sigmoidoscopy was also significantly greater at the intervention sites (47% vs. 4%; P

Medical students' knowledge, attitudes, skills, and practices of cancer prevention and detection.

BACKGROUND: Surveys of U.S. physicians show deficiencies in cancer detection and counseling skills. Thus, there is a compelling need to provide skills teaching during medical school for cancers with preventable mortality and for counseling techniques for smoking prevention and cessation. METHODS: In advance of the integration of initiatives for cancer education into the medical school curriculum, the authors conducted a baseline survey of students' knowledge, attitudes, skills, practices, observation, and training (KASPOT) related to cancer education. Eighty-one percent of Boston University School of Medicine students (n = 499) completed surveys. RESULTS: The students reported higher levels of KASPOT for breast and cervical cancers, compared with skin cancer examination or tobacco use cessation or prevention counseling. More than half of third- and fourth-year students reported that too little emphasis was given to cancer control education. CONCLUSIONS: It appears that students' practice and skills for detection of the most common cancer (skin cancer), and for cancers with the greatest mortality (tobacco-related cancers) are deficient. Revisions in medical students' curricula should seek to address these shortcomings.

CTLA-4 blockade enhances the immune response induced by mycobacterial infection but does not lead to increased protection.

The murine immune response to a pulmonary mycobacterial infection is slow to develop, allowing bacterial numbers to increase in the lung for several weeks after infection. We sought to enhance the protective immune response induced during Mycobacterium bovis BCG infection by administering an antibody that blocks the interaction of CTLA-4 with its ligands, CD80 and CD86. We found that injection of anti-CTLA-4 monoclonal antibody (MAb) greatly enhanced and accelerated the immune response, as measured by increased cellularity of the draining mediastinal lymph nodes, and enhanced antigen-inducible proliferation and gamma interferon production by mediastinal lymphocytes in vitro. However, despite the apparently enhanced immune response in the mediastinal lymph node following treatment with anti-CTLA-4 MAb, there was no improvement in clearance of mycobacteria in the lungs, liver, or spleen. Examination of the primary site of infection, the lung, revealed that CTLA-4 blockade had no effect on the number or function of lymphocytes infiltrating the infected lung tissue. Taken together, these data suggest that in vivo CTLA-4 blockade enhances mycobacterial-infection-induced lymphocyte expansion and effector cell cytokine production in the draining lymph node but does not alter the number or function of lymphocytes at the primary site of infection and therefore does not lead to enhanced clearance of the infection.

Risk factors for a decline in upper body function following treatment for early stage breast cancer.

PURPOSE: To identify risk factors for a decline in upper body function following treatment for early stage breast cancer. METHODS: We conducted a cross-sectional observational study of 213 women > 55 years of age newly diagnosed with early stage breast cancer interviewed three to five months following their definitive surgery. Patients were classified as having impaired upper body function related to their breast cancer treatment if: 1) they reported having no difficulty in performing any of three tasks requiring upper body function (pushing or pulling large objects; lifting objects weighing more than 10 pounds; and reaching or extending arms above shoulder level) prior to treatment, but reported that any of these tasks were somewhat or very difficult in the four weeks prior to interview, or 2) they reported that performing any of the three tasks requiring upper body function was somewhat difficult prior to treatment, but reported that any of these tasks were very difficult in the four weeks prior to interview. RESULTS: In multiple logistic regression models, both the extent and type of primary tumor therapy and cardiopulmonary comorbidity were significantly associated with a decline in upper body function following breast cancer treatment. CONCLUSION: Given the critical importance of upper body function in maintaining independent living, clinicians should consider the functional consequences of treatment when they discuss treatment options and post-operative care with older women who have early stage breast cancer.

A functionally distinct TATA box required for late progression through the Epstein-Barr virus life cycle.

During EBV infection, lytic DNA replication activates late gene expression in trans via an uncharacterized pathway. In this study, we mapped the target of this regulatory cascade to a variant TATA box (TATTAAA) and the 3' flanking region within the core promoter of the BcLF1 gene. The inherent late activity of this core promoter is, surprisingly, disrupted by a heterologous enhancer, suggesting that late gene expression is regulated through core promoter sequences located in a transcriptionally inert environment.

Autosomal mutations affecting adhesion between wing surfaces in Drosophila melanogaster.

Integrins are evolutionarily conserved transmembrane alpha,beta heterodimeric receptors involved in cell-to-matrix and cell-to-cell adhesions. In Drosophila the position-specific (PS) integrins mediate the formation and maintenance of junctions between muscle and epidermis and between the two epidermal wing surfaces. Besides integrins, other proteins are implicated in integrin-dependent adhesion. In Drosophila, somatic clones of mutations in PS integrin genes disrupt adhesion between wing surfaces to produce wing blisters. To identify other genes whose products function in adhesion between wing surfaces, we conducted a screen for autosomal mutations that produce blisters in somatic wing clones. We isolated 76 independent mutations in 25 complementation groups, 15 of which contain more than one allele. Chromosomal sites were determined by deficiency mapping, and genetic interactions with mutations in the beta PS integrin gene myospheroid were investigated. Mutations in four known genes (blistered, Delta, dumpy and mastermind) were isolated. Mutations were isolated in three new genes (piopio, rhea and steamer duck) that affect myo-epidermal junctions or muscle function in embryos. Mutations in three other genes (kakapo, kiwi and moa) may also affect cell adhesion or muscle function at hatching. These new mutants provide valuable material for the study of integrin-dependent cell-to-cell adhesion.

Head and neck cancer screening among 4611 tobacco users older than forty years.

We implemented screening for squamous cell carcinomas of the oral cavity, pharynx, and larynx with symptom assessment and systematic inspection of the oral mucosa by primary care practitioners at health care sites serving inner-city residents of Boston; 4611 tobacco users older than 40 years were screened, and 313 with specific criteria were referred to otolaryngology for diagnostic evaluations. In these screened patients, the prevalence of oral mucosal lesions was almost 13% and prevalence of persistent hoarseness was more than 11%. Although the identification of these cancers was rare (nearly 3%), abnormal findings were seen in more than 70% of referred patients. These clinical and histologic diagnoses are described. We have documented the range of pathologic conditions in high-risk patients screened for upper aerodigestive tract malignancy.

Dominance of insecticide resistance presents a plastic response.

Dominance level of insecticide resistance provided by one major gene (an insensitive acetylcholinesterase) in the mosquito Culex pipiens was studied in two distinct environments. Dominance level was found to be very different environments, varying from almost complete dominance to almost recessive when either propoxur (a carbamate insecticide) or chlorpyrifos (an organophosphorus insecticide) was used. To better understand this plastic response, three environmental parameters were manipulated and their interactions studied. For chlorpyrifos, each parameter had a small effect, but when all parameters were changed, the dominance level was greatly affected. For propoxur, one environmental parameter had a large effect by itself. It was further studied to understand the causal relationship of this plasticity. Recessivity of resistance was associated with more demanding environments. These results are discussed in the context of the various theories of the evolution of dominance. It appears that dominance of insecticide resistance cannot be directly predicted by Wright's physiological theory.

The epidemiology of AL and AA amyloidosis.

The limited available epidemiological information on AL amyloidosis suggests that there may be differences between population-based studies and case series data with respect to variables such as age and racial patterns. Much more work in this area is required before specific aetiologic hypotheses can be tested. Most available data to approximate the epidemiology of AA amyloidosis are derived from autopsies. Most patients with AA amyloidosis die from causes other than amyloidosis, therefore mortality data based on death certificates is of limited value in AA amyloidosis. Case ascertainment in autopsy studies may be difficult due to the frequent lack of adequate histological controls. Establishment of registries for both AL and AA amyloidosis would facilitate epidemiological research in these disorders.

Cancer and poverty: breaking the cycle.

Poverty contributes to an increase in cancer incidence and mortality. The economically disadvantaged have a higher incidence for several cancers and lower survival rates for all cancer sites combined. A number of factors are responsible for the increased mortality and morbidity from cancer among the poor and include lack of employment, lack of education, inadequate housing, lack of access to medical care, chronic malnutrition, and a fatalistic attitude. Successful strategies must be taken to reverse these trends.