Helicobacter pylori CagA Triggers Expression of the Bactericidal Lectin REG3γ via Gastric STAT3 Activation

Background: Most of what is known about the Helicobacter pylori (H. pylori) cytotoxin, CagA, pertains to a much-vaunted role as a determinant of gastric inflammation and cancer. Little attention has been devoted to potential roles of CagA in the majority of H. pylori infected individuals not showing oncogenic progression, particularly in relation to host tolerance. Regenerating islet-derived (REG)3c encodes a secreted C-type lectin that exerts direct bactericidal activity against Grampositive bacteria in the intestine. Here, we extend this paradigm of lectin-mediated innate immunity, showing that REG3c expression is triggered by CagA in the H. pylori-infected stomach. Methodology/Principal Findings: In human gastric mucosal tissues, REG3c expression was significantly increased in CagApositive, compared to CagA-negative H. pylori infected individuals. Using transfected CagA-inducible gastric MKN28 cells, we recapitulated REG3c induction in vitro, also showing that tyrosine phosphorylated, not unphosphorylated CagA triggers REG3c transcription. In concert with induced REG3c, pro-inflammatory signalling downstream of the gp130 cytokine coreceptor via the signal transducer and activator of transcription (STAT)3 and transcription of two cognate ligands, interleukin(IL)-11 and IL-6, were significantly increased. Exogenous IL-11, but not IL-6, directly stimulated STAT3 activation and REG3c transcription. STAT3 siRNA knockdown or IL-11 receptor blockade respectively abrogated or subdued CagAdependent REG3c mRNA induction, thus demonstrating a requirement for uncompromised signalling via the IL-11/STAT

Confronting chemobrain: an in-depth look at survivors’ reports of impact on work, social networks, and health care response

Mild cognitive impairment following chemotherapy is one of the most commonly reported post treatment symptoms by breast cancer survivors. This deterioration in cognitive function, commonly referred to as “chemobrain” or “chemofog,” was largely unacknowledged by the medical community until recent years. Although chemobrain has now become the subject of more vigorous exploration, little is known about this specific phenomenon’s psychosocial impact on breast cancer survivors. This research documents in-depth the effects that cognitive impairment has on women’s personal and professional lives, and our data suggest that greater attention needs to be focused on this arena of survivorship. The results are based on an in-depth qualitative study of 74 white and African American breast cancer survivors in California who experience post-treatment side effects. The data reported herein were obtained through the use of focus groups and in-depth interviews. Our data indicate that cognitive impairment can be problematic for survivors, with many asserting that it is their most troublesome post treatment symptom. Survivors report diminished quality of life and daily functioning as a result of chemobrain. Respondents detail a range of coping strategies that they are forced to employ in order to manage their social and professional lives. Chemobrain significantly impairs a proportion of cancer survivors, at great cost to them economically, emotionally, and interpersonally. This suggests that more research needs to be conducted on the psychosocial ramifications of post treatment symptoms in order to inform the efforts of the medical and mental health communities as well as the support networks of survivors. A better and broader understanding of the effects of cognitive impairment both in the medical community and among lay people could pave the way for improved social and psychological services for this population

Local immune regulation of mucosal inflammation by tacrolimus

Purpose: Tacrolimus is a potent immunomodulator that is effective in the treatment of inflammatory bowel disease (IBD). However, potential toxicity and systemic effects with oral intake limit its use. Local tacrolimus treatment is effective in a subgrou

Robust Metabolic Responses to Varied Carbon Sources in Natural and Laboratory Strains of Saccharomyces cerevisiae

Understanding factors that regulate the metabolism and growth of an organism is of fundamental biologic interest. This study compared the influence of two different carbon substrates, dextrose and galactose, on the metabolic and growth rates of the yeast Saccharomyces cerevisiae. Yeast metabolic and growth rates varied widely depending on the metabolic substrate supplied. The metabolic and growth rates of a yeast strain maintained under long-term laboratory conditions was compared to strain isolated from natural condition when grown on different substrates. Previous studies had determined that there are numerous genetic differences between these two strains. However, the overall metabolic and growth rates of a wild isolate of yeast was very similar to that of a strain that had been maintained under laboratory conditions for many decades. This indicates that, at in least this case, metabolism and growth appear to be well buffered against genetic differences. Metabolic rate and cell number did not co-vary in a simple linear manner. When grown in either dextrose or galactose, both strains showed a growth pattern in which the number of cells continued to increase well after the metabolic rate began a sharp decline. Previous studied have reported that O2 consumption in S. cerevisiae grown in reduced dextrose levels were elevated compared to higher levels. Low dextrose levels have been proposed to induce caloric restriction and increase life span in yeast. However, there was no evidence that reduced levels of dextrose increased metabolic rates, measured by either O2 consumption or CO2 production, in the strains used in this study

Self-efficacy instruments for patients with chronic diseases suffer from methodological limitations - a systematic review

BACKGROUND: Measurement of self-efficacy requires carefully developed and validated instruments. It is currently unclear whether available self-efficacy instruments for chronic diseases fulfill these requirements. Our aim was to systematically identify all existing self-efficacy scales for five major chronic diseases and to assess their development and validation process. METHODS: We conducted a systematic literature search in electronic databases (MEDLINE, PSYCHINFO, and EMBASE) to identify studies describing the development and/or validation process of self-efficacy instruments for the five chronic diseases diabetes, chronic obstructive pulmonary disease (COPD), asthma, arthritis, and heart failure. Two members of the review team independently selected articles meeting inclusion criteria. The self-efficacy instruments were evaluated in terms of their development (aim of instrument, a priori considerations, identification of items, selection of items, development of domains, answer options) and validation (test-retest reliability, internal consistency reliability, validity, responsiveness) process. RESULTS: Of 584 potentially eligible papers we included 25 (13 for diabetes, 5 for asthma, 4 for arthritis, 3 for COPD, 0 for heart failure) which covered 26 different self-efficacy instrument versions. For 8 instruments (30.8%), the authors described the aim before the scales were developed whereas for the other instruments the aim was unclear. In one study (3.8%) a priori considerations were specified. In none of the studies a systematic literature search was carried out to identify items. The item selection process was often not clearly described (38.5%). Test-retest reliability was assessed for 9 instruments (34.6%), validity using a correlational approach for 18 (69.2%), and responsiveness to change for 3 (11.5%) instruments. CONCLUSION: The development and validation process of the majority of the self-efficacy instruments had major limitations. The aim of the instruments was often not specified and for most instruments, not all measurement properties that are important to support the specific aim of the instrument (for example responsiveness for evaluative instruments) were assessed. Researchers who develop and validate self-efficacy instruments should adhere more closely to important methodological concepts for development and validation of patient-reported outcomes and report their methods more transparently. We propose a systematic five step approach for the development and validation of self-efficacy instruments

Angiotensin II Activates the Calcineurin/NFAT Signaling Pathway and Induces Cyclooxygenase-2 Expression in Rat Endometrial Stromal Cells

Cyclooxygenase (COX)-2, the inducible isoform of cyclooxygenase, plays a role in the process of uterine decidualization and blastocyst attachment. On the other hand, overexpression of COX-2 is involved in the proliferation of the endometrial tissue during endometriosis. Deregulation of the renin-angiotensin-system plays a role in the pathophysiology of endometriosis and pre-eclampsia. Angiotensin II increases intracellular Ca2+ concentration by targeting phospholypase C-gamma in endometrial stromal cells (ESC). A key element of the cellular response to Ca2+ signals is the activity of the Ca2+- and calmodulin-dependent phosphatase calcineurin. Our first aim was to study whether angiotensin II stimulated Cox-2 gene expression in rat ESC and to analyze whether calcineurin activity was involved. In cells isolated from non-pregnant uteri, COX-2 expression -both mRNA and protein- was induced by co-stimulation with phorbol ester and calcium ionophore (PIo), as well as by angiotensin II. Pretreatment with the calcineurin inhibitor cyclosporin A inhibited this induction. We further analyzed the role of the calcineurin/NFAT signaling pathway in the induction of Cox-2 gene expression in non-pregnant rat ESC. Cyclosporin A abolished NFATc1 dephosphorylation and translocation to the nucleus. Cyclosporin A also inhibited the transcriptional activity driven by the Cox-2 promoter. Exogenous expression of the peptide VIVIT -specific inhibitor of calcineurin/NFAT binding- blocked the activation of Cox-2 promoter and the up-regulation of COX-2 protein in these cells. Finally we analyzed Cox-2 gene expression in ESC of early-pregnant rats. COX-2 expression -both mRNA and protein- was induced by stimulation with PIo as well as by angiotensin II. This induction appears to be calcineurin independent, since it was not abrogated by cyclosporin A. In conclusion, angiotensin II induced Cox-2 gene expression by activating the calcineurin/NFAT signaling pathway in endometrial stromal cells of non-pregnant but not of early-pregnant rats. These results might be related to differential roles that COX-2 plays in the endometrium

Expression of a Constitutively Active Calcineurin Encoded by an Intron-Retaining mRNA in Follicular Keratinocytes

Hair growth is a highly regulated cyclical process. Immunosuppressive immunophilin ligands such as cyclosporin A (CsA) and FK506 are known as potent hair growth modulatory agents in rodents and humans that induce active hair growth and inhibit hair follicle regression. The immunosuppressive effectiveness of these drugs has been generally attributed to inhibition of T cell activation through well-characterized pathways. Specifically, CsA and FK506 bind to intracellular proteins, principally cyclophilin A and FKBP12, respectively, and thereby inhibit the phosphatase calcineurin (Cn). The calcineurin (Cn)/NFAT pathway has an important, but poorly understood, role in the regulation of hair follicle development. Here we show that a novel-splicing variant of calcineurin Aß CnAß-FK, which is encoded by an intron-retaining mRNA and is deficient in the autoinhibitory domain, is predominantly expressed in mature follicular keratinocytes but not in the proliferating keratinocytes of rodents. CnAß-FK was weakly sensitive to Ca2+ and dephosphorylated NFATc2 under low Ca2+ levels in keratinocytes. Inhibition of Cn/NFAT induced hair growth in nude mice. Cyclin G2 was identified as a novel target of the Cn/NFATc2 pathway and its expression in follicular keratinocytes was reduced by inhibition of Cn/NFAT. Overexpression of cyclin G2 arrested the cell cycle in follicular keratinocytes in vitro and the Cn inhibitor, cyclosporin A, inhibited nuclear localization of NFATc2, resulting in decreased cyclin G2 expression in follicular keratinocytes of rats in vivo. We therefore suggest that the calcineurin/NFAT pathway has a unique regulatory role in hair follicle development

Practice Inquiry: Clinical Uncertainty as a Focus for Small-Group Learning and Practice Improvement

PROBLEM: Many primary care physicians in nonacademic settings lack a collegial forum for engaging the clinical uncertainties inherent in their work. PROGRAM DESCRIPTION: “Practice Inquiry” is proposed as a set of small-group, practice-based learning and improvement (PBLI) methods designed to help clinicians better manage case-based clinical uncertainty. Clinicians meet regularly at their offices/clinics to present dilemma cases, share clinical experience, review evidence for blending with experience, and draw implications for practice improvement. From 2001 through 2005, Practice Inquiry was introduced to sites in the San Francisco Bay Area as a demonstration effort. Meeting rosters, case logs, a feedback survey, and meeting field notes documented implementation and provided data for a formative, qualitative evaluation. PROGRAM EVALUATION: Of the 30 sites approached, 14 held introductory meetings. As of summer 2006, 98 clinicians in 11 sites continue to hold regularly scheduled group meetings. Of the 118 patient cases presented in the seven oldest groups, clinician–patient relationship and treatment dilemmas were most common. Clinician feedback and meeting transcript data provided insights into how busy practitioners shared cases, developed trust, and learned new knowledge/skills for moving forward with patients. DISCUSSION: Ongoing clinician involvement suggests that Practice Inquiry is a feasible, acceptable, and potentially useful set of PBLI methods. Two of the Practice Inquiry’s group learning tasks received comparatively less focus: integrating research evidence with clinical experience and tracking dilemma case outcomes. Future work should focus on reducing the methodological limitations of a demonstration effort and examining factors affecting clinician participation. Set-aside work time for clinicians, or other equally potent incentives, will be necessary for the further elaboration of these PBLI methods aimed at managing uncertainty

Ontogeny of Toll-Like Receptor Mediated Cytokine Responses of Human Blood Mononuclear Cells

Newborns and young infants suffer increased infectious morbidity and mortality as compared to older children and adults. Morbidity and mortality due to infection are highest during the first weeks of life, decreasing over several years. Furthermore, most vaccines are not administered around birth, but over the first few years of life. A more complete understanding of the ontogeny of the immune system over the first years of life is thus urgently needed. Here, we applied the most comprehensive analysis focused on the innate immune response following TLR stimulation over the first 2 years of life in the largest such longitudinal cohort studied to-date (35 subjects). We found that innate TLR responses (i) known to support Th17 adaptive immune responses (IL-23, IL-6) peaked around birth and declined over the following 2 years only to increase again by adulthood; (ii) potentially supporting antiviral defense (IFN-α) reached adult level function by 1 year of age; (iii) known to support Th1 type immunity (IL-12p70, IFN-γ) slowly rose from a low at birth but remained far below adult responses even at 2 years of age; (iv) inducing IL-10 production steadily declined from a high around birth to adult levels by 1 or 2 years of age, and; (v) leading to production of TNF-α or IL-1β varied by stimuli. Our data contradict the notion of a linear progression from an ‘immature’ neonatal to a ‘mature’ adult pattern, but instead indicate the existence of qualitative and quantitative age-specific changes in innate immune reactivity in response to TLR stimulation

Part II, Provider perspectives: should patients be activated to request evidence-based medicine? a qualitative study of the VA project to implement diuretics (VAPID)

<p>Abstract</p> <p>Background</p> <p>Hypertension guidelines recommend the use of thiazide diuretics as first-line therapy for uncomplicated hypertension, yet diuretics are under-prescribed, and hypertension is frequently inadequately treated. This qualitative evaluation of provider attitudes follows a randomized controlled trial of a patient activation strategy in which hypertensive patients received letters and incentives to discuss thiazides with their provider. The strategy prompted high discussion rates and enhanced thiazide-prescribing rates. Our objective was to interview providers to understand the effectiveness and acceptability of the intervention from their perspective, as well as the suitability of patient activation for more widespread guideline implementation.</p> <p>Methods</p> <p>Semi-structured phone interviews were conducted with 21 primary care providers. Interviews were transcribed verbatim and reviewed by the interviewer before being analyzed for content. Interviews were coded, and relevant themes and specific responses were identified, grouped, and compared.</p> <p>Results</p> <p>Of the 21 providers interviewed, 20 (95%) had a positive opinion of the intervention, and 18 of 20 (90%) thought the strategy was suitable for wider use. In explaining their opinions of the intervention, many providers discussed a positive effect on treatment, but they more often focused on the process of patient activation itself, describing how the intervention facilitated discussions by informing patients and making them more pro-active. Regarding effectiveness, providers suggested the intervention worked like a reminder, highlighted oversights, or changed their approach to hypertension management. Many providers also explained that the intervention 'aligned' patients' objectives with theirs, or made patients more likely to accept a change in medications. Negative aspects were mentioned infrequently, but concerns about the use of financial incentives were most common. Relevant barriers to initiating thiazide treatment included a hesitancy to switch medications if the patient was at or near goal blood pressure on a different anti-hypertensive.</p> <p>Conclusions</p> <p>Patient activation was acceptable to providers as a guideline implementation strategy, with considerable value placed on the activation process itself. By 'aligning' patients' objectives with those of their providers, this process also facilitated part of the effectiveness of the intervention. Patient activation shows promise for wider use as an implementation strategy, and should be tested in other areas of evidence-based medicine.</p> <p>Trial registration</p> <p>National Clinical Trial Registry number NCT00265538</p