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Insulin-like growth factor 1 (IGF-1) regulates dairy cow reproduction, while the paracrine IGF system locally influences fertility. In both systems, IGF-1 bioactivity is regulated through binding proteins (IGFBPs) inhibiting IGF-1 binding to its receptor (IGF1R). This study aimed to investigate a possible transfer between this endocrine and paracrine system. Therefore, blood and follicular fluid (FF) from postpartum dairy cows were analysed for ß-hydroxybutyrate (BHB), IGF-1, IGFBP-2, -3, -4, -5, and an IGFBP fragment in two study parts. The mRNA expression of IGFBP-2 , IGFBP-4 , IGF1R , and the pregnancy-associated plasma protein A ( PAPP-A ) in granulosa cells was measured. The results showed correlations between plasma and FF for IGF-1 (r = 0.57, p < 0.001) and IGFBP-2 (r = -0.57, p < 0.05). Blood BHB negatively correlated with IGF-1 in blood and FF and IGFBP-3, -5 and total IGFBP in blood (IGF-1 plasma: r = -0.26, p < 0.05; FF: r = -0.35, p < 0.05; IGFBP-3: r = -0.64, p = 0.006; IGFBP-5: r = -0.49, p < 0.05; total IGFBP: r = -0.52, p < 0.05). A negative correlation was found between IGFBP-2 expression and IGF-1 concentration in FF (r = -0.97, p = 0.001), while an IGFBP fragment positively correlated with IGF1R -mRNA in FF (r = 0.82, p = 0.042). These findings suggest a transfer and local regulation between the somatotropic axis and the follicular IGF system, linking the metabolic status with local effects on dairy cow fertility.

Insulin-like growth factors (IGFs) are essential for oocyte maturation. Their bioavailability is regulated by their respective binding proteins (IGFBPs) and proteases. IGFBP-4 blocks the biological effects of IGFs. High IGFBP-4 expression has been associated with follicle atresia. We hypothesized that IGFBP-4 affects oocyte developmental competence during maturation. Therefore, the aim of this study was to examine the effect of IGFBP-4 on the developmental rate of bovine cumulus-oocyte complexes (COCs) during in vitro embryo production. Abattoir-derived COCs were matured with rbIGFBP-4 (2000, 540, and 54 ng/mL) compared to a control. Cumulus expansion, oocyte maturation, cleavage, blastocyst, and hatching rates were evaluated. Furthermore, blastocyst gene expression of SOCS2, STAT3, SLC2A1, SLCA3, BAX, and POU5F1 transcripts were quantified using RT-qPCR. No statistical differences were detected among the groups for cumulus expansion, maturation, cleavage, blastocyst rates, or all gene transcripts analyzed. However, at day 8 and 9, the number of total hatching and successfully hatched blastocysts was lower in 2000 ng/mL rbIGFBP-4 compared to the control (day 8: total hatching: 17.1 ± 0.21 vs. 31.2 ± 0.11%, p = 0.02 and hatched blastocyst 6.7 ± 0.31 vs. 21.5 ± 0.14%, p = 0.004; day 9 total hatching 36.4 ± 0.18 vs. 57.7 ± 0.10%, p = 0.009 and hatched blastocyst 18.2 ± 0.21 vs. 38.1 ± 0.11%, p = 0.004). We concluded that high concentrations of rbIGFBP-4 might negatively affect the subsequent ability of the embryo to hatch and possibly compromise further elongation.

Insulin-like growth factor I (IGF-I) is a growth-promoting anabolic hormone that fosters cell growth and tissue homeostasis. IGF-I deficiency is associated with several diseases, including growth disorders and neurological and musculoskeletal diseases due to impaired regeneration. Despite the vast regenerative potential of IGF-I, its unfavorable pharmacokinetic profile has prevented it from being used therapeutically. In this study, we resolved these challenges by the local administration of IGF-I mRNA, which ensures desirable homeostatic kinetics and non-systemic, local dose-dependent expression of IGF-I protein. Furthermore, IGF-I mRNA constructs were sequence engineered with heterologous signal peptides, which improved in vitro protein secretion (2- to 6-fold) and accelerated in vivo functional regeneration (16-fold) over endogenous IGF-I mRNA. The regenerative potential of engineered IGF-I mRNA was validated in a mouse myotoxic muscle injury and rabbit spinal disc herniation models. Engineered IGF-I mRNA had a half-life of 17-25 h in muscle tissue and showed dose-dependent expression of IGF-I over 2-3 days. Animal models confirm that locally administered IGF-I mRNA remained at the site of injection, contributing to the safety profile of mRNA-based treatment in regenerative medicine. In summary, we demonstrate that engineered IGF-I mRNA holds therapeutic potential with high clinical translatability in different diseases., Competing Interests: Versameb AG is a privately held company focusing on discovering and developing innovative RNA-based drugs based in Basel, Switzerland. All authors affiliated with Versameb AG were employees during the course of this work and equity holders of Versameb., (© 2023 The Author(s).)

Background: Individuals with mental health issues experience profound stigma and discrimination, which may contribute to a lack of accommodation utilization to address functional limitations of their work., Objectives: This study examined how psychosocial factors may predict the request of accommodations by employed individuals with mental disabilities through the framework of social cognitive career theory., Methods: In the United States, 148 employed adults with mental disabilities completed an online questionnaire to ascertain self-efficacy, outcome expectation, affect, and workplace support. Logistic regression analyses were conducted to examine associations between respondents' psychosocial factors and request of accommodations., Results: Psychosocial factors (i.e., self-efficacy in accommodation request, outcome expectancy in employers' compliance with accommodation request, and non-person cost associated with request) were associated with impacting decisions to request accommodations among individuals with mental disabilities., Conclusions: A focus on bolstering self-efficacy and outcome expectation may assist rehabilitation professionals with facilitating positive occupational outcomes for individuals with mental disabilities. Incorporating increased education on the possible implications of mental disabilities in the workplace may also promote successful employment outcomes.

Background: Prevalence of people with multimorbidity rises. Multimorbidity constitutes a challenge to the healthcare system, and treatment of patients with multimorbidity is prone to high-quality variations. Currently, no set of quality indicators (QIs) exists to assess quality of care, let alone incorporating the patient perspective. We therefore aim to identify aspects of quality of care relevant to the patients' perspective and match them to a literature-based set of QIs., Methods: We conducted eight focus groups with patients with multimorbidity and three focus groups with patients' relatives using a semistructured guide. Data were analysed using Kuckartz's qualitative content analysis. We derived deductive categories from the literature, added inductive categories (new quality aspects) and translated them into QI., Results: We created four new QIs based on the quality aspects relevant to patients/relatives. Two QIs (patient education/self-management, regular updates of medication plans) were consented by an expert panel, while two others were not (periodical check-ups, general practitioner-coordinated care). Half of the literature-based QIs, for example, assessment of biopsychosocial support needs, were supported by participants' accounts, while more technical domains regarding assessment and treatment regimens were not addressed in the focus groups., Conclusion: We show that focus groups with patients and relatives adding relevant aspects in QI development should be incorporated by default in QI development processes and constitute a reasonable addition to traditional QI development. Our QI set constitutes a framework for assessing the quality of care in the German healthcare system. It will facilitate implementation of treatment standards and increase the use of existing guidelines, hereby helping to reduce overuse, underuse and misuse of healthcare resources in the treatment of patients with multimorbidity., Trial Registration Number: German clinical trials registry (DRKS00015718), Pre-Results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Using complete genome analysis, we sequenced five bladder tumors accrued from patients with muscle-invasive transitional cell carcinoma of the urinary bladder (TCC-UB) and identified a spectrum of genomic aberrations. In three tumors, complex genotype changes were noted. All three had tumor protein p53 mutations and a relatively large number of single-nucleotide variants (SNVs; average of 11.2 per megabase), structural variants (SVs; average of 46), or both. This group was best characterized by chromothripsis and the presence of subclonal populations of neoplastic cells or intratumoral mutational heterogeneity. Here, we provide evidence that the process of chromothripsis in TCC-UB is mediated by nonhomologous end-joining using kilobase, rather than megabase, fragments of DNA, which we refer to as "stitchers," to repair this process. We postulate that a potential unifying theme among tumors with the more complex genotype group is a defective replication-licensing complex. A second group (two bladder tumors) had no chromothripsis, and a simpler genotype, WT tumor protein p53, had relatively few SNVs (average of 5.9 per megabase) and only a single SV. There was no evidence of a subclonal population of neoplastic cells. In this group, we used a preclinical model of bladder carcinoma cell lines to study a unique SV (translocation and amplification) of the gene glutamate receptor ionotropic N-methyl D-aspertate as a potential new therapeutic target in bladder cancer.

Overexpression of the T cell cytokine IL-22 is linked to the development of some chronic diseases, but little is known about IL-22 deficiency in humans. As demonstrated in this study, acne inversa (AI; also designated as Hidradenitis suppurativa) lesions show a relative deficiency of IL-22 and IL-20, but not of IL-17A, IL-26, IFN-γ, IL-24, or IL-1β. Moreover, AI lesions had reduced expression of membranous IL-22 and IL-20 receptors and increased expression of the natural IL-22 inhibitor, IL-22 binding protein. AI is a chronic inflammatory skin disease with prevalence up to 4% of the population and in which cutaneous bacterial persistence represents an important pathogenetic factor. Accordingly, we also found a relative deficiency of antimicrobial proteins (AMPs) in AI lesions and a positive correlation between lesional IL-22 and IL-20 versus AMP levels. IL-22, like its tissue cell downstream mediator IL-20, upregulated AMPs in reconstituted human epidermis and was critical for increased AMP levels under inflammatory conditions. The relative IL-22 deficiency in AI was not linked to lesional T cell numbers or Th22/Th1/Th17 subset markers and -inducing cytokines. However, IL-10 was highly expressed in AI lesions and correlated negatively with IL-22 expression. Moreover, IL-10 inhibited IL-22 but not IL-17 production in vitro. The IL-10 overexpression, in turn, was not associated with an elevated presence of regulatory T cells but with the enhanced presence of an IL-10-inducing cytokine. We conclude that IL-22 deficiency may contribute to the pathogenesis of certain chronic disorders as postulated in this paper for AI.

Mannose-binding lectin (MBL) mediates important functions within the innate immune system, and its deficiency was associated with infectious complications. However, in adults without concomitant immunodeficiency the clinical relevance of MBL deficiency remains controversial. We analyzed the distribution of MBL deficiency and its association with concomitant immunodeficiency in 228 adult Caucasian patients with a history of recurrent and/or severe infections. Two hundred forty-one unrelated Caucasians without recurrent or severe infections served as control subjects. The frequency of severe MBL deficiency (plasma levels

Recent data suggest valganciclovir (VGC) to be as effective as ganciclovir for cytomegalovirus (CMV) prophylaxis. The objective of this study was to analyze the effect of oral valganciclovir in renal transplant patients with symptomatic CMV infection. Twenty-one patients with symptomatic CMV infection received VGC in doses adjusted to renal function until resolution of CMV antigenemia. The patients were followed for a mean of 5.5 months. During therapy, CMV antigenemia dropped in all patients from pretreatment positive levels of 5.2 +/- 3.7 to negative values of 0.25 +/- 0.2 positive cells/10,000 PBMC (P<0.001). After cessation of therapy, none of patients developed relapse of CMV antigenemia/symptoms within the follow-up. VGC therapy was well tolerated in all patients and no major adverse effects occurred. This pilot trial showed VGC to be safe and highly effective in antiviral therapy after renal transplantation. However, subsequent multicenter clinical trials for treatment of CMV disease are necessary.

An increase in circulating levels of IL-10 is believed to contribute to immunosuppression caused by major surgery. Cortisol and catecholamines have been shown to be important costimulatory factors for IL-10 secretion in humans. As thoracic epidural block (TEB) should blunt the perioperative increases in cortisol and catecholamines we investigated whether IL-10 secretion is influenced by TEB. Twenty-six patients undergoing coronary artery bypass graft surgery using cardiopulmonary bypass were randomized to receive either general anesthesia (GA) or GA plus TEB. Sensory and pain levels were measured to demonstrate clinical effectiveness. Plasma concentrations of epinephrine, norepinephrine, cortisol, IL-6 and IL-10 as well as monocyte surface expression of HLA-DR and their ex vivo capacity to release TNF-alpha after LPS stimulation were measured perioperatively. TEB was clinically effective and patients receiving TEB showed decreased circulating levels of IL-10. However, this decrease was independent of decreased levels of cortisol or epinephrine. No influence of TEB on IL-6 levels, monocyte capacity to ex vivo release TNF-alpha upon LPS stimulation or their expression of HLA-DR was found. In conclusion, high TEB reduces antiinflammatory immune suppressing mediators including IL-10 and stress mediators. At least in cardiac surgery patients the monocyte functional depression is not related to systemic release of IL-10 and the influence of cortisol or epinephrine is less important for early monocyte deactivation than what in vitro and animal models have suggested.

Background: Infections are the most common cause of late complications in cardiopulmonary bypass (CPB) surgery patients, and are difficult to predict. Here we studied the diagnostic value of a standardized immune monitoring program based on recent advances in flow cytometry (exact quantification of surface-marker expression) and cytokine determination (semiautomatic systems)., Methods: CPB patients (56) at risk for complications (age >70 years and/or preoperative left-ventricular ejection fraction < 25 %) were classified into three groups: without (33), with suspected (14), and with confirmed (9) infection. Applying the Quantibrite trade mark -system, we daily quantified the expression of CD11b, CD64, CD71, CD86, and HLA-DR on monocytes/granulocytes. Furthermore, the ex vivo secretion of tumor necrosis factor (TNF)-alpha as well as the plasma interleukin (IL)-10 levels were determined by a semiautomatic system. Ex vivo elastase release was measured by enzyme-linked immunosorbent assay (ELISA)., Results: All patients showed signs of granulocyte activation and monocyte deactivation. Monocytic HLA-DR and plasma IL-10 were the best markers to discriminate patients with infection from those without as early as day 1. Using a cutoff of 5792 HLA-DR molecules per cell, both sensitivity and negative predictive value for patients who developed microbiologically confirmed infection was 1.0, and the area under the curve (AUC) was 0.85., Conclusions: Our data suggest that a standardized immune monitoring at day 1 might be useful for early discrimination of patients at elevated risk for infections., (Copyright 2003 Wiley-Liss, Inc.)