12 research outputs found
Taliento v. Portland West Neighborhood Council: The At Will Doctrine Continues to Thrive in Maine
No full textIn Taliento v. Portland West Neighborhood Planning Council, Neil Taliento, a program director at Portland West, brought suit against his former employer claiming breach of contract for improper discharge, and alleging that Portland West failed to follow the procedure for termination set forth in its personnel policy. The trial court granted Portland West\u27s motion for summary judgment, concluding that Taliento had failed to establish that he was anything other than an employee-at-will, irrespective of the plain language of Portland West\u27s Personnel Policy and its seemingly binding nature. Subsequently, Taliento appealed to the Supreme Judicial Court of Maine. Taliento provided the Law Court with an opportunity to consider whether personnel policies should be interpreted as binding, implied contracts between employer and employee. The Law Court found that Taliento was an employee for an indefinite term and, therefore, was terminable at the will of Portland West. This Author contends that there was, however, an implied contract between Taliento and Portland West. At the very least, an issue of material fact existed that should have been submitted to a jury. The trend in a majority of jurisdictions has been toward limiting the traditional employee-at-will doctrine. There are legitimate reasons why Maine should follow that trend. For example, as a matter of public policy, employers should not have employee handbook provisions and personnel policies that bind only the employees. To an unwitting employee, such policies appear to be binding on both parties and effectively lead the employee into a false sense of security. In reality, the policies are worth little more to the employee than the paper on which they are written. The majority of jurisdictions have recognized personnel policies and employee handbooks as creating an implied contract between employer and employee. These jurisdictions reason that offer, acceptance, and consideration are ascertainable in these “handbook cases.” Although many times employee handbooks contain unilateral offers to contract, they are offers nonetheless. These jurisdictions intimate that if employers want to avoid changing the employee\u27s durational status, they have the option of boldly disclaiming that the policies constitute a part of the employee\u27s employment contract. Maine has gone to great lengths to prevent handbooks and personnel policies from changing employees\u27 durational status. This Author contends that contract principles should be applied with uniformity regardless of the substance of the dispute and especially in these handbook cases in which the elements of an implied-in-fact contract are so readily apparent. It is with these issues of contract law that this Note ultimately concerns itself
HDAC2-deficient CD4+ T cells in a psoriasis-like mouse model of skin autoimmunity
No full textPsoriasis ist eine Autoimmunerkrankung der Haut, von der 2–4 % der Weltbevölkerung betroffen sind und wogegen derzeit spezifische Medikamente noch fehlen. Die Haut ist ein wichtiges Barrieregewebe des Körpers, in dem Effektor-T-Zellen (Teff) und Foxp3+-regulatorische T-Zellen (Treg) die Immunhomöostase bestimmen. Daher ist das Verständnis der molekularen Mechanismen, die die Differenzierung und Funktion kutaner CD4+ T-Zellen steuern, von entscheidender Bedeutung für die Entwicklung neuartiger T-Zell-basierter Therapien für T-Zell-vermittelte Autoimmunerkrankungen der Haut. Viele Mausmodelle versuchten, menschliche Psoriasis zu reproduzieren, doch das komplexe molekulare Netzwerk, das die Krankheit charakterisiert, macht es schwierig, die Krankheit zu rekapitulieren. Histondeacetylasen (HDACs) haben unterschiedliche Funktionen bei der Regulierung der Biologie und Funktion von T-Zellen. Allerdings ist die Rolle von HDAC2 in kutanen T-Zellen noch immer nicht geklärt. Die Ziele meines Doktoratsprojekts bestehen darin, das Immunmilieu und die Wechselwirkung zwischen Immunzellen und Strukturzellen in einem etablierten Modell der Autoimmunerkrankung der Haut zu charakterisieren und die Auswirkungen des HDAC2-Mangels auf CD4+ T-Zellen bei Autoimmunerkrankungen der Haut zu untersuchen. Zu diesem Zweck verwendeten wir ein Mausmodell einer experimentellen Autoimmunentzündung der Haut (bezeichnet als K5/TGO). In diesem Modell haben wir WT- oder HDAC2-defiziente naive Ova-spezifische OTII CD4+ T-Zellen adoptiv in K5/TGO-Empfängermäuse übertragen, die eine induzierbare Expression von Ova in der Epidermis aufweisen. Adoptiv übertragene T-Zellen reagieren auf in der Haut exprimierte Ova-Antigene und lösen eine Autoimmunerkrankung aus, die hauptsächlich durch Th1- und Th17-Zellen reguliert wird. Wir beobachteten das Immunmilieu der Haut und histologische Merkmale, die Hautläsionen von Psoriasis-Patienten ähnelten. Bei der Untersuchung der Rolle von HDAC2 in CD4+-T-Zellen stellten wir bei K5/TGO-Mäusen, die HDAC2-defiziente T-Zellen erhalten hatten, eine erhöhte Überlebensrate und eine verringerte Hautentzündung fest. Darüber hinaus zeigten unsere Ergebnisse, dass das Fehlen von HDAC2, den Phänotyp (z. B. die Expression von CTLA-4) von Foxp3+ Treg reguliert. Mit unseren Erkenntnissen werden wir ein alternatives Modell der Psoriasis und die molekulare Grundlage für die Entwicklung isoformspezifischer HDAC-Inhibitoren zur Behandlung von Autoimmunerkrankungen liefern.submitted by Alice Emma Taliento, MScLiteraturverzeichnis: Seite 77-88Das + im Titel ist hoch gestelltDissertation University of Salzburg 202
PNPLA3 I148M gene variant and chronic kidney disease in Type 2 diabetic patients with NAFLD: Clinical and experimental findings
No full textBackground and Aims: Emerging evidence suggests an association between patatin-like phospholipase domain-containing protein-3 (PNPLA3) rs738409 (I148M protein variant) and risk of chronic kidney disease (CKD), but the mechanisms underpinning this association are poorly understood. Methods: We studied 157 patients with type 2 diabetes (T2DM) who underwent ultrasonography and vibration-controlled transient elastography for diagnosing nonalcoholic fatty liver disease (NAFLD). CKD was defined as estimated glomerular filtration rate (e-GFR) '60 mL/min/1.73 m
2 and/or abnormal albuminuria. We surveyed PNPLA3 mRNA expression in human tissues, using the liver as a positive control, and also measured PNPLA3 mRNA and protein expression levels in human cell lines represented in the kidney and the liver. Results: In all, 112 patients had NAFLD and 43 had CKD. Patients homozygous for the I148M variant (n = 11) had lower e-GFR levels (60.6 ± 11.7 vs 77.8 ± 15.9 vs 83.5 ± 16.5 mL/min/1.73 m
2, P =.0001) and higher prevalence of CKD (63.6% vs 24.2% vs 25.0%, P =.028), compared to those with I/M (n = 66) and I/I (n = 80) PNPLA3 genotype. The association of I148M homozygosity with lower e-GFR levels (P '.0001) and higher risk of CKD (adjusted-odds ratio 6.65; 95% CI 1.65-26.8, P =.008) was independent of liver disease severity (as detected by liver stiffness ≥7kPa) and other risk factors. PNPLA3 mRNA expression was greatest in liver and renal cortex, and podocytes showed high PNPLA3 mRNA and protein levels, comparable to that of hepatocytes and hepatic stellate cells respectively. Conclusions: The PNPLA3 I148M variant was associated with CKD, independently of common renal risk factors and severity of NAFLD PNPLA3 expression levels were particularly high in renal podocytes.
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Postoperative pain after MiniLap percutaneous versus standard laparoscopic salpingo‐oophorectomy: A propensity‐matched study
No full textObjective: The aim of this study was to compare postoperative outcomes in patients undergoing standard laparoscopic salpingo-oophorectomy versus those using the MiniLap percutaneous surgical system, aiming to demonstrate the non-inferiority of this ultra-minimally invasive surgical technique compared to the current gold standard. Methods: This was a retrospective, single-center propensity-matched case-control study. A total of 80 surgical patients undergoing salpingo-oophorectomy for benign pathology were selected, with 40 in each group (MiniLap in group A and S-LPS in group B). Postoperative pain was subjectively reported at 2, 4, 12, and 24 h after surgery. The secondary outcomes of this study were to evaluate differences in the duration of surgery, intraoperative blood loss, postoperative complications, and cosmetic results. Results: The median operative time was 57.7 min (range, 28-125) in group A and 75.5 min (range, 22-180) in group B (P value 0.005). No statistical differences were recorded in terms of estimated blood loss (P value 0.05), length of hospital stay (P value 0.74), complications (P-value 0.31), and postoperative pain (P value 0.06 at 2 h postoperatively). Cosmetic outcomes acquired through subjective assessment by the patient and surgeon at discharge and 1 month after surgery demonstrated a statistically significant higher satisfaction rate in the MiniLap compared to the S-LPS group. Conclusion: Our study demonstrates that salpingo-oophorectomy performed with the MiniLap system is feasible, safe, and well-tolerated by patients. Furthermore, this technique has proven to be non-inferior to standard LPS in terms of postoperative pain, blood loss, hospital stay duration, and complications
Surgical management of anastomotic leakage related to ovarian cancer surgery: a narrative review
No full textThis narrative review describes the state of the art in the management of anastomotic leakage in ovarian cancer. Multiple surgical procedures, including bowel resection, are often required to achieve “optimal” cytoreduction in locally advanced ovarian cancer. Intestinal anastomosis is currently the most common way to restore bowel continuity. However, in some patients, a temporary protective stoma is indicated to prevent anastomotic leakage. This is an important issue to improve surgical outcomes and until recently there has been a lack of objective data to clarify the risk factors for anastomotic leakage. This review describes the risk factors for AL associated with surgery and compares the results of recent studies. We also review the current indications for placement of a protective ileostomy and treatment options for conservative management of AL. We present two examples of practical clinical AL risk calculators, in addition to the most assessed AL risk factor. To date, the decision-making processes that lead surgeons to perform a protective ileostomy are quite heterogeneous and based on the personal experience of the surgeon, mainly depending on individual training. Three different management options after colorectal anastomosis in OC are described: conservative management, diversion ileostomy and ghost ileostomy
Novel Insights into the Genetic Landscape of Nonalcoholic Fatty Liver Disease
No full textNonalcoholic fatty liver disease (NAFLD), the most common liver disorder worldwide, is epidemiologically associated with overweight, insulin resistance features and type 2 diabetes, and can progress to advanced liver fibrosis and hepatocellular carcinoma. Genetic factors play an important role in the development of NAFLD, which is a multifactorial disease. Several common naturally occurring variants modulating lipid and retinol metabolism in hepatocytes predispose to NAFLD development and progression, in particular those in PNPLA3, TM6SF2, MBOAT7, and HSD17B13. In addition, genetic variants that protect hepatic cells from oxidative stress modulate the susceptibility to progressive NAFLD. Although the molecular mechanisms linking these genetic variants with liver disease are not yet fully understood, hepatic fat has emerged as a major driver of the disease, while altered retinol metabolism and mitochondrial oxidative stress play a role in determining the development of advanced NAFLD
HDAC-regulated effects of CD4+ T cells on B cell differentiation and function
No full textMany skin autoimmune diseases are known to be driven by autoreactive CD4+ effector T (Teff) cells. Among the different CD4+ T helper subsets, follicular helper T (Tfh) cells are known to induce antibody-mediated autoimmunity as they regulate B cell activation and antibody production. Histone deacetylases (HDACs) regulate the differentiation of CD4+ T cells in CD4+ T cell-mediated diseases. However, their function in Tfh cell differentiation is yet to be elucidated. My master’s project aimed to study Tfh cell differentiation and antigen-specific antibody production in a mouse model of skin autoimmunity. In this model, I also assessed the role of class I HDACs in the regulation of Tfh cell differentiation. For this purpose, we adoptively transferred naïve OT-II CD4+ T cells into a mouse model (K5/TGO) that expresses ovalbumin (OVA) specifically in the epidermis of the skin in an inducible manner. Upon OVA recognition, naïve CD4+ T cells differentiated into multiple Teff subtypes, including Tfh, and induced a CD4+ T cell-driven skin autoimmune disease. Additionally, we detected total and OVA-specific IgG antibodies in the inflamed skin and the serum, respectively. These data are in line with the notion that Tfh cells contribute to the autoimmune response to the OVA self-antigen and that this mouse model is suitable for studying Tfh cell differentiation and autoreactive antibodies in skin autoimmune diseases. To analyze the role of HDACs in this setting, we transferred either wild-type (WT), HDAC1-deficient, or HDAC2-deficient CD4+ T cells into K5/TGO mice. Previous PhD students in our group (Alice Emma Taliento and Melanie Jensen) observed that the disease severity was regulated by HDAC1 and HDAC2 deficiency in CD4+ T cells. We hypothesized that these differences in disease were antibody-dependent. Indeed, the transfer of CD4+ T cells induced IgG2c secretion, and the concentration of this immunoglobulin in the skin correlated with disease severity. Moreover, HDAC1 deficiency in CD4+ T cells resulted in increased IgG2c levels in the skin compared to WT recipients, which fit with a more severe phenotype of HDAC1-cKO T cell recipients as described by Melanie Jensen. By contrast, HDAC2 expression in CD4+ T cells did not affect antibody secretion. These data suggest distinct roles for HDAC1 and HDAC2 in the development of CD4+ T cell-driven skin autoimmunity. This work revealed previously unknown roles of class I HDACs in skin autoimmunity that are associated with cutaneous antibodies and might thus inform future therapeutic approaches to treating CD4-driven skin autoimmune diseases.submitted by Laia Ribera Franco, BScLiteraturverzeichnis: Seite 48-50Masterarbeit Paris Lodron University of Salzburg 202
HDAC-regulated effects of CD4+ T cells on B cell differentiation and function
No full textMany skin autoimmune diseases are known to be driven by autoreactive CD4+ effector T (Teff) cells. Among the different CD4+ T helper subsets, follicular helper T (Tfh) cells are known to induce antibody-mediated autoimmunity as they regulate B cell activation and antibody production. Histone deacetylases (HDACs) regulate the differentiation of CD4+ T cells in CD4+ T cell-mediated diseases. However, their function in Tfh cell differentiation is yet to be elucidated. My master’s project aimed to study Tfh cell differentiation and antigen-specific antibody production in a mouse model of skin autoimmunity. In this model, I also assessed the role of class I HDACs in the regulation of Tfh cell differentiation. For this purpose, we adoptively transferred naïve OT-II CD4+ T cells into a mouse model (K5/TGO) that expresses ovalbumin (OVA) specifically in the epidermis of the skin in an inducible manner. Upon OVA recognition, naïve CD4+ T cells differentiated into multiple Teff subtypes, including Tfh, and induced a CD4+ T cell-driven skin autoimmune disease. Additionally, we detected total and OVA-specific IgG antibodies in the inflamed skin and the serum, respectively. These data are in line with the notion that Tfh cells contribute to the autoimmune response to the OVA self-antigen and that this mouse model is suitable for studying Tfh cell differentiation and autoreactive antibodies in skin autoimmune diseases. To analyze the role of HDACs in this setting, we transferred either wild-type (WT), HDAC1-deficient, or HDAC2-deficient CD4+ T cells into K5/TGO mice. Previous PhD students in our group (Alice Emma Taliento and Melanie Jensen) observed that the disease severity was regulated by HDAC1 and HDAC2 deficiency in CD4+ T cells. We hypothesized that these differences in disease were antibody-dependent. Indeed, the transfer of CD4+ T cells induced IgG2c secretion, and the concentration of this immunoglobulin in the skin correlated with disease severity. Moreover, HDAC1 deficiency in CD4+ T cells resulted in increased IgG2c levels in the skin compared to WT recipients, which fit with a more severe phenotype of HDAC1-cKO T cell recipients as described by Melanie Jensen. By contrast, HDAC2 expression in CD4+ T cells did not affect antibody secretion. These data suggest distinct roles for HDAC1 and HDAC2 in the development of CD4+ T cell-driven skin autoimmunity. This work revealed previously unknown roles of class I HDACs in skin autoimmunity that are associated with cutaneous antibodies and might thus inform future therapeutic approaches to treating CD4-driven skin autoimmune diseases.submitted by Laia Ribera Franco, BScLiteraturverzeichnis: Seite 48-50Masterarbeit Paris Lodron University of Salzburg 202
Frontiers in Immunology / NLRP3 promotes allergic responses to birch pollen extract in a model of intranasal sensitization
No full textIntroduction & Objective: Allergic sensitization is an essential step in the development of allergic airway inflammation to birch pollen (BP); however, this process remains to be fully elucidated. Recent scientific advances have highlighted the importance of the allergen context. In this regard, microbial patterns (PAMPs) present on BP have attracted increasing interest. As these PAMPs are recognized by specialized pattern recognition receptors (PRRs), this study aims at investigating the roles of intracellular PRRs and the inflammasome regulator NLRP3.
Methods: We established a physiologically relevant intranasal and adjuvant-free sensitization procedure to study BP-induced systemic and local lung inflammation.
Results: Strikingly, BP-sensitized Nlrp3-deficient mice showed significantly lower IgE levels, Th2-associated cytokines, cell infiltration into the lung, mucin production and epithelial thickening than their wild-type counterparts, which appears to be independent of inflammasome formation. Intriguingly, bone-marrow chimera revealed that expression of NLRP3 in the hematopoietic system is required to trigger an allergic response.
Conclusion: Overall, this study identifies NLRP3 as an important driver of BP-induced allergic immune responses
