Miracle-dz/UniFAR-FTUs huggingface dataset:
A critical examination of the time and workload involved in the design and delivery of an e-module in postgraduate clinical education

Background: Although there is increasing pressure on Universities to implement e-learning, this ‘glorious revolution’ has been met with disappointing results and universities have struggled to engage academic staff, who are major stakeholders, with its use. Although literature suggests online teaching adds to traditional faculty workload, information surrounding the actual ‘cost’ to individuals is sparse. For academics involved in postgraduate clinical education, it is even more incomplete. Involvement can be a risky undertaking for academics unfamiliar with the resources required. Aims: This study outlines staff resources required to create an e-module for busy, practicing clinicians. Method: Data (web analytics, email traffic, and work logs) was collected and statistical analysis performed outlining time involved, work patterns and responsibilities. Results: Data analysis revealed 75% of academic time occurred out of normal office hours. Sixteen total staff hours (12 planning and four delivery) were required to support one hour student online activity. Technical responsibilities were essential throughout, but unpredictable. Conclusions: Universities struggle to engage staff with e-learning due to its unrecognized and (many academics believe) unsustainable workload. Avoiding ‘traditional’ workload assumptions that are inaccurate, this study provides academics and managers involved in clinical education clear guidance and an increased understanding of workload with a goal to inform practice.
Inhibition of FOXP3/NFAT Interaction Enhances T Cell Function after TCR Stimulation

Regulatory T cell (Treg) activity is modulated by a cooperative complex between the transcription factor NFAT and FOXP3, a lineage specification factor for Tregs. FOXP3/NFAT interaction is required to repress expression of IL-2, upregulate expression of the Treg markers CTLA4 and CD25, and confer suppressor function to Tregs. However, FOXP3 is expressed transiently in conventional CD4+ T cells upon TCR stimulation and may lead to T cell hyporesponsiveness. We found that a short synthetic peptide able to inhibit FOXP3/NFAT interaction impaired suppressor activity of conventional Tregs in vitro. Specific inhibition of FOXP3/NFAT interaction with this inhibitory peptide revealed that FOXP3 downregulates NFAT-driven promoter activity of CD40L and IL-17. Inhibition of FOXP3/NFAT interaction upregulated CD40L expression on effector T cells and enhanced T cell proliferation and IL-2, IFN-γ, IL-6, or IL-17 production in response to TCR stimulation. The inhibitory peptide impaired effector T cell conversion into induced Tregs in the presence of TGF-β. Moreover, in vivo peptide administration showed antitumor efficacy in mice bearing Hepa129 or TC1 tumor cells when combined with sorafenib or with an antitumor vaccine, respectively. Our results suggest that inhibition of NFAT/FOXP3 interaction might improve antitumor immunotherapies.
Impact of a fellowship program for faculty development on the self-efficacy beliefs of health professions teachers: A longitudinal study

Background: Teachers’ belief in their ability to teach influences how much of the new knowledge and skills gained during faculty development (FD) programs are actually implemented at the workplace. Aim: To study the effect of a longitudinal FD program on the self-efficacy beliefs (SEB) of teachers of health professions using quasi-experimental methodology. Methods: The SEB of 70 teachers of health professions enrolling for a longitudinal FD program at three sites in India and one site in South Africa and an equal number of comparable controls were measured using the “teacher efficacy belief systems-self” (TEBS-self) scale. The scale was re-administered at 6 and 12 months to both the groups. Results: Teachers enrolled in the program had lower scores than controls at the beginning of the program but demonstrated a significant increase at 6 months with an effect size of 0.56. The 12-month scores demonstrated a further rise in the participating teachers. The control group maintained the scores but did not show any significant change either at 6 or at 12 months. Conclusion: Longitudinal FD program has positive effect on SEB of teachers.
Epigenetic Downregulation of SFRP4 Contributes to Epidermal Hyperplasia in Psoriasis

Psoriasis is a chronic recurrent inflammatory skin disorder characterized by the dysregulated cross-talk between epidermal keratinocytes and immune cells, leading to keratinocyte hyperproliferation. Several studies demonstrated that Wnt pathway genes were differentially expressed in psoriatic plaques and likely were involved in the pathophysiology of disease. However, the molecular mechanisms underlying Wnt signaling regulation in epidermal hyperplasia in psoriasis remain largely unknown. We report that the expression of secreted frizzled-related protein (SFRP) 4, a negative regulator of the Wnt signaling pathway, was diminished in lesional skin of mouse models and patients with psoriasis. SFRP4 directly inhibited excessive keratinocyte proliferation evoked by proinflammatory cytokines in vitro. Pharmacological inhibition of Wnt signaling or intradermal injection of SFRP4 decreased the severity of the psoriasiform skin phenotype in vivo, including decreased acanthosis and reduced leukocyte infiltration. Mechanistically, we identified that aberrant promoter methylation resulted in epigenetic downregulation of SFRP4 in inflamed skin of patients with psoriasis and in the IL-23–induced mouse model. Our findings suggest that this epigenetic event is critically involved in the pathogenesis of psoriasis, and the downregulation of SFRP4 by CpG island methylation is one possible mechanism contributing to the hyperplasia of epidermis in the disease.
Frizzled-6 Regulates Hematopoietic Stem/Progenitor Cell Survival and Self-Renewal

Adult hematopoietic stem/progenitor cell (HSPC) numbers remain stable in the absence of external stressors. After bone marrow (BM) transplant, HSPCs need to expand substantially to repopulate the BM and replenish the peripheral blood cell pool. In this study, we show that a noncanonical Wnt receptor, Frizzled-6 (Fzd6), regulates HSPC expansion and survival in a hematopoietic cell-intrinsic manner. Fzd6 deficiency increased the ratio of Flt3hi multipotent progenitors to CD150+ stem cells in the mouse BM, suggesting defective stem cell maintenance. Competitive transplantation experiments demonstrated that Fzd6−/− HSPCs were able to home to the BM but were severely impaired in their capacity to reconstitute a lethally irradiated host. Lack of Fzd6 resulted in a strong activation of caspase-3 and a gradual loss of donor HSPCs and peripheral blood granulocytes. Fzd6 was also necessary for the efficient HSPC expansion during emergency hematopoiesis. Mechanistically, Fzd6 is a negative regulator of Cdc42 clustering in polarized cells. Furthermore, β-catenin–dependent signaling may be disinhibited in Fzd6−/− HSPCs. Collectively, our data reveal that Fzd6 has an essential role in HSPC maintenance and survival. Noncanonical Wnt–Fzd6 signaling pathway could thus present an interesting target for promoting HSPC expansion and multilineage hematopoietic recovery after transplant.
International Food Risk Analysis Journal

Fortification of foodstuffs with folic acid is mandatory in many countries. Although the effect of folic acid in reducing neural tube defects in utero is well accepted, questions have been raised about possible adverse effects of higher intakes of folic acid on adult health. An increase in colorectal cancer and some other cancers has been postulated. As part of a larger fortification monitoring program in Australia, we conducted a systematic review of trials of folic acid for these outcomes. We found 26 trials using between 0.420mg folic acid/day which reported all-cause mortality or the incidence of specified cancers or recurrence of colorectal adenoma. Using the in-trial follow-up data, the relative risks were 1.04 for total incident cancer (13 studies), 1.0 for colorectal and lung cancers, 0.82 for breast cancer, 1.16 for prostate cancer, 0.97 for the recurrence of colorectal adenoma and 1.11 for the recurrence of advanced colorectal adenoma. There was no association with all-cause mortality (relative risk=0.99, 23 studies). None of the relative risks were statistically significant at the customary alpha level. Our findings are similar to those of previous meta-analyses that have used different inclusion criteria to select studies.
Genetic Vaccines To Potentiate the Effective CD103+ Dendritic Cell–Mediated Cross-Priming of Antitumor Immunity

The development of effective cancer vaccines remains an urgent, but as yet unmet, clinical need. This deficiency is in part due to an incomplete understanding of how to best invoke dendritic cells (DC) that are crucial for the induction of tumor-specific CD8+ T cells capable of mediating durable protective immunity. In this regard, elevated expression of the transcription factor X box–binding protein 1 (XBP1) in DC appears to play a decisive role in promoting the ability of DC to cross-present Ags to CD8+ T cells in the therapeutic setting. Delivery of DNA vaccines encoding XBP1 and tumor Ag to skin DC resulted in increased IFN-α production by plasmacytoid DC (pDC) from skin/tumor draining lymph nodes and the cross-priming of Ag-specific CD8+ T cell responses associated with therapeutic benefit. Antitumor protection was dependent on cross-presenting Batf3+ DC, pDC, and CD8+ T cells. CD103+ DC from the skin/tumor draining lymph nodes of the immunized mice appeared responsible for activation of Ag-specific naive CD8+ T cells, but were dependent on pDC for optimal effectiveness. Similarly, human XBP1 improved the capacity of human blood- and skin-derived DC to activate human T cells. These data support an important intrinsic role for XBP1 in DC for effective cross-priming and orchestration of Batf3+ DC–pDC interactions, thereby enabling effective vaccine induction of protective antitumor immunity.
Vitamin E Isoform γ-Tocotrienol Downregulates House Dust Mite–Induced Asthma

Inflammation and oxidative damage contribute to the pathogenesis of asthma. Although corticosteroid is the first-line treatment for asthma, a subset of patients is steroid resistant, and chronic steroid use causes side effects. Because vitamin E isoform γ-tocotrienol possesses both antioxidative and anti-inflammatory properties, we sought to determine protective effects of γ-tocotrienol in a house dust mite (HDM) experimental asthma model. BALB/c mice were sensitized and challenged with HDM. Bronchoalveolar lavage (BAL) fluid was assessed for total and differential cell counts, oxidative damage biomarkers, and cytokine levels. Lungs were examined for cell infiltration and mucus hypersecretion, as well as the expression of antioxidants and proinflammatory biomarkers. Sera were assayed for IgE and γ-tocotrienol levels. Airway hyperresponsiveness in response to methacholine was measured. γ-Tocotrienol displayed better free radical–neutralizing activity in vitro and inhibition of BAL fluid total, eosinophil, and neutrophil counts in HDM mouse asthma in vivo, as compared with other vitamin E isoforms, including α-tocopherol. Besides, γ-tocotrienol abated HDM-induced elevation of BAL fluid cytokine and chemokine levels, total reactive oxygen species and oxidative damage biomarker levels, and of serum IgE levels, but it promoted lung-endogenous antioxidant activities. Mechanistically, γ-tocotrienol was found to block nuclear NF-κB level and enhance nuclear Nrf2 levels in lung lysates to greater extents than did α-tocopherol and prednisolone. More importantly, γ-tocotrienol markedly suppressed methacholine-induced airway hyperresponsiveness in experimental asthma. To our knowledge, we have shown for the first time the protective actions of vitamin E isoform γ-tocotrienol in allergic asthma.
Effects of Artemisia lanata Extract on Reproductive Parameters of Female Rats

Objective: Until date, there is no report on safety of Artemisia lanata. This study aimed to determine the possible undesirable effects of A. lanata on reproduction of female rats. Materials and Methods: The pregnant rats were treated (i.p.) with vehicle or 200 and 400 mg/kg of A. lanata hydroalcoholic extract from the 2-8 day of pregnancy. Then, number and weight of neonates, duration of pregnancy, and percent of dead fetuses were determined. Furthermore, cytotoxicity of this plant was tested using fibroblast (L929) and Chinese hamster ovary (Cho) cell lines. Results: The A. lanata had no significant effect on duration of pregnancy, average number of neonates, and weight of neonates. However, administration of 200 and 400 mg/kg of the extract led to 30 and 44% abortion in animals, respectively. The extract at concentrations ≥ 200 µg/ml significantly (P < 0.001) inhibited the proliferation of L929 fibroblast cells. Regarding the Cho cells, the extract induced toxicity only at concentration of 800 µg/ml (P < 0.010). Conclusion: Our results showed that continuous consumption of A. lanata in pregnancy may increase the risk of abortion and also may have toxic effect on some cells.
Immunosuppression and Aberrant T Cell Development in the Absence of N-Myristoylation

N-myristoylation refers to the attachment of myristic acid to the N-terminal glycine of proteins and substantially affects their intracellular targeting and functions. The thymus represents an organ with a prominent N-myristoylation activity. To elucidate the role of protein N-myristoylation for thymocyte development, we generated mice with a T cell lineage–specific deficiency in N-myristoyl transferase (Nmt)1 and 2. Depletion of Nmt activity in T cells led to a defective transmission of TCR signals, a developmental blockage of thymocytes at the transition from double-negative 3 to 4 stages, and a reduction of all the following stages. We could demonstrate that Lck and myristoylated alanine-rich C kinase substrate, two main myristoylated kinases in T cells, were mislocalized in the absence of Nmt activity. N-myristoylation was also indispensable for early and distal TCR signaling events such as CD3ζ, Zap70, and Erk activation and for release of cytokines such as IFN-γ and IL-2. As a consequence, the initiation and propagation of the TCR signaling cascade was severely impaired. Furthermore, we showed that the absence of myristoylation had an immunosuppressive effect on T cells in vivo after treatment with CpG and stimulation of the TCR with the staphylococcal enterotoxin B superantigen. Therefore, protein myristoylation is indispensable in T cell development and activation and its inhibition might offer a novel strategy to achieve immunosuppression.
Pharmacogenomics in Cardiovascular Medicine

The completion of the Human Genome Project (HGP) holds promise for further insight into how genetic differences contribute to an individual's response to a medicine(s). Even before the completion of the HGP, cardiovascular medicine was thrust into the arena of pharmacogenomics by the observation that many drugs, cardiovascular and noncardiovascular, promote cardiac arrhythmias. It is now recognized that these adverse responses as well as beneficial responses to cardiovascular medicines can be influenced by alterations in the genes for metabolizing enzymes, drug transporters, and drug targets. To the present, much basic information regarding gene–drug interactions has accumulated, but translation to clinical care has been slow. It is anticipated that the pace of clinical cardiovascular pharmacogenomics will increase as the result of better‐designed studies and technological advances. The final adoption of this area of investigation into clinical practice will also be influenced by financial, psychosocial, and legal factors. Drug Dev. Res. 62:180–190, 2004. © 2004 Wiley‐Liss, Inc.
B Cell–Specific MHC Class II Deletion Reveals Multiple Nonredundant Roles for B Cell Antigen Presentation in Murine Lupus

B cells have both Ab-dependent and Ab-independent functions in systemic autoimmune diseases, including systemic lupus erythematosus (SLE). Ab-independent functions are known to be important, because mice with B cells but no secreted Ig have severe disease. These functions could include roles in lymphoid development, cytokine secretion, and Ag presentation; however, these possibilities have not been directly tested in SLE models. In this study, we show by lineage-specific ablation of MHC class II (MHCII) that B cell Ag presentation plays a nonredundant role in CD4+ T cell activation and effector differentiation in the MRL.Faslpr mouse model of SLE. MHCII-mediated interactions between B and T cells further promote B cell proliferation and differentiation, and, in fact, inefficient MHCII deletion on B cells led to strong selection of escaped cells in activated and plasmablast compartments, further underscoring the central role of B cell Ag presentation. Despite the leakiness in the system, B cell–specific MHCII deletion resulted in substantially ameliorated clinical disease. Hence, B cell Ag presentation is critical for T and B cell activation and differentiation, as well as target organ damage.
Impairment of Mature B Cell Maintenance upon Combined Deletion of the Alternative NF-κB Transcription Factors RELB and NF-κB2 in B Cells

BAFF is critical for the survival and maturation of mature B cells. BAFF, via BAFFR, activates multiple signaling pathways in B cells, including the alternative NF-κB pathway. The transcription factors RELB and NF-κB2 (p100/p52) are the downstream mediators of the alternative pathway; however, the B cell–intrinsic functions of these NF-κB subunits have not been studied in vivo using conditional alleles, either individually or in combination. We in this study report that B cell–specific deletion of relb led to only a slight decrease in the fraction of mature splenic B cells, whereas deletion of nfkb2 caused a marked reduction. This phenotype was further exacerbated upon combined deletion of relb and nfkb2 and most dramatically affected the maintenance of marginal zone B cells. BAFF stimulation, in contrast to CD40 activation, was unable to rescue relb/nfkb2-deleted B cells in vitro. RNA-sequencing analysis of BAFF-stimulated nfkb2-deleted versus normal B cells suggests that the alternative NF-κB pathway, in addition to its critical role in BAFF-mediated cell survival, may control the expression of genes involved in the positioning of B cells within the lymphoid microenvironment and in the establishment of T cell–B cell interactions. Thus, by ablating the downstream transcription factors of the alternative NF-κB pathway specifically in B cells, we identify in this study a critical role for the combined activity of the RELB and NF-κB2 subunits in B cell homeostasis that cannot be compensated for by the canonical NF-κB pathway under physiological conditions.
Impact of Toxoplasma gondii on Dendritic Cell Subset Function in the Intestinal Mucosa

The function of mucosal dendritic cell (DC) subsets in immunity and inflammation is not well understood. In this study, we define four DC subsets present within the lamina propria and mesenteric lymph node compartments based on expression of CD103 and CD11b. Using IL-12p40 YFP (Yet40) reporter mice, we show that CD103+CD11b− mucosal DCs are primary in vivo sources of IL-12p40; we also identified CD103−CD11b− mucosal DCs as a novel population producing this cytokine. Infection was preferentially found in CD11b+ DCs that were negative for CD103. Lamina propria DCs containing parasites were negative for IL-12p40. Instead, production of the cytokine was strictly a property of noninfected cells. We also show that vitamin A metabolism, as measured by ALDH activity, was preferentially found in CD103+CD11b+ DC and was strongly downregulated in all mucosal DC subsets during infection. Finally, overall apoptosis of lamina propria DC subsets was increased during infection. Combined, these results highlight the ability of intestinal Toxoplasma infection to alter mucosal DC activity at both the whole population level and at the level of individual subsets.
Cutting Edge: Plasmacytoid Dendritic Cells in Late-Stage Lupus Mice Defective in Producing IFN-α

Plasmacytoid dendritic cells (pDCs) are professional type I IFN producers believed to promote lupus. However, questions exist about whether they function at the same level throughout the course of lupus disease. We analyzed high-purity pDCs sorted from lupus mice. Although pDCs produced a large amount of IFN-α during disease initiation, those sorted from late-stage lupus mice were found to be defective in producing IFN-α. These pDCs expressed an increased level of MHC, suggesting a functional drift to Ag presentation. We examined the potential mechanism behind the defect and identified a novel transcriptional factor, Foxj2, which repressed the expression of several genes in pDCs, but not IFN-α. Dysregulation in pDCs appears to be predisposed, because they exhibited an altered transcriptional profile before the onset of clinical signs. Our results suggest that pDCs do not function the same throughout the disease course and lose the ability to produce IFN-α in late-stage lupus mice.
State of the Science: Women and the Nonpharmacological Treatment of Substance Abuse

BACKGROUND: Substance abuse affects men and women differently, and as a result, treatment programs should be designed specific to their unique needs. The nonpharmacological treatment of substance abuse among women has been largely neglected in the literature. OBJECTIVE: The purpose of this review was to analyze critically the existing literature related to the nonpharmacological treatment of substance abuse among women. The methodological rigor of existing research was critiqued and gaps in knowledge identified. DESIGN : The databases Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, Sociological Abstracts, and MEDLINE were searched using the key words women and substance abuse treatment. Studies included in the review were those that were published between 1975 and 2003 and were related to the nonpharmacological treatment of substance abuse for women. RESULTS: Forty-three articles were reviewed. Evidence suggests that there are gender and cultural differences related to substance abuse. There is a dearth of research related to the effectiveness of treatment interventions designed specifically for women who abuse substances. The research that exists is limited in its theoretical foundation and methodological rigor. CONCLUSIONS : Few treatment programs reflect gender and cultural differences, leaving gaps in substance abuse treatment among women. Furthermore, existing research related to women and substance abuse treatment lacks a robust scientific foundation. Future research should be theoretically based and methodologically sound to advance the evidence base of substance abuse treatment for women.
Monocyte-Derived Dendritic Cells Promote Th Polarization, whereas Conventional Dendritic Cells Promote Th Proliferation

Monocyte-derived dendritic cells (moDCs) dramatically increase in numbers upon infection and inflammation; accordingly, we found that this also occurs during allogeneic responses. Despite their prominence, how emergent moDCs and resident conventional DCs (cDCs) divide their labor as APCs remain undefined. Hence, we compared both direct and indirect presentation by murine moDCs versus cDCs. We found that, despite having equivalent MHC class II expression and in vitro survival, moDCs were 20-fold less efficient than cDCs at inducing CD4+ T cell proliferation through both direct and indirect Ag presentation. Despite this, moDCs were more potent at inducing Th1 and Th17 differentiation (e.g., 8-fold higher IFN-γ and 2-fold higher IL-17A in T cell cocultures), whereas cDCs induced 10-fold higher IL-2 production. Intriguingly, moDCs potently reduced the ability of cDCs to stimulate T cell proliferation in vitro and in vivo, partially through NO production. We surmise that such division of labor between moDCs and cDCs has implications for their respective roles in the immune response.