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SUMMARY Hormonal dysfunction involving the hypothalamic-pituitary-adrenal (HPA) axis, prolactin (PRL) secretion and sex hormone status has been supposed to contribute to the development or persistence of rheumatoid arthritis (RA). In addition, a reduced number of glucocorticoid receptors on circulating lymphocytes has been found in patients with RA. However, so far most studies have been performed in pre-treated patients. A combined test for total anterior pituitary reserve was performed in 10 patients with newly diagnosed untreated RA. Before and after stimulation with the respective hypothalamic releasing hormones, RA patients showed no difference in plasma concentrations of adrenocorticotrophic hormone (ACTH), cortisol, prolactin (PRL) and thyroid-stimulating hormone (TSH) when compared to healthy controls. In contrast, the growth hormone (GH) response to growth hormone-releasing hormone (GHRH) was blunted in RA patients. The hypothalamic-pituitary-thyroid/gonadal and adrenal axes seem to be unaltered in RA. However, if one considers the presence of chronic inflammation, normal plasma ACTH and cortisol concentrations must be considered as inappropriately low. The observed blunted GH release could be mediated by cytokines (e.g. IL-1), which are known to be elevated in RA. [ABSTRACT FROM PUBLISHER]

Beall's list is widely used to identify potentially predatory journals. With this study, we aim to investigate the impact of Beall's list on the perception of listed journals as well as on the publication and citation behavior of the scientific community. We performed comprehensive bibliometric analyses of data extracted from the ISSN database, PubMed, PubMed Central (PMC), Crossref, Scopus and Web of Science. Citation analysis was performed by data extracted from the Crossref Cited-by database. At the time of analysis, Beall's list consisted of 1,289 standalone journals and 1,162 publishers, which corresponds to 21,735 individual journals. Of these, 3,206 (38.8%) were located in the United States, 2,484 in India (30.0%), and 585 in United Kingdom (7.1%). The majority of journals were listed in the ISSN database (n = 8,266), Crossref (n = 5,155), PubMed (n = 1,139), Scopus (n = 570), DOAJ (n = 224), PMC (n = 135) or Web of Science (n = 50). The number of articles published by journals on Beall's list as well as on the DOAJ continuously increased from 2011 to 2017. In 2018, the number of articles published by journals on Beall's list decreased. Journals on Beall's list were more often cited when listed in Web of Science (CI 95% 5.5 to 21.5; OR = 10.7) and PMC (CI 95% 6.3 to 14.1; OR = 9.4). It seems that the importance of Beall's list for the scientific community is overestimated. In contrast, journals are more likely to be selected for publication or citation when indexed by commonly used and renowned databases. Thus, the providers of these databases must be aware of their impact and verify that good publication practice standards are being applied by the journals listed., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Richtig et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: older people remain underrepresented in clinical trials, and evidence generated in younger populations cannot always be generalized to older patients., Objective: to identify key barriers and to discuss solutions to specific issues affecting recruitment and retention of older participants in clinical trials based on experience gained from six current European randomised controlled trials (RCTs) focusing on older people., Methods: a multidisciplinary group of experts including representatives of the six RCTs held two networking conferences and compiled lists of potential barriers and solutions. Every item was subsequently allocated points by each study team according to how important it was perceived to be for their RCTs., Results: the six RCTs enrolled 7,612 older patients. Key barriers to recruitment were impaired health status, comorbidities and diverse health beliefs including priorities within different cultural systems. All trials had to increase the number of recruitment sites. Other measures felt to be effective included the provision of extra time, communication training for the study staff and a re-design of patient information. Key barriers for retention included the presence of severe comorbidities and the occurrence of adverse events. Long study duration, frequent study visits and difficulties accessing the study site were also mentioned. Solutions felt to be effective included spending more time maintaining close contact with the participants, appropriate measures to show appreciation and reimbursement of travel arrangements., Conclusion: recruitment and retention of older patients in trials requires special recognition and a targeted approach. Our results provide scientifically-based practical recommendations for optimizing future studies in this population., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

We prospectively performed a longitudinal analysis of circulating tumor DNA (ctDNA) from 149 plasma samples and CT scans in Stage III and IV metastatic melanoma patients ( n = 20) treated with targeted agents or immunotherapy using two custom next-generation sequencing (NGS) Ion AmpliSeq™ HD panels including 60 and 81 amplicons in 18 genes, respectively. Concordance of matching cancer-associated mutations in tissue and plasma was 73.3%. Mutant allele frequency (MAF) levels showed a range from 0.04% to 28.7%, well detectable with NGS technologies utilizing single molecule tagging like the AmpliSeq™ HD workflow. Median followup time of the tissue and/or plasma positive cohort ( n = 15) was 24.6 months and median progression-free survival (PFS) was 7.8 months. Higher MAF ≥ 1% at baseline was not significantly associated with a risk of progression (Odds Ratio = 0.15; p = 0.155). Although a trend could be seen, MAF levels did not differ significantly over time between patients with and without a PFS event ( p = 0.745). Depending on the cell-free DNA amount, NGS achieved a sensitivity down to 0.1% MAF and allowed for parallel analysis of multiple mutations and previously unknown mutations. Our study indicates that NGS gene panels could be useful for monitoring disease burden during therapy with ctDNA in melanoma patients.

The transfer of genetic information into living cells is a powerful tool to manipulate their protein expression by the regulation of protein synthesis. This can be used for the treatment of genetically caused diseases (gene therapy). However, the systemic application of genes is associated with a number of problems, such as a targeted gene delivery and potential side effects. Here we present a method for the spatial application of nanoparticle-based gene therapy. Titanium was electrophoretically coated with DNA-functionalized calcium phosphate nanoparticles. NIH3T3 cells and HeLa cells were transfected with pcDNA3-EGFP. We monitored the transfection in vitro by fluorescence microscopy, flow cytometry, and Western Blot analysis. By coating a transparent substrate, i.e., indium tin oxide (ITO), with nanoparticles, we followed the transfection by live cell imaging.

There is controversy about the origin of the alterations in T helper 1 (TH1)/TH2 cell activity after major surgical procedures such as on-pump cardiac surgery. We hypothesized that a postoperative decrease in interferon (IFN) gamma-producing TH1 lymphocyte activity may be the sole cause of this TH1/TH2 shift and that the addition of recombinant IL-12 can reverse TH1 suppression. Peripheral blood mononuclear cell fractions from 20 low-risk elective cardiac surgery patients were analyzed preoperatively (d0) and on the first (d1), third (d3), and sixth (d6) postoperative days. We determined the absolute numbers of T helper lymphocytes, IFN-gamma-producing TH1 cells, and IL-4-producing TH2 cells after stimulation and measured IFN-gamma and IL-4 levels in the supernatants of stimulated peripheral blood mononuclear cell cultures, absolute monocyte counts, human leukocyte antigen-DR expression, and intracellular IL-12 synthesis under comparable conditions. Recombinant IL-12 alone or in combination with a neutralizing antibody was added. T helper lymphocyte counts were reduced postoperatively from d1 to d6 (P < 0.05). Absolute IFN-gamma- and IL-4-positive T helper lymphocyte counts were reduced on d1 (P < 0.05). Intracellular IL-4 production in T helper lymphocytes remained postoperatively unchanged. Interferon gamma synthesis was significantly reduced until d3 (P = 0.001) and significantly increased after IL-12 addition (P < 0.05). This effect was reversed by the addition of a neutralizing anti-IL-12 antibody. The TH1/TH2 shift after cardiac surgery seems to be caused primarily by a decrease in cellular IFN-gamma synthesis in TH1 lymphocytes. Because TH1 suppression can be reversed by IL-12, it is more likely to be the result of altered stimulation pathways than cellular defects.

Background: Despite low-dose gluco-corticoid (GC) treatment, many patients with rheumatoid arthritis (RA) require additional flare therapy with GC at higher doses. Since low dose GC has been suggested to confer resistance to higher doses, we aimed to assess if resistance was detectable on the clinical level in patients with active RA., Methods: Eighty-nine patients with active RA (Disease Activity Score 28, DAS28>3.2; mean age 54.5 years, mean duration of RA 9.7 years) were consecutively enrolled into a one-week trial of a total of 250 mg prednisolone. We compared improvement of the DAS28 and the Simplified Disease Activity Index (SDAI) in groups of patients with (n=41) and without (n=48) low-dose GC at baseline (by t-test). In addition, we analyzed changes of all individual core set measures of disease activity using multivariate statistics., Results: All clinical, serological and functional measures improved significantly over one week (p<0.001). Baseline RA activity of patients with and without low-dose GC was on average +/- standard deviation similar among the two groups (DAS28: 4.8+/-1.2 and 4.9+/-1.1; mean SDAI: 26.1+/-14.0 and 25.9+/-13.0, respectively), and likewise there was no difference between the two groups in the final disease activity reached, for both the DAS28 (1.4+/-1.1 vs. 1.1+/-1.0; p=0.14) and the SDAI (11.1+/-13.4 vs. 11.1+/-11.4; p=0.99). Improvement in all individual measures was also not different using a multivariate model (p=0.26)., Conclusion: Pre-treatment with low-dose GC does not appear to portend GC resistance at least clinically, since the responsiveness to GC boosts is unaffected.

Spontaneous growth of myeloid colonies (colony-forming unit-granulocyte-macrophage [CFU-GM]) can be observed in methylcellulose cultures containing peripheral blood mononuclear cells (PB-MNCs) and is supposedly caused by the release of colony-stimulating factors (CSF) by accessory cells. Because of its cytokine synthesis-inhibiting effects on T lymphocytes and monocytes, interleukin-10 (IL-10) may be a potential candidate for indirect modulation of hematopoiesis. We studied the effect of recombinant human IL-10 (rhIL-10) on spontaneous growth of myeloid colonies derived from human PB-MNCs. A total of 10 ng/mL of IL-10 almost completely inhibited spontaneous CFU-GM proliferation (by 95.1%; P < .001, n = 7) in unseparated PB-MNCs. This effect was dose-dependent and specific, because a neutralizing anti-IL-10 antibody was able to prevent IL-10-induced suppression of CFU-GM growth. Spontaneous CFU-GM growth, which required the presence of both monocytes (CD14+ cells) and T lymphocytes (CD3+ cells), was also greatly suppressed by a neutralizing anti-granulocyte-macrophage CSF (GM-CSF) antibody but was only slightly or not at all inhibited by antibodies against G-CSF or IL-3. Moreover, IL-10-suppressed colony growth could be completely restored by the addition of exogenous GM-CSF. Using semiquantitative polymerase chain reaction, we were able to show that GM-CSF transcripts that spontaneously increased in PB-MNCs within 48 hours of culture were markedly reduced by the addition of IL-10. Inhibiton of GM-CSF production in PB-MNCs by IL-10 was also confirmed at the protein level by measuring GM-CSF levels in suspension cultures. Our findings suggest that autonomous CFU-GM growth, resulting from an interaction of monocytes and T lymphocytes, is mainly caused by endogenous GM-CSF release and can be profoundly suppressed by the addition of exogenous IL-10. Considering the strong inhibitory action of IL-10 on GM-CSF production and spontaneous cell growth in vitro, this cytokine may be useful in myeloid malignancies in which autocrine and/or paracrine mechanisms involving GM-CSF are likely to play a pathogenetic role.