Counseling increases immediate postpartum Long-Acting Reversible Contraception (LARC) acceptability in Hispanic women.

OBJECTIVE: Determine if providing basic contraceptive counseling during prenatal visits increases pregnant Hispanic women's acceptance of immediate postpartum long-acting reversible contraception (LARC). STUDY DESIGN: Respondents completed a short survey consisting of demographic information, an acculturation scale, and perceptions of immediate postpartum LARC use. After reading a brief educational excerpt on intrauterine devices (IUDs) and the subdermal contraceptive implant, LARC acceptability was reassessed. The study included 198 Hispanic women, ages 14 and older, in the 2nd or 3rd trimester of pregnancy receiving care at an academic practice along the United States-Mexico border in West Texas. Analysis was performed using a McNemar test, univariate and multivariable relative risk (RR) regression. RESULTS: Prior to an educational intervention, 34.5% of respondents indicated that they were planning to use immediate postpartum LARC. Following the educational intervention, 74.5% of respondents indicated they would consider a postpartum LARC. The pre/post comparison on the intent to use postpartum LARC showed that a significant number of respondents changed their intention to use LARC after reading the educational intervention (RR= 2.54, p<0.0001). LARC acceptability was high among single women, those less than 25-years-old, women with current unintended pregnancies, and women using a contraceptive method that failed when they became pregnant. CONCLUSION: In communities with a high proportion of Hispanic women, postpartum contraceptive counseling is crucial for patient education and family planning. When women are provided with brief, structured contraceptive counseling during prenatal visits, they are more willing to consider use of an immediate postpartum LARC for their future family planning.

Postauricular apocrine hidrocystoma: a case and dermoscopy review.

Apocrine hidrocystoma (AH) is a benign cystic proliferation of apocrine sweat glands that classically presents as a slow-growing nodule on the face, especially in the periorbital region. Histopathological evaluation is required to definitively diagnose an apocrine hidrocystoma. Previous studies have described apocrine hidrocystomas in unusual locations. However, the authors have identified only two reported cases of apocrine hidrocystoma in the postauricular region. We present a third case of a postauricular hidrocystoma in a 26-year-old woman, as well as a brief review of the dermoscopic findings of apocrine hidrocystomas in the existing literature.

Functional pathways regulated by microRNA networks in CD8 T-cell aging.

One of the most prominent immunological changes during human aging is the alteration in CD8 T-cell subset distribution, predominated by a loss of naïve CD8 T cells. The molecular mechanisms that contribute to the loss of naïve CD8 T-cells during aging remain unclear. Considering that many CD8 T-cell functions are influenced by microRNAs (miRNAs), we explored miRNA expression profiling to identify novel dysfunctions that contribute to naïve CD8 T-cell loss during aging. Here, we describe age-dependent miRNA expression changes in naïve, central memory, and effector memory CD8 T-cell subsets. Changes in old naïve CD8 T-cells partially resembled those driven by an underlying shift in cellular differentiation toward a young central memory phenotype. Pathways enriched for targets of age-dependent miRNAs included FOXO1, NF-κB, and PI3K-AKT signaling. Transcriptome analysis of old naïve CD8 T-cells yielded corresponding patterns that correlated to those seen with reduced FOXO1 or altered NF-κB activities. Of particular interest, IL-7R expression, controlled by FOXO1 signaling, declines on naïve CD8 T cells with age and directly correlates with the frequencies of naïve CD8 T cells. Thus, age-associated changes in miRNA networks may ultimately contribute to the failure in CD8 T-cell homeostasis exemplified by the loss in naïve cells.

Activation of miR-21-Regulated Pathways in Immune Aging Selects against Signatures Characteristic of Memory T Cells.

Induction of protective vaccine responses, governed by the successful generation of antigen-specific antibodies and long-lived memory T cells, is increasingly impaired with age. Regulation of the T cell proteome by a dynamic network of microRNAs is crucial to T cell responses. Here, we show that activation-induced upregulation of miR-21 biases the transcriptome of differentiating T cells away from memory T cells and toward inflammatory effector T cells. Such a transcriptome bias is also characteristic of T cell responses in older individuals who have increased miR-21 expression and is reversed by antagonizing miR-21. miR-21 targets negative feedback circuits in several signaling pathways. The concerted, sustained activity of these signaling pathways in miR-21high T cells disfavors the induction of transcription factor networks involved in memory cell differentiation. Our data suggest that curbing miR-21 upregulation or activity in older individuals may improve their ability to mount effective vaccine responses.

Defective T Memory Cell Differentiation after Varicella Zoster Vaccination in Older Individuals.

Vaccination with attenuated live varicella zoster virus (VZV) can prevent zoster reactivation, but protection is incomplete especially in an older population. To decipher the molecular mechanisms underlying variable vaccine responses, T- and B-cell responses to VZV vaccination were examined in individuals of different ages including identical twin pairs. Contrary to the induction of VZV-specific antibodies, antigen-specific T cell responses were significantly influenced by inherited factors. Diminished generation of long-lived memory T cells in older individuals was mainly caused by increased T cell loss after the peak response while the expansion of antigen-specific T cells was not affected by age. Gene expression in activated CD4 T cells at the time of the peak response identified gene modules related to cell cycle regulation and DNA repair that correlated with the contraction phase of the T cell response and consequently the generation of long-lived memory cells. These data identify cell cycle regulatory mechanisms as targets to reduce T cell attrition in a vaccine response and to improve the generation of antigen-specific T cell memory, in particular in an older population.

Diversification of the antigen-specific T cell receptor repertoire after varicella zoster vaccination.

Diversity and size of the antigen-specific T cell receptor (TCR) repertoire are two critical determinants for successful control of chronic infection. Varicella zoster virus (VZV) that establishes latency during childhood can escape control mechanisms, in particular with increasing age. We examined the TCR diversity of VZV-reactive CD4 T cells in individuals older than 50 years by studying three identical twin pairs and three unrelated individuals before and after vaccination with live attenuated VZV. Although all individuals had a small number of dominant T cell clones, the breadth of the VZV-specific repertoire differed markedly. A genetic influence was seen for the sharing of individual TCR sequences from antigen-reactive cells but not for repertoire richness or the selection of dominant clones. VZV vaccination favored the expansion of infrequent VZV antigen-reactive TCRs, including those from naïve T cells with lesser boosting of dominant T cell clones. Thus, vaccination does not reinforce the in vivo selection that occurred during chronic infection but leads to a diversification of the VZV-reactive T cell repertoire. However, a single-booster immunization seems insufficient to establish new clonal dominance. Our results suggest that repertoire analysis of antigen-specific TCRs can be an important readout to assess whether a vaccination was able to generate memory cells in clonal sizes that are necessary for immune protection.

Expression of CD39 on Activated T Cells Impairs their Survival in Older Individuals.

In an immune response, CD4(+) T cells expand into effector T cells and then contract to survive as long-lived memory cells. To identify age-associated defects in memory cell formation, we profiled activated CD4(+) T cells and found an increased induction of the ATPase CD39 with age. CD39(+) CD4(+) T cells resembled effector T cells with signs of metabolic stress and high susceptibility to undergo apoptosis. Pharmacological inhibition of ATPase activity dampened effector cell differentiation and improved survival, suggesting that CD39 activity influences T cell fate. Individuals carrying a low-expressing CD39 variant responded better to vaccination with an increase in vaccine-specific memory T cells. Increased inducibility of CD39 after activation may contribute to the impaired vaccine response with age.

The Genetic Absence Epilepsy Rats from Strasbourg model of absence epilepsy exhibits alterations in fear conditioning and latent inhibition consistent with psychiatric comorbidities in humans.

Behavioural, neurological, and genetic similarities exist in epilepsies, their psychiatric comorbidities, and various psychiatric illnesses, suggesting common aetiological factors. Rodent models of epilepsy are used to characterize the comorbid symptoms apparent in epilepsy and their neurobiological mechanisms. The present study was designed to assess Pavlovian fear conditioning and latent inhibition in a polygenetic rat model of absence epilepsy, i.e. Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and the non-epileptic control (NEC) strain. Electrophysiological recordings confirmed the presence of spike-wave discharges in young adult GAERS but not NEC rats. A series of behavioural tests designed to assess anxiety-like behaviour (elevated plus maze, open field, acoustic startle response) and cognition (Pavlovian conditioning and latent inhibition) was subsequently conducted on male and female offspring. Results showed that GAERS exhibited significantly higher anxiety-like behaviour, a characteristic reported previously. In addition, using two protocols that differed in shock intensity, we found that both sexes of GAERS displayed exaggerated cued and contextual Pavlovian fear conditioning and impaired fear extinction. Fear reinstatement to the conditioned stimuli following unsignalled footshocks did not differ between the strains. Male GAERS also showed impaired latent inhibition in a paradigm using Pavlovian fear conditioning, suggesting that they may have altered attention, particularly related to previously irrelevant stimuli in the environment. Neither the female GAERS nor NEC rats showed evidence of latent inhibition in our paradigm. Together, the results suggest that GAERS may be a particularly useful model for assessing therapeutics designed to improve the emotional and cognitive disturbances associated with absence epilepsy.

Naive T cell maintenance and function in human aging.

In studies of immune aging, naive T cells frequently take center stage. Describing the complexity of the human naive T cell repertoire remains a daunting task; however, emerging data suggest that homeostatic mechanisms are robust enough to maintain a large and diverse CD4 T cell repertoire with age. Compartment shrinkage and clonal expansions are challenges for naive CD8 T cells. In addition to population aspects, identification of potentially targetable cellular defects is receiving renewed interest. The last decade has seen remarkable progress in identifying genetic and biochemical pathways that are pertinent for aging in general and that are instructive to understand naive T cell dysfunction. One hallmark sets naive T cell aging apart from most other tissues except stem cells: they initiate but do not complete differentiation programs toward memory cells. Maintaining quiescence and avoiding differentiation may be the ultimate challenge to maintain the functions unique for naive T cells.

B-cell repertoire responses to varicella-zoster vaccination in human identical twins.

Adaptive immune responses in humans rely on somatic genetic rearrangements of Ig and T-cell receptor loci to generate diverse antigen receptors. It is unclear to what extent an individual's genetic background affects the characteristics of the antibody repertoire used in responding to vaccination or infection. We studied the B-cell repertoires and clonal expansions in response to attenuated varicella-zoster vaccination in four pairs of adult identical twins and found that the global antibody repertoires of twin pair members showed high similarity in antibody heavy chain V, D, and J gene segment use, and in the length and features of the complementarity-determining region 3, a major determinant of antigen binding. These twin similarities were most pronounced in the IgM-expressing B-cell pools, but were seen to a lesser extent in IgG-expressing B cells. In addition, the degree of antibody somatic mutation accumulated in the B-cell repertoire was highly correlated within twin pair members. Twin pair members had greater numbers of shared convergent antibody sequences, including mutated sequences, suggesting similarity among memory B-cell clonal lineages. Despite these similarities in the memory repertoire, the B-cell clones used in acute responses to ZOSTAVAX vaccination were largely unique to each individual. Taken together, these results suggest that the overall B-cell repertoire is significantly shaped by the underlying germ-line genome, but that stochastic or individual-specific effects dominate the selection of clones in response to an acute antigenic stimulus.

OX40L blockade is therapeutic in arthritis, despite promoting osteoclastogenesis.

An immune response is essential for protection against infection, but, in many individuals, aberrant responses against self tissues cause autoimmune diseases such as rheumatoid arthritis (RA). How to diminish the autoimmune response while not augmenting infectious risk is a challenge. Modern targeted therapies such as anti-TNF or anti-CD20 antibodies ameliorate disease, but at the cost of some increase in infectious risk. Approaches that might specifically reduce autoimmunity and tissue damage without infectious risk would be important. Here we describe that TNF superfamily member OX40 ligand (OX40L; CD252), which is expressed predominantly on antigen-presenting cells, and its receptor OX40 (on activated T cells), are restricted to the inflamed joint in arthritis in mice with collagen-induced arthritis and humans with RA. Blockade of this pathway in arthritic mice reduced inflammation and restored tissue integrity predominantly by inhibiting inflammatory cytokine production by OX40L-expressing macrophages. Furthermore, we identify a previously unknown role for OX40L in steady-state bone homeostasis. This work shows that more targeted approaches may augment the "therapeutic window" and increase the benefit/risk in RA, and possibly other autoimmune diseases, and are thus worth testing in humans.

Delivering colonoscopy screening for low-income populations in Suffolk County: strategies, outcomes, and benchmarks.

BACKGROUND: Current and pending legislation provides colorectal cancer screening reimbursement for previously uninsured populations. Colonoscopy is currently the screening method most frequently recommended by physicians for insured patients. The experience of the SCOPE (Suffolk County Preventive Endoscopy) demonstration project (Project SCOPE) at Stony Brook University Medical Center provides a model for delivering colonoscopy screening to low-income populations to meet anticipated increasing demands. METHODS: Project SCOPE, based in the Department of Preventive Medicine, featured internal collaboration with the academic medical center's large gastroenterology practice and external collaboration with the Suffolk County Department of Health Services' network of community health centers. Colonoscopies were performed by faculty gastroenterologists or supervised fellows. Measures of colonoscopy performance were compared with quality indicators and differences between faculty and supervised fellows were identified. RESULTS: During a 40-month screening period, 800 initial colonoscopies were performed. Approximately 21% of women screened were found to have adenomatous polyps compared with 36% of men. Five cancers were detected. The majority of the population screened (70%) were members of minority populations. African American individuals had a higher percentage of proximally located adenomas (78%) compared with white individuals (65%) and Hispanics (49%), based on the location of the most advanced lesion. Hispanic individuals had a 36% lower risk of adenomas compared with white individuals. Performance measures including the percentage of procedures with adequate bowel preparation, cecum reached, scope withdrawal time, and adenoma detection rate met quality benchmarks when performed by either faculty or supervised fellows. CONCLUSIONS: Project SCOPE's operational strategies demonstrated a feasible method for an academic medical center to provide high-quality screening colonoscopy for low-income populations.

Clinical case management and navigation for colonoscopy screening in an academic medical center.

BACKGROUND: One of 5 nationally funded Centers for Disease Control and Prevention Colorectal Cancer (CRC) Screening Demonstration Programs, Project SCOPE, was conducted at an academic medical center and provided colonoscopy screening at no cost to underserved minority patients from local community health centers. METHODS: Established barriers to CRC screening (eg, financial, language, transportation) among the target population were addressed through clinical coordination of care by key project staff. The use of a clinician with a patient navigator allowed for the performance of precolonoscopy "telephone visits" instead of office visits to the gastroenterologist in virtually all patients. The clinician elicited information relevant to making screening decisions (eg, past medical and surgical history, focused review of systems, medication/supplement use, CRC screening history). The patient navigator reduced barriers, including, but not limited to, scheduling, transportation, and physical navigation of the medical center on the day of colonoscopy. RESULTS: Preprogram preparation was vital in laying groundwork for the project, yet enhancements to the program were ongoing throughout the screening period. Detailed referral forms from primary care physicians, coupled with information obtained during telephone interviews, facilitated high colonoscopy completion rates and excellent patient satisfaction. Similarly valuable was the employment of a bilingual patient navigator, who provided practical and emotional patient support. CONCLUSIONS: Academic medical centers can be efficient models for providing CRC screening to disadvantaged populations. Coordination of care by a preventive medicine department, directing the recruitment, scheduling, prescreening education, and the evaluation and preparation of target populations had an overall positive effect on CRC screening with colonoscopy among patients from a community health center.

IL-7- and IL-15-mediated TCR sensitization enables T cell responses to self-antigens.

Regulation of the ERK pathway is intimately involved in determining whether TCR stimulation is productive or induces anergy. T cells from patients with rheumatoid arthritis (RA) have increased ERK responsiveness, which may be relevant for disease pathogenesis. Inflammatory cytokines such as TNF-α did not reproduce the TCR hypersensitivity typical for RA in T cells from healthy individuals. In contrast, priming with the homeostatic cytokines (HCs) IL-7 and IL-15 amplified ERK phosphorylation to TCR stimulation 2- to 3-fold. The underlying mechanism involved a priming of the SOS-dependent amplification loop of RAS activation. The sensitization of the TCR signaling pathway has downstream consequences, such as increased proliferation and preferential Th1 differentiation. Importantly, priming with IL-7 or IL-15 enabled T cell responses to autoantigens associated with RA. Production of HCs is induced in lymphopenic conditions, which have been shown to predispose for autoimmunity and which appear to be present in the preclinical stages of RA. We propose that HCs, possibly induced by lymphopenia, decrease the signaling threshold for TCR activation and are thereby partly responsible for autoimmunity in RA.

Systems biology of vaccination in the elderly.

Aging population demographics, combined with suboptimal vaccine responses in the elderly, make the improvement of vaccination strategies in the elderly a developing public health issue. The immune system changes with age, with innate and adaptive cell components becoming increasingly dysfunctional. As such, vaccine responses in the elderly are impaired in ways that differ depending on the type of vaccine (e.g., live attenuated, polysaccharide, conjugate, or subunit) and the mediators of protection (e.g., antibody and/or T cell). The rapidly progressing field of systems biology has been shown to be useful in predicting immunogenicity and offering insights into potential mechanisms of protection in young adults. Future application of systems biology to vaccination in the elderly may help to identify gene signatures that predict suboptimal responses and help to identify more accurate correlates of protection. Moreover, the identification of specific defects may be used to target novel vaccination strategies that improve efficacy in elderly populations.

K-RAS GTPase- and B-RAF kinase-mediated T-cell tolerance defects in rheumatoid arthritis.

Autoantibodies to common autoantigens and neoantigens, such as IgG Fc and citrullinated peptides, are immunological hallmarks of rheumatoid arthritis (RA). We examined whether a failure in maintaining tolerance is mediated by defects in T-cell receptor activation threshold settings. RA T cells responded to stimulation with significantly higher ERK phosphorylation (P < 0.001). Gene expression arrays of ERK pathway members suggested a higher expression of KRAS and BRAF, which was confirmed by quantitative PCR (P = 0.003), Western blot, and flow cytometry (P < 0.01). Partial silencing of KRAS and BRAF lowered activation-induced phosphorylated ERK levels (P < 0.01). In individual cells, levels of these signaling molecules correlated with ERK phosphorylation, attesting that their concentrations are functionally important. In confocal studies, B-RAF/K-RAS clustering was increased in RA T cells 2 min after T-cell receptor stimulation (P < 0.001). Overexpression of B-RAF and K-RAS in normal CD4 T cells amplified polyclonal T-cell proliferation and facilitated responses to citrullinated peptides. We propose that increased expression of B-RAF and K-RAS lowers T-cell activation thresholds in RA T cells, enabling responses to autoantigens.

Chronic inflammation and aging: DNA damage tips the balance.

The aged immune system, typically hyporesponsive to infection and vaccination, can be hyperresponsive in the context of inflammatory pathology. Here we review current work examining the mechanisms behind the amplified inflammatory profile of aged adaptive immunity, and the reciprocal relationship between chronic inflammation and immune aging. Aged hematopoietic stem cells are driven to differentiate following accumulated DNA damage, thus depleting the stem cell pool and increasing the number of damaged effector cells in the circulation. Chronic DNA damage responses in lymphocytes as well as senescent cells of other lineages initiate the production of inflammatory mediators. In addition, aged lymphocytes become less reliant on specific antigen for stimulation and more prone to activation through innate receptors. When these lymphocytes are exposed to inflammatory signals produced by senescent tissues, the bias toward inflammation exacerbates destruction without necessarily improving immunity.

Finding Balance: T cell Regulatory Receptor Expression during Aging.

Aging is associated with a variety of changes to immune responsiveness. Reduced protection against infection, reduced responses to vaccination and increased risk of autoimmunity are all hallmarks of advanced age. Here we consider how changes in the expression of regulatory receptors on the T cell surface contribute to altered immunity during aging.

An academic medical center model for community colorectal cancer screening: the Centers for Disease Control and Prevention demonstration program experience.

During 2005-2009, the Centers for Disease Control and Prevention funded five colorectal cancer (CRC) screening demonstration projects around the United States; only one was based in an academic medical center (AMC) rather than a health department. The Suffolk County Preventive Endoscopy Project (Project SCOPE) was a collaborative effort between Stony Brook University Medical Center (SBUMC) and the Suffolk County Department of Health Services. Project SCOPE's objective was to increase CRC screening among Suffolk County residents at least 50 years old who had inadequate or no insurance coverage for CRC screening. The demonstration application drew on the screening, diagnostic, and treatment resources of the AMC and the indigent populations using its outpatient clinics. Patients at 10 county health centers were a primary target for (previously inaccessible) colonoscopy screening. The project's organizational center was SBUMC's preventive medicine department, which was linked to SBUMC's large gastroenterology practice. The specific staffing, financial, and training issues faced by this project provide insights for others who are similarly interested in community engagement. During 40 months of screening, 800 indigent, culturally diverse patients were recruited, and they underwent colonoscopy. Challenges encountered included unreachable referred patients (425 patients; 28% of referrals) and medical ineligibility (e.g., symptomatic comorbid conditions). Pending legislation providing federal funding for a national program offers other AMCs the opportunity to adopt a model such as that proven feasible during Project SCOPE. The lessons learned may have broader application for fostering collaborative AMC partnerships and for enhancing recruitment and retention of participants through outreach.