Exposure to childhood adversities (CHAD) has been found to be strongly associated with individuals' mental health and social development. Recently, it has been suggested that certain CHAD patterns ...exist in the population, which are more closely related to individuals' later mental health than the simple summation of adversities. The current study aims 1) to establish CHAD patterns based on self-reported child abuse and family dysfunction and 2) to assess their associations with mental disorders and sociodemographic indicators reported in adulthood.
Data used in this cross-sectional study were derived from the representative CoLaus/PsyCoLaus population-based cohort (N = 5111, 35 to 88 years). Latent class analysis was conducted for the identification of CHAD patterns, while their associations with mental disorders and socioeconomic achievements (e. g. education and income) were investigated using correspondence analysis.
Four CHAD patterns emerged. While the majority (70.7%) of the sample showed an overall low adversity pattern (c1), 13.6% had not been raised by both of their biological parents due to divorce or being placed in foster home (c2), 11.0% had been raised by conflictive / dysfunctional / abusive parents (c3), and 4.7% showed high overall adversities (c4). Patterns c3 and c4 were most strongly associated with various mental disorders, especially c3 with internalizing anxiety disorders, while c2 was closely related to lower educational achievement.
Four CHAD patterns characterised by varying levels of child abuse and family dysfunction existed in this community sample. They yielded distinct associations with mental disorders and socioeconomic indicators.
•One of the scarce studies that examine the childhood adversity (CHAD) patterns within randomly selected community samples•CHAD patterns representing different combinations of child abuse and family dysfunction items were established•These patterns showed different clustering profiles with common mental disorders and socioeconomic indicators in adulthood•The conflict-abuse class c3 and the high adversities class c4 were most strongly associated with various mental disorders•The conflict-abuse class c3 was especially closely associated with internalizing anxiety or mood disorders•The separation class c2 was closely related to lower educational achievement
Lower respiratory tract bacterial infections are characterized by neutrophilic inflammation in the airways. The carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 8 is expressed in and ...released by human granulocytes. Our study demonstrates that human granulocytes release CEACAM8 in response to bacterial DNA in a TLR9-dependent manner. Individuals with a high percentage of bronchial lavage fluid (BALF) granulocytes were more likely to have detectable levels of released CEACAM8 in the BALF than those with a normal granulocyte count. Soluble, recombinant CEACAM8-Fc binds to CEACAM1 expressed on human airway epithelium. Application of CEACAM8-Fc to CEACAM1-positive human pulmonary epithelial cells resulted in reduced TLR2-dependent inflammatory responses. These inhibitory effects were accompanied by tyrosine phosphorylation of the immunoreceptor tyrosine-based inhibitory motif (ITIM) of CEACAM1 and by recruitment of the phosphatase SHP-1, which could negatively regulate Toll-like receptor 2-dependent activation of the phosphatidylinositol 3-OH kinase-Akt kinase pathway. Our results suggest a new mechanism by which granulocytes reduce pro-inflammatory immune responses in human airways via secretion of CEACAM8 in neutrophil-driven bacterial infections.
It is a common aim to reduce psychiatric readmissions. Although risk factors for readmissions were described, specific data in the group of patients with potentially aversively experienced ...involuntary admissions are lacking. To better understand underlying mechanisms, it is important to identify factors that are linked to readmissions in this specific patient group, which is the purpose of the current paper.
A four-year cohort of N = 3575 involuntary admissions (IA) was followed-up for subsequent re-hospitalization. Demographic, administrative and clinical factors associated with short- (within 30 days) or long-term (> 30 days) readmissions were examined using logistic regression modelling.
Almost half of all IA cases were readmitted within the observation period, whereof every fifth readmission was within the first month after discharge from the involuntary index hospitalization. Adjusted regression modelling revealed problematic substance use at admission and assisted living or homelessness as risk factors for readmission, while high functioning at discharge, anxiety disorders, no subsequent treatment after discharge or IA due to danger to others were negatively associated with readmission. Factors specifically linked to short-term readmission were substance use and personality disorders, abscondence or discharge by initiation of the clinic, as well as being discharged to any place except the patient's home. There were no specific risk-factors for long-term readmission.
To prevent readmissions after IA, especially for patients at risk, the aim of treatment strategies should be to focus on intensive discharge planning, enable continuous treatment in the outpatient setting, and provide social support.
The relevance of estrogen receptor (ER) expression in pancreatic ductal adenocarcinoma (PDAC) is largely unknown. Clinical trials targeting ER with selective estrogen receptor modulators in ...pancreatic cancer did not show any benefit. Here, we analyze the impact of recently characterized ER isoform beta on survival in a cohort of patients with resected PDAC.
Eighty-four patients having undergone pancreatic resection for PDAC at a single institution were identified. Tissue microarrays were constructed of archival tumor specimens. The expression of ER beta was determined by immunohistochemistry and quantified by a system established for estrogen receptor expression in breast cancer. ER beta expression was then correlated with clinicopathological parameters, and univariate and multivariate survival analyses were performed.
Nuclear expression of ER beta was found in 31% of tumors. No significant correlation was found between ER beta expression and TNM status, tumor grade, age or sex. Univariate analysis revealed nodal metastasis and the expression of ER beta as factors correlating with a shorter overall survival and disease free survival. When comparing ER beta expression in patients surviving more than 24 months with those who died from the tumor within 12 or 24 months, respectively, a significantly lower ER beta expression was found in the long term survivors. In multivariate analysis, ER beta expression was demonstrated to be an independent predictor of shorter overall survival.
In resected PDAC, expression of ER beta seems to correlate with poor prognosis. These data may help to identify patients who may benefit from additional systemic therapy including selective estrogen receptor modulators.
The interaction and crosstalk of Toll-like receptors (TLRs) is an established pathway in which the innate immune system recognises and fights pathogens. In a single nucleotide polymorphisms (SNP) ...analysis of an Indian cohort, we found evidence for both TLR4-399T and TRL8-1A conveying increased susceptibility towards tuberculosis (TB) in an interdependent manner, even though there is no established TLR4 ligand present in
(Mtb), which is the causative pathogen of TB. Docking studies revealed that TLR4 and TLR8 can build a heterodimer, allowing interaction with TLR8 ligands. The conformational change of TLR4-399T might impair this interaction. With immunoprecipitation and mass spectrometry, we precipitated TLR4 with TLR8-targeted antibodies, indicating heterodimerisation. Confocal microscopy confirmed a high co-localisation frequency of TLR4 and TLR8 that further increased upon TLR8 stimulation. The heterodimerisation of TLR4 and TLR8 led to an induction of IL12p40, NF-κB, and IRF3. TLR4-399T in interaction with TLR8 induced an increased NF-κB response as compared to TLR4-399C, which was potentially caused by an alteration of subsequent immunological pathways involving type I IFNs. In summary, we present evidence that the heterodimerisation of TLR4 and TLR8 at the endosome is involved in Mtb recognition via TLR8 ligands, such as microbial RNA, which induces a Th1 response. These findings may lead to novel targets for therapeutic interventions and vaccine development regarding TB.
is a highly successful pathogen infecting various body parts and forming biofilms on natural and artificial surfaces resulting in difficult-to-treat and chronic infections. We investigated the ...secreted cytokines and proteomes of isolated peripheral blood mononuclear cells (PBMCs) from healthy volunteers exposed to methicillin-resistant
(MRSA) biofilms or planktonic bacteria. Additionally, the cytokine profiles in sera from patients with community-acquired pneumonia (CAP) caused by
were investigated. The aim was to gain insights into the immune response involved and differentiate between the planktonic and sessile MRSA forms. We identified 321 and 298 targets that were significantly differently expressed in PBMCs when exposed to planktonic or biofilm-embedded bacteria, respectively. PBMCs exposed to planktonic MRSA cells secreted increased levels of TNF-α, while IL-18 was elevated when exposed to the biofilm. The machine-learning analyses of the cytokine profiles obtained for the
PBMCs and CAP sera distinguished between the two types of bacteria forms based on cytokines IL-18, IL12, and IL-17, and with a lower importance IL-6. Particularly, IL-18 which has not been correlated with
biofilms so far might represent a suitable marker for monitoring chronification during MRSA infection to individualize the therapy, but this hypothesis must be proved in clinical trials.
In challenging terrains, constructing structures, such as antennas and cable car masts, often requires the use of helicopters to transport loads via ropes. The swinging of the loads, exacerbated by ...wind, impairs positioning accuracy, therefore necessitating precise manual placement by ground crews. This increases costs and the risk of injuries. Challenging this paradigm, we present Geranos, a specialized multirotor unmanned aerial vehicle (UAV) designed to enhance aerial transportation and assembly. Geranos demonstrates exceptional prowess in accurately positioning vertical poles, achieving this through an innovative integration of load transport and precision. Its unique ring design mitigates the impact of high pole inertia, while a lightweight two-part grasping mechanism ensures secure load attachment without active force. With four primary propellers countering gravity and four auxiliary ones enhancing lateral precision, Geranos achieves comprehensive position and attitude control around hovering. Our experimental demonstration mimicking antenna/cable car mast installations showcases Geranos' ability in stacking poles (3 kg, 2 m long) with remarkable sub-5-cm placement accuracy without the need of human manual intervention.
Exposure of human monocytes to lipopolysaccharide (LPS) or other pathogen-associated molecular pattern (PAMPs) induces a temporary insensitivity to subsequent LPS challenges, a cellular state called ...endotoxin tolerance (ET), associated with the pathogenesis of sepsis. In this study, we aimed to characterize the cellular state of human monocytes from healthy donors stimulated with
in comparison to TLR2-specific ligands. We analyzed
induced gene expression changes after 2 and 24 hours by amplicon sequencing (RNA-AmpliSeq) and compared the pro-inflammatory response after 2 hours with the response in re-stimulation experiments. In parallel, glycoprotein expression changes in human monocytes after 24 hours of
stimulation were analyzed by proteomics and compared to stimulation experiments with TLR2 ligands Malp-2 and Pam3Cys and TLR4 ligand LPS. Finally, we analyzed peripheral blood monocytes of patients with
bloodstream infection for their
inflammatory responses towards
stimulation and their glycoprotein expression profiles. Our results demonstrate that monocytes from healthy donors stimulated with
and TLR ligands of Gram-positive bacteria entered the tolerant cell state after activation similar to LPS treatment. In particular reduced gene expression of pro-inflammatory cytokines (TNF, IL1β) and chemokines (CCL20, CCL3, CCL4, CXCL2, CXCL3 and CXCL8) could be demonstrated. Glycoprotein expression changes in monocytes tolerized by the different TLR agonists were highly similar while
-stimulated monocytes shared some of the PAMP-induced changes but also exhibited a distinct expression profile. 11 glycoproteins (CD44, CD274, DSC2, ICAM1, LAMP3, LILRB1, PTGS2, SLC1A3, CR1, FGL2, and HP) were similarly up- or downregulated in all four comparisons in the tolerant cell state. Monocytes from patients with
bacteremia revealed preserved pro-inflammatory responsiveness to
stimulation ex vivo, expressed increased CD44 mRNA but no other glycoprotein of the tolerance signature was differentially expressed.
The C-type lectin receptor Dectin-1 is expressed mainly on myeloid cells mediating the immune response targeting respiratory pathogens such as Aspergillus fumigatus and Mycobacterium tuberculosis. ...The pulmonary epithelium serves as an important interface for interactions between these pathogens and the respiratory tract. Therefore, we analyzed the expression pattern of Dectin-1 in the human lung. Immunohistochemically stained human lung sections from 17 out of 19 individuals were positive for Dectin-1, which was expressed mainly apically on bronchial and alveolar epithelium. Our results showed no correlation with chronic obstructive pulmonary disease (COPD) or the smoking habits of the patients. Nontypeable Haemophilus influenzae (NTHI), an important bacterial pathogen of the respiratory tract with significant importance in COPD, has also been proposed to be recognized by Dectin-1, suggesting a possible impact on the NTHI-dependent immune response in human airways. Therefore, the involvement of Dectin-1 in NTHI-triggered cytokine responses was investigated in primary normal human bronchial epithelial (NHBE) cells and in the A549 cell line stably transfected with Dectin-1. The presence of Dectin-1 significantly increased cytokine release in response to NTHI in NHBE and A549 cells. In addition, phosphorylation of the Dectin-1 hem-immunoreceptor tyrosine-based activation motif (hemITAM) was essential for the Dectin-1-triggered response to NTHI in A549 cells. In conclusion, in human airways, epithelium-expressed Dectin-1 may play a significant role in generating an NTHI-mediated, proinflammatory immune response.
In this study, we demonstrated, for the first time, the expression of Dectin-1 on human lung tissues and, in particular, pulmonary epithelium by making use of immunohistochemical staining. The epithelial lining of the human airways is an important interface for host-pathogen interactions. Therefore, our data suggest that epithelium-expressed Dectin-1 is of considerable importance for the interaction of the human airways with pathogens detected by this receptor, such as A. fumigatus and M. tuberculosis. Moreover, we further demonstrated that, in pulmonary epithelial cells, Dectin-1 enhances the proinflammatory immune response to NTHI. In COPD patients, NTHI is a major cause of respiratory tract infections and is associated with proinflammatory immune responses in the lower airways. Therefore, our data suggest that the functional interaction of Dectin-1 with NTHI in human airways may have an important impact on the pathogenesis of COPD.
Exposure of human monocytes to lipopolysaccharide (LPS) induces a temporary insensitivity to subsequent LPS challenges, a cellular state called endotoxin tolerance. In this study, we investigated the ...LPS-induced global glycoprotein expression changes of tolerant human monocytes and THP-1 cells to identify markers and glycoprotein targets capable to modulate the immunosuppressive state. Using hydrazide chemistry and LC-MS/MS analysis, we analyzed glycoprotein expression changes during a 48 h LPS time course. The cellular snapshots at different time points identified 1491 glycoproteins expressed by monocytes and THP-1 cells. Label-free quantitative analysis revealed transient or long-lasting LPS-induced expression changes of secreted or membrane-anchored glycoproteins derived from intracellular membrane coated organelles or from the plasma membrane. Monocytes and THP-1 cells demonstrated marked differences in glycoproteins differentially expressed in the tolerant state. Among the shared differentially expressed glycoproteins G protein-coupled receptor 84 (GPR84) was identified as being capable of modulating pro-inflammatory TNFα mRNA expression in the tolerant cell state when activated with its ligand Decanoic acid.
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