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Background Systemic sclerosis is a rheumatoid disease best known for its fibrotic skin manifestations called scleroderma. Alternatively activated (M2-type) macrophages are normally involved in the resolution of inflammation and wound healing but also in fibrosing diseases such as scleroderma. TRPA1 is a non-selective cation channel, activation of which causes pain and neurogenic inflammation. In the present study, we investigated the role of TRPA1 in bleomycin-induced skin fibrosis mimicking scleroderma. Methods Wild type and TRPA1-deficient mice were challenged with intradermal bleomycin injections to induce a scleroderma-mimicking disease. Macrophages were investigated in vitro to evaluate the underlying mechanisms. Results Bleomycin induced dermal thickening and collagen accumulation in wild type mice and that was significantly attenuated in TRPA1-deficient animals. Accordingly, the expression of collagens 1A1, 1A2, and 3A1 as well as pro-fibrotic factors TGF-beta, CTGF, fibronectin-1 and YKL-40, and M2 macrophage markers Arg1 and MRC1 were lower in TRPA1-deficient than wild type mice. Furthermore, bleomycin was discovered to significantly enhance M2-marker expression particularly in the presence of IL-4 in wild type macrophages in vitro, but not in macrophages harvested from TRPA1-deficient mice. IL-4-induced PPARγ-expression in macrophages was increased by bleomycin, providing a possible mechanism behind the phenomenon. Conclusions In conclusion, the results indicate that interfering TRPA1 attenuates fibrotic and inflammatory responses in bleomycin-induced scleroderma. Therefore, TRPA1-blocking treatment could potentially alleviate M2 macrophage driven diseases like systemic sclerosis and scleroderma.

CHEK2 is a well-established breast cancer susceptibility gene. The most frequent pathogenic CHEK2 variant is 1100delC, a loss-of-function mutation conferring 2-fold risk for breast cancer. This gene also harbors other rare variants encountered in the clinical gene panels for hereditary cancer. One of these is CHEK2 c.1312 G > T, p.(Asp438Tyr) in the kinase domain of the protein, but due to its rarity its clinical significance for breast cancer predisposition has remained unclear. Here, we tested the prevalence of CHEK2 p.(Asp438Tyr) allele showing enrichment in the Northern Finnish population, in a total of 2284 breast cancer patients from this geographical region. Genotyping was performed for DNA samples extracted from peripheral blood using high-resolution melt analysis. Fourteen CHEK2 p.(Asp438Tyr) carriers were identified (14/2284, 0.6%, P = 0.67): two in the cohort of breast cancer cases with the indication of inherited disease susceptibility (2/281, 0.7%, P = 1.00) and twelve in the breast cancer cohort unselected for the family history of disease and age at disease onset (12/2003, 0.6%, P = 0.66). This frequency did not differ from the frequency in the general population (10/1299, 0.8%). No CHEK2 p.(Asp438Tyr) homozygotes were identified. Our results indicate that CHEK2 p.(Asp438Tyr) carriers do not have an increased risk for breast cancer and the classification of the CHEK2 p.(Asp438Tyr) variant can be changed from the variant of uncertain significance (VUS) to likely benign for breast cancer.

Background Dysbiotic intestinal and oral microbiota have been implicated in the pathogenesis of rheumatoid arthritis (RA), but the mechanisms how microbiota could impact disease activity have remained elusive. The aim of this study was to assess the association of the biological activity of serum lipopolysaccharides (LPS) with disease activity and likelihood of achieving remission in RA patients. Methods We measured Toll-like receptor (TLR) 4-stimulating activity of sera of 58 RA patients with a reporter cell line engineered to produce secreted alkaline phosphatase in response to TLR4 stimulation. Levels of LPS-binding protein, CD14, and CD163 were determined by ELISA assays. Results The patient serum-induced TLR4 activation (biological activity of LPS) was significantly associated with inflammatory parameters and body mass index at baseline and at 12 months and with disease activity (DAS28-CRP, pp=0.031) and, in 28 early RA patients, the likelihood of achieving remission at 12 months (p=0.009). The level of LPS bioactivity was similar at baseline and 12-month visits, suggesting that LPS bioactivity is an independent patient-related factor. Neutralization of LPS in serum by polymyxin B abrogated the TLR4 signaling, suggesting that LPS was the major contributor to TLR4 activation. Conclusion We describe a novel approach to study the biological activity of serum LPS and their impact in diseases. The results suggest that LPS contribute to the inflammatory burden and disease activity on patients with RA and that serum-induced TLR4 activation assays can serve as an independent prognostic factor. Graphical Abstract A graphical summary of the conclusions of the study.

Development in multidimensional self-regulation is important because it can be leveraged to enable healthy long-term adjustment. This four-wave study investigated longitudinal associations between two domains of adolescent self-regulation, specifically its cognitive (e.g., planning and decision-making) and emotional components (e.g., control of negative emotions). Participants included 500 adolescents (52% female; T1 Mage = 13.31 years; 76% White; average yearly family income > 100,000 USD). A random-intercepts cross-lagged panel model revealed that, once trait-level longitudinal stability in each regulatory component was controlled, there were small cross-lagged effects from cognitive self-regulation to later emotional self-regulation. Findings warrant additional future research that describes adolescents’ multidimensional self-regulation development and its antecedents, in part by appropriately distinguishing between intra- and inter-individual effects.

Ectopic ACTH syndrome (EAS) is rare. We established a national cohort to increase awareness and address unmet needs.The Finnish national EAS cohort includes 60 patients diagnosed in 1997-2016. We assessed clinical features, diagnostic work-ups, treatments, incidence, and outcomes of subgroups occult tumor (OT), well-differentiated neuroendocrine tumor G1/G2 (NETG1/G2) and NET G3/neuroendocrine carcinoma (NETG3/NEC).The distribution of OT, NETG1/G2, and NETG3/NEC was 10 (17%), 20 (33%), and 30 (50%), respectively; and median follow-up 22 months (0-249). Annual incidence (0.20-0.93 per million inhabitants) and tumor subgroups (OT vs. NEC) varied across the country. The longest diagnostic delay from EAS onset to radiological tumor identification was 48 months. In NET/NEC, 6/50 (12%) were diagnosed 1-24 years before EAS onset. Osteoporotic fractures (32%) and severe infections (55%) were common. The CRH stimulation test accurately diagnosed EAS in 25/31 (81%). Metyrapone (≤6 g daily, prescribed in 88%) was well tolerated. In NETG1/G2, 13/20 (65%) underwent curative resection of the primary tumor; four experienced recurrence within 2-12 years. In OT, 70% underwent bilateral adrenalectomy. Five-year overall survival in OT, NETG1/G2, and NETG3/NEC was 90%, 55%, and 0%, respectively (P 0.001). Morning cortisol, hypokalemia, infections, metastatic disease, and acute onset were negative, whereas resection of the primary tumor and bilateral adrenalectomy were positive predictors of survival.NET/NEC may precede EAS onset by several years. In NETG1/G2, recurrences may occur10 years after successful primary surgery. Tumor subgroup (OT, NETG1/G2, NEC) was an independent predictor of survival.

Harsh parenting can predispose a child to emotional distress, whereas a supportive childhood environment furthers later subjective well-being. We investigated whether the mother’s self-reported assessment of her strictness and the adult offspring’s recollections of the disciplinary methods of their parents are reflected in the adult offspring’s recalled parental images and current emotional distress, anxiety and depression as assessed by the Hopkins Symptom Check List (HSCL-25). Further, we investigated whether the offspring’s parental images were also associated with the HSCL-25 scores. Data was collected from northern Finland. The mothers responded to a questionnaire when their child was seven years old (N = 354) and the adult offspring responded at age 28–29 (N = 337). The mother’s assessment of her own strictness was associated both with the adult offspring’s dominating images of their parents and their current emotional distress, anxiety and depression. The offspring’s recollections of restriction and corporal punishment were associated with dominating parental images, and these images further with current emotional distress, anxiety and depression of the offspring. Correspondingly, the offspring’s recollections of parental dialogic discipline were associated with supportive and sociable parental images, and recalled paternal dialogic discipline was associated with lower current emotional distress, particularly in the female offspring. In conclusion, harsh parenting was associated with dominating parental images, which in turn were associated with emotional distress in adulthood. Dialogic discipline and the father’s role in parenting were emphasized in the offspring’s well-being, but more research is needed to assess the importance of paternity for the offspring’s subjective well-being.

The present study considered whether helicopter parenting in emerging adulthood is linked to adjustment outcomes (i.e., social competence, prosocial behavior, depression, substance use, and lifetime criminality) above and beyond other parenting practices (i.e., acceptance, psychological and firm control), and whether any associations are mediated by personal mastery and/or self-regulation. Young adults ages 18 to 24 years responded to anonymous internet surveys (N= 302; 64.9% female, 79.4% white, 9.1% Hispanic). High helicopter parenting was linked to low mastery, self-regulation, and social competence, and to high depression. Only associations with depression were attenuated when other parenting practices were controlled. Direct effects of helicopter parenting on depression and social competence were mitigated to non-significance when self-regulation and/or mastery were modeled. Helicopter parenting and parental acceptance had indirect effects on all forms of adjustment via self-regulation, as well as indirect effects via mastery for depression. Collectively, the findings suggest that helicopter parenting has comparatively stronger impacts for socio-emotional versus behavioral adjustment, operating indirectly via self-regulation versus mastery.

It has been argued that companies face the challenge of being innovative while at the same time having to standardize and control organizational processes. While management control research has mostly focused on how control supports innovation, the present study aims to improve our understanding of how controls can support the co-existence of process and management innovations with standardization. The paper adopts a single-case study method and analyses the use of a management control system in the context of a business process outsourcing company which faces the simultaneous need for process and management innovation and standardization. The study examines the relationships between different levers of control and their nature to explain how levers of control can create consistent and countervailing reinforcement that supports the co-existence of innovation and standardization. Moreover, we provide an insight into how certain controls, specifically diagnostic and interactive lean controls, combine the levers of control, so creating countervailing reinforcement. We show that the identified reinforcement enables the coexistence of different innovations and standardization at various organizational levels. Thus, the current study contributes to the stream of research on how management controls work collectively, acknowledging their impact on innovation and the concurrent need for standardization.

Background Pain persists in a moderate number of patients following hip or knee replacement surgery. Persistent pain may subsequently lead to the prolonged consumption of analgesics after surgery and expose patients to the adverse drug events of opioids and NSAIDs, especially in older patients and patients with comorbidities. This study aimed to identify risk factors for the increased use of opioids and other analgesics 1 year after surgery and focused on comorbidities and surgery-related factors. Methods All patients who underwent a primary hip or knee replacement for osteoarthritis from 2002 to 2013 were identified. Redeemed prescriptions for acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), and opioids (mild and strong) were collected from a nationwide Drug Prescription Register. The user rates of analgesics and the adjusted risks ratios for analgesic use 1 year after joint replacement were calculated. Results Of the 6238 hip replacement and 7501 knee replacement recipients, 3591 (26.1%) were still using analgesics 1 year after surgery. Significant predictors of overall analgesic use (acetaminophen, NSAID, or opioid) were (risk ratio (95% CI)) age 65–74.9 years (reference 75 years, 1.2 (1.1–1.3); female gender, 1.2 (1.1–1.3); BMI 30–34.9 kg/m2 (reference 2), 1.1 (1.04–1.2); BMI > 35 kg/m2, 1.4 (1.3–1.6); and a higher number of comorbidities (according to the modified Charlson Comorbidity Index score), 1.2 (1.1–1.4). Diabetes and other comorbidities were not significant independent predictors. Of the other clinical factors, the preoperative use of analgesics, 2.6 (2.5–2.8), and knee surgery, 1.2 (1.1–1.3), predicted the use of analgesics, whereas simultaneous bilateral knee replacement (compared to unilateral procedure) was a protective factor, 0.86 (0.77–0.96). Opioid use was associated with obesity, higher CCI score, epilepsy, knee vs hip surgery, unilateral vs bilateral knee operation, total vs unicompartmental knee replacement, and the preoperative use of analgesics/opioids. Conclusions Obesity (especially BMI > 35 kg/m2) and the preoperative use of analgesics were the strongest predictors of an increased postoperative use of analgesics. It is remarkable that also older age and higher number of comorbidities predicted analgesic use despite these patients being the most vulnerable to adverse drug events.

Cardiotoxicity is the most important side effect of trastuzumab treatment. Heart function monitoring is recommended during the treatment which has led to growing use of resources. The aim of this retrospective study was to determine the frequency and timing of trastuzumab cardiotoxicity and its risk factors in real-world setting. Single institute, retrospective collection of data on HER2+ breast cancer patients (n = 246) was carried out through a pharmacy search for patients who had received trastuzumab in 2006–2014. Clinical and pathological factors, treatment history, EF measurements, cardiac medications, cardiovascular disease history, cardiac symptoms, and survival data were collected from patient records. 32 patients (13%) had EF decline ≥ 10%, eleven (4.5%) had EF decline ≥ 20% within 1 year after trastuzumab initiation, and trastuzumab was discontinued due to suspected cardiotoxicity in six patients (2.4%). 49 patients (19.9%) experienced symptoms related to cardiotoxicity during therapy, which accumulated among those with EF drop. Underlying cardiovascular diseases and multiple (≥ 2) cardiac medications were related to EF drop (≥ 20%) and trastuzumab discontinuation. Majority of EF drops (≥ 10%) and trastuzumab discontinuations were seen within 6months of trastuzumab initiation and recovery of EF drop to

openaire: EC/H2020/745115/EU//OPLD Bose–Einstein condensation is a remarkable manifestation of quantum statistics and macroscopic quantum coherence. Superconductivity and superfluidity have their origin in Bose–Einstein condensation. Ultracold quantum gases have provided condensates close to the original ideas of Bose and Einstein, while condensation of polaritons and magnons has introduced novel concepts of non-equilibrium condensation. Here, we demonstrate a Bose–Einstein condensate of surface plasmon polaritons in lattice modes of a metal nanoparticle array. Interaction of the nanoscale-confined surface plasmons with a room-temperature bath of dye molecules enables thermalization and condensation in picoseconds. The ultrafast thermalization and condensation dynamics are revealed by an experiment that exploits thermalization under propagation and the open-cavity character of the system. A crossover from a Bose–Einstein condensate to usual lasing is realized by tailoring the band structure. This new condensate of surface plasmon lattice excitations has promise for future technologies due to its ultrafast, room-temperature and on-chip nature.

Mitogen-activated protein kinase phosphatase 1 (MKP-1) expression is induced by inflammatory factors and serves as an endogenous p38 MAPK suppressor to limit inflammatory response. Glucocorticoids are very effective anti-inflammatory drugs and they are used for the treatment of many inflammatory diseases, such as asthma and COPD. We investigated the role of MKP-1 in the inhibition of cytokine production by dexamethasone in human A549 bronchial epithelial cells. We found that dexamethasone increased MKP-1 expression, inhibited p38 MAPK phosphorylation, and suppressed TNF and MIP-3α production in A549 cells. Interestingly, the suppression of p38 MAPK phosphorylation and the inhibition of TNF expression by dexamethasone were attenuated in cells, where MKP-1 expression was silenced by siRNA. In conclusion, these data suggest that dexamethasone increases MKP-1 expression and this results in the suppression of p38 MAPK signaling leading to the inhibition of cytokine production in human bronchial epithelial cells. These results point to the role of MKP-1 as an important factor in the therapeutic effects of glucocorticoids in the treatment of inflammatory lung diseases.

In the research field of extracellular vesicles (EVs), the use of fetal bovine serum (FBS) depleted of EVs for in vitro studies is advocated to eliminate the confounding effects of media derived EVs. EV-depleted FBS may either be prepared by ultracentrifugation or purchased commercially. Nevertheless, these preparations do not guarantee an RNA-free FBS for in vitro use. In this study we address the RNA contamination issue, of small non-coding (nc)RNA in vesicular or non-vesicular fractions of FBS, ultracentrifugation EV-depleted FBS, commercial EV-depleted FBS, and in our recently developed filtration based EV-depleted FBS. Commercially available serum- and xeno-free defined media were also screened for small ncRNA contamination. Our small ncRNA sequencing data showed that all EV-depleted media and commercially available defined media contained small ncRNA contaminants. Out of the different FBS preparations studied, our ultrafiltration-based method for EV depletion performed the best in depleting miRNAs. Certain miRNAs such miR-122 and miR-203a proved difficult to remove completely and were found in all media. Compared to miRNAs, other small ncRNA (snRNA, Y RNA, snoRNA, and piRNA) were difficult to eliminate from all the studied media. Additionally, our tested defined media contained miRNAs and other small ncRNAs, albeit at a much lower level than in serum preparations. Our study showed that no media is free of small ncRNA contaminants. Therefore, in order to screen for baseline RNA contamination in culturing media, RNA sequencing data should be carefully controlled by adding a media sample as a control. This should be a mandatory step before performing cell culture experiments in order to eliminate the confounding effects of media.

Iron oxide nanoparticles are available in two common phases, namely magnetite (Fe3O4) and maghemite (Fe2O3). Upon exposure to oxygen atoms, the magnetite phase readily oxidizes into the maghemite phase with the partial conversion of ferrous ions into ferric ions. We report on the approach to determine the ratio of magnetite and maghemite in iron oxide nanoparticles synthesized by the wet chemical route. X-ray diffraction studies and transmission electron microscopy observations confirmed the formation of highly crystalline nanoparticles of size $$\left( {7 \pm 2} \right)$$ nm. The average particle size is in the magnetic single-domain range suitable for the superparamagnetic behavior. The Mossbauer spectrum of the sample is composed of two six-line patterns in perfect agreement with the theoretically predicted model. The extracted Mossbauer parameters show contribution of two phases accounting for 47% magnetite and 53% maghemite. The hysteresis loops of the iron nanoparticles demonstrated the “S-shaped” pattern with negligible coercivity and remanence magnetization. This result reveals a promising method to synthesize and characterize magnetic nanoparticles of uniform size with a potential for biomedical applications.

Background Angiopoietin growth factors (Angs) regulate angiogenesis and lymphangiogenesis by binding to the endothelial Tie2 receptor. Ang2 expression is elevated in tissue hypoxia and inflammation, which also induce cleavage of the extracellular domain of the orphan Tie1 receptor. Here we have examined if the concentrations of Ang2 and the soluble extracellular domain of Tie1 in patient plasma are associated with the prognosis of patients with metastatic breast cancer. Methods Plasma Tie1 and Ang2 levels were measured in metastatic breast cancer patients treated in a phase II trial with a taxane-bevacizumab combination chemotherapy in the first-line treatment setting. They were analyzed before treatment, after 6 weeks and 6 months of treatment, and at the final study visit. Using the median concentrations as cutoffs, Tie1 and Ang2 data were dichotomized into low and high concentration groups. Additionally, we analyzed Tie1 concentrations in plasma from 10 healthy women participating in a breast cancer primary prevention study. Results Plasma samples were available from 58 (89%) of the 65 patients treated in the trial. The baseline Tie1 levels of the healthy controls were significantly lower than those of the metastatic patients (p

One of the most important components of the developmental environment is the emotional atmosphere. Childhood experiences and perceptions of parental roles and behavior result in memory models and images, which may affect the children’s relationships in adulthood. In the present study, the cross-sectional associations between childhood parental images and the quality of current intimate adult relationships were studied in a sub-study of a mother–child follow-up in northern Finland. The data were collected with a questionnaire mailed to 28–29-year-old adults, with a total of 337 replies. The present study included those respondents (N = 253) who were married or cohabiting (153 women, 100 men). Since offspring can be affected by gender-specific parenting patterns, the analyses were made separately for both genders. In women, supportiveness in both maternal and paternal images was associated with a balanced intimate relationship, the latter also being associated with a loving relationship and providing protection against quarrelsome and repressive–submissive aspects of the relationship. In men, maternal supportiveness was linked with a balanced and loving intimate relationship and protected against a quarrelsome relationship. Paternal domination was associated with repressive–submissive relationships regardless of gender. In conclusion, the qualities of recalled childhood parenting are important to adult well-being in intimate relationships in a gender-specific manner. The specific importance of the father to the children’s later life was also observed. This would indicate that supporting the relationship of the child with both parents is equally important for professionals working with children and families.

By analyzing the whole-exome sequences of 4,264 schizophrenia cases, 9,343 controls and 1,077 trios, we identified a genome-wide significant association between rare loss-of-function (LoF) variants in SETD1A and risk for schizophrenia (P = 3.3 × 10(-9)). We found only two heterozygous LoF variants in 45,376 exomes from individuals without a neuropsychiatric diagnosis, indicating that SETD1A is substantially depleted of LoF variants in the general population. Seven of the ten individuals with schizophrenia carrying SETD1A LoF variants also had learning difficulties. We further identified four SETD1A LoF carriers among 4,281 children with severe developmental disorders and two more carriers in an independent sample of 5,720 Finnish exomes, both with notable neuropsychiatric phenotypes. Together, our observations indicate that LoF variants in SETD1A cause a range of neurodevelopmental disorders, including schizophrenia. Combining these data with previous common variant evidence, we suggest that epigenetic dysregulation, specifically in the histone H3K4 methylation pathway, is an important mechanism in the pathogenesis of schizophrenia.