Skewed distribution of proinflammatory CD4+CD28null T cells in rheumatoid arthritis

Expanded populations of CD4+ T cells lacking the co-stimulatory molecule CD28 (CD4+CD28null T cells) have been reported in several inflammatory disorders. In rheumatoid arthritis, increased frequencies of CD4+CD28null T cells in peripheral blood have previously been associated with extra-articular manifestations and human cytomegalovirus (HCMV) infection, but their presence in and contribution to joint manifestations is not clear. In the present article we investigated the distribution of CD4+CD28null T cells in the synovial membrane, synovial fluid and peripheral blood of RA patients, and analysed the association with erosive disease and anti-citrullinated protein antibodies. CD4+CD28null T cells were infrequent in the synovial membrane and synovial fluid, despite significant frequencies in the circulation. Strikingly, the dominant TCR-Vβ subsets of CD4+CD28null T cells in peripheral blood were often absent in synovial fluid. CD4+CD28null T cells in blood and synovial fluid showed specificity for HCMV antigens, and their presence was clearly associated with HCMV seropositivity but not with anti-citrullinated protein antibodies in the serum or synovial fluid, nor with erosive disease. Together these data imply a primary role for CD4+CD28null T cells in manifestations elsewhere than in the joints of patients with HCMV-seropositive rheumatoid arthritis

Screening and diagnosing depression in women visiting GPs' drop in clinic in Primary Health Care

<p>Abstract</p> <p>Background</p> <p>Only half of all depressions are diagnosed in Primary Health Care (PHC). Depression can remain undetected for a long time and entail high costs for care and low quality of life for the individuals. Drop in clinic is a common form of organizing health care; however the visits are short and focus on solving the most urgent problems. The aim of this study was to investigate the prevalence and severity of depression among women visiting the GPs' drop in clinic and to identify possible clues for depression among women.</p> <p>Methods</p> <p>The two-stage screening method with "high risk feedback" was used. Beck's Depression Inventory (BDI) was used to screen 155 women visiting two GPs' drop in clinic. Women who screened positive (BDI score ≥10) were invited by the GP to a repeat visit. Major depression (MDD) was diagnosed according to DSM-IV criteria and the severity was assessed with Montgomery-Asberg Depression Rating Scale (MADRS). Women with BDI score <10 constituted a control group. Demographic characteristics were obtained by questionnaire. Chart notations were examined with regard to symptoms mentioned at the index visit and were categorized as somatic or mental.</p> <p>Results</p> <p>The two-stage method worked well with a low rate of withdrawals in the second step, when the GP invited the women to a repeat visit. The prevalence of depression was 22.4% (95% CI 15.6–29.2). The severity was mild in 43%, moderate in 53% and severe in 3%. The depressed women mentioned mental symptoms significantly more often (69%) than the controls (15%) and were to a higher extent sick-listed for a longer period than 14 days. Nearly one third of the depressed women did not mention mental symptoms. The majority of the women who screened as false positive for depression had crisis reactions and needed further care from health professionals in PHC. Referrals to a psychiatrist were few and revealed often psychiatric co-morbidity.</p> <p>Conclusion</p> <p>The prevalence of previously undiagnosed depression among women visiting GPs' drop in clinic was high. Clues for depression were identified in the depressed women's symptom presentation; they often mention mental symptoms when they visit the GP for somatic reasons e.g. respiratory infections. We suggest that GPs do selective screening for depression when women mention mental symptoms and offer to schedule a repeat visit for follow-up rather than just recommending that the patient return if the mental symptoms do not disappear.</p

Galiellalactone Inhibits Stem Cell-Like ALDH-Positive Prostate Cancer Cells

Galiellalactone is a potent and specific inhibitor of STAT3 signaling which has been shown to possess growth inhibitory effects on prostate cancer cells expressing active STAT3. In this study we aimed to investigate the effect of galiellalactone on prostate cancer stem cell-like cells. We explored the expression of aldehyde dehydrogenase (ALDH) as a marker for cancer stem cell-like cells in different human prostate cancer cell lines and the effects of galiellalactone on ALDH expressing (ALDH+) prostate cancer cells. ALDH+ subpopulations were detected and isolated from the human prostate cancer cell lines DU145 and long-term IL-6 stimulated LNCaP cells using ALDEFLUOR® assay and flow cytometry. In contrast to ALDH− cells, ALDH+ prostate cancer cells showed cancer stem cell-like characteristics such as increased self-renewing and colony forming capacity and tumorigenicity. In addition, ALDH+ cells showed an increased expression of putative prostate cancer stem cell markers (CD44 and integrin α2β1). Furthermore, ALDH+ cells expressed phosphorylated STAT3. Galiellalactone treatment decreased the proportion of ALDH+ prostate cancer cells and induced apoptosis of ALDH+ cells. The gene expression of ALDH1A1 was downregulated in vivo in galiellalactone treated DU145 xenografts. These findings emphasize that targeting the STAT3 pathway in prostate cancer cells, including prostate cancer stem cell-like cells, is a promising therapeutic approach and that galiellalactone is an interesting compound for the development of future prostate cancer drugs

KRAB–Zinc Finger Proteins and KAP1 Can Mediate Long-Range Transcriptional Repression through Heterochromatin Spreading

Krüppel-associated box domain-zinc finger proteins (KRAB–ZFPs) are tetrapod-specific transcriptional repressors encoded in the hundreds by the human genome. In order to explore their as yet ill-defined impact on gene expression, we developed an ectopic repressor assay, allowing the study of KRAB–mediated transcriptional regulation at hundreds of different transcriptional units. By targeting a drug-controllable KRAB–containing repressor to gene-trapping lentiviral vectors, we demonstrate that KRAB and its corepressor KAP1 can silence promoters located several tens of kilobases (kb) away from their DNA binding sites, with an efficiency which is generally higher for promoters located within 15 kb or less. Silenced promoters exhibit a loss of histone H3-acetylation, an increase in H3 lysine 9 trimethylation (H3K9me3), and a drop in RNA Pol II recruitment, consistent with a block of transcriptional initiation following the establishment of silencing marks. Furthermore, we reveal that KRAB–mediated repression is established by the long-range spreading of H3K9me3 and heterochromatin protein 1 β (HP1β) between the repressor binding site and the promoter. We confirm the biological relevance of this phenomenon by documenting KAP1–dependent transcriptional repression at an endogenous KRAB–ZFP gene cluster, where KAP1 binds to the 3′ end of genes and mediates propagation of H3K9me3 and HP1β towards their 5′ end. Together, our data support a model in which KRAB/KAP1 recruitment induces long-range repression through the spread of heterochromatin. This finding not only suggests auto-regulatory mechanisms in the control of KRAB–ZFP gene clusters, but also provides important cues for interpreting future genome-wide DNA binding data of KRAB–ZFPs and KAP1

Correction for Johansson et al., An open challenge to advance probabilistic forecasting for dengue epidemics.

Correction for “An open challenge to advance probabilistic forecasting for dengue epidemics,” by Michael A. Johansson, Karyn M. Apfeldorf, Scott Dobson, Jason Devita, Anna L. Buczak, Benjamin Baugher, Linda J. Moniz, Thomas Bagley, Steven M. Babin, Erhan Guven, Teresa K. Yamana, Jeffrey Shaman, Terry Moschou, Nick Lothian, Aaron Lane, Grant Osborne, Gao Jiang, Logan C. Brooks, David C. Farrow, Sangwon Hyun, Ryan J. Tibshirani, Roni Rosenfeld, Justin Lessler, Nicholas G. Reich, Derek A. T. Cummings, Stephen A. Lauer, Sean M. Moore, Hannah E. Clapham, Rachel Lowe, Trevor C. Bailey, Markel García-Díez, Marilia Sá Carvalho, Xavier Rodó, Tridip Sardar, Richard Paul, Evan L. Ray, Krzysztof Sakrejda, Alexandria C. Brown, Xi Meng, Osonde Osoba, Raffaele Vardavas, David Manheim, Melinda Moore, Dhananjai M. Rao, Travis C. Porco, Sarah Ackley, Fengchen Liu, Lee Worden, Matteo Convertino, Yang Liu, Abraham Reddy, Eloy Ortiz, Jorge Rivero, Humberto Brito, Alicia Juarrero, Leah R. Johnson, Robert B. Gramacy, Jeremy M. Cohen, Erin A. Mordecai, Courtney C. Murdock, Jason R. Rohr, Sadie J. Ryan, Anna M. Stewart-Ibarra, Daniel P. Weikel, Antarpreet Jutla, Rakibul Khan, Marissa Poultney, Rita R. Colwell, Brenda Rivera-García, Christopher M. Barker, Jesse E. Bell, Matthew Biggerstaff, David Swerdlow, Luis Mier-y-Teran-Romero, Brett M. Forshey, Juli Trtanj, Jason Asher, Matt Clay, Harold S. Margolis, Andrew M. Hebbeler, Dylan George, and Jean-Paul Chretien, which was first published November 11, 2019; 10.1073/pnas.1909865116. The authors note that the affiliation for Xavier Rodó should instead appear as Catalan Institution for Research and Advanced Studies (ICREA) and Climate and Health Program, Barcelona Institute for Global Health (ISGlobal). The corrected author and affiliation lines appear below. The online version has been corrected

An open challenge to advance probabilistic forecasting for dengue epidemics.

A wide range of research has promised new tools for forecasting infectious disease dynamics, but little of that research is currently being applied in practice, because tools do not address key public health needs, do not produce probabilistic forecasts, have not been evaluated on external data, or do not provide sufficient forecast skill to be useful. We developed an open collaborative forecasting challenge to assess probabilistic forecasts for seasonal epidemics of dengue, a major global public health problem. Sixteen teams used a variety of methods and data to generate forecasts for 3 epidemiological targets (peak incidence, the week of the peak, and total incidence) over 8 dengue seasons in Iquitos, Peru and San Juan, Puerto Rico. Forecast skill was highly variable across teams and targets. While numerous forecasts showed high skill for midseason situational awareness, early season skill was low, and skill was generally lowest for high incidence seasons, those for which forecasts would be most valuable. A comparison of modeling approaches revealed that average forecast skill was lower for models including biologically meaningful data and mechanisms and that both multimodel and multiteam ensemble forecasts consistently outperformed individual model forecasts. Leveraging these insights, data, and the forecasting framework will be critical to improve forecast skill and the application of forecasts in real time for epidemic preparedness and response. Moreover, key components of this project-integration with public health needs, a common forecasting framework, shared and standardized data, and open participation-can help advance infectious disease forecasting beyond dengue

CD4CD28T cells from peripheral blood and synovial fluid show human cytomegalovirus specificity

<p><b>Copyright information:</b></p><p>Taken from "Skewed distribution of proinflammatory CD4CD28T cells in rheumatoid arthritis"</p><p>http://arthritis-research.com/content/9/5/R87</p><p>Arthritis Research & Therapy 2007;9(5):R87-R87.</p><p>Published online 7 Sep 2007</p><p>PMCID:PMC2212553.</p><p></p> The functional capacity of CD4CD28T cells in peripheral blood (PB) and synovial fluid (SF) was investigated after stimulation of mononuclear cells from paired PB and SF from rheumatoid arthritis patients by plate-bound anti-CD3 antibodies. The reactivity of CD4CD28T cells in paired PB and SF to human cytomegalovirus (HCMV) antigens was analysed after stimulation by the pp65 or immediate early (IE) antigens

Skewed distribution of CD4CD28T cells in synovial fluid and peripheral blood

<p><b>Copyright information:</b></p><p>Taken from "Skewed distribution of proinflammatory CD4CD28T cells in rheumatoid arthritis"</p><p>http://arthritis-research.com/content/9/5/R87</p><p>Arthritis Research & Therapy 2007;9(5):R87-R87.</p><p>Published online 7 Sep 2007</p><p>PMCID:PMC2212553.</p><p></p> Paired samples of synovial fluid (SF) and peripheral blood (PB) from 128 rheumatoid arthritis patients were compared for the frequency of CD4CD28T cells by flow cytometry. Frequencies of CD4CD28T cells in SF tend to be higher in patients with large populations in PB. Comparison of the frequency of CD4CD28T cells in SF from two different synovial compartments. Open circle, elbow; open squares, shoulder joints. Frequencies of CD4CD28T cells in SF and PB in patients seronegative and seropositive for human cytomegalovirus (HCMV). Frequencies of CD4CD28T cells in paired PB and SF of patients seropositive for HCMV