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The article calls for pharmacy preceptors to integrate professional identity formation (PIF) into experiential pharmacy education and training of students and residents. It suggests ways to incorporate PIF into learning experiences including open discussion, creating a zone of psychological safety and converting theoretical frameworks into practical activities. It presents examples of PIF activities such as mock challenging situations, role modeling, layered learning and reflective writing.

This retrospective cross-sectional study aimed to explore interactions between signs of periodontal inflammation and systemic parameters in athletes. Members of German squads with available data on sports medical and oral examination were included. Groups were divided by gingival inflammation (median of papillary bleeding index, PBI ≥ median) and signs of periodontitis (Periodontal Screening Index, PSI ≥ 3). Age, gender, anthropometry, blood parameters, echocardiography, sports performance on ergometer, and maximal aerobic capacity (VO2max) were evaluated. Eighty-five athletes (f = 51%, 20.6 ± 3.5 years) were included (PBI < 0.42: 45%; PSI ≥ 3: 38%). Most associations were not statistically significant. Significant group differences were found for body fat percentage and body mass index. All blood parameters were in reference ranges. Minor differences in hematocrit, hemoglobin, basophils, erythrocyte sedimentation rates, urea, and HDL cholesterol were found for PBI, in uric acid for PSI. Echocardiographic parameters (n = 40) did not show any associations. Athletes with PSI ≥ 3 had lower VO2max values (55.9 ± 6.7 mL/min/kg vs. 59.3 ± 7.0 mL/min/kg; p = 0.03). In exercise tests (n = 30), athletes with PBI < 0.42 achieved higher relative maximal load on the cycling ergometer (5.0 ± 0.5 W/kg vs. 4.4 ± 0.3 W/kg; p = 0.03). Despite the limitations of this study, potential associations between signs of periodontal inflammation and body composition, blood parameters, and performance were identified. Further studies on the systemic impact of oral inflammation in athletes, especially regarding performance, are necessary. [ABSTRACT FROM AUTHOR]

Purpose: This retrospective cross‐sectional study aimed to evaluate oral health status (dental, periodontal, and functional) and oral health behavior in young German athletes including the comparison of competitive (CA) and amateur sports (AA). Methods: Data of CA (German national teams, perspective, and youth squads) and AA aged between 18 and 30 years with an available oral examination in 2019 were included. Clinical examination: caries experience (DMF‐T), non‐carious wear (erosion, BEWE), partially erupted wisdom teeth, gingival inflammation (PBI), plaque index, periodontal screening (PSI), and temporomandibular dysfunction (TMD) screening. Questionnaires: oral health behavior and periodontal symptoms. Results: 88 CA (w = 51%, 20.6 ± 3.5 years) of endurance sports and 57 AA (w = 51%, 22.2 ± 2.1 years) were included. DMF‐T was comparable (CA: 2.7 ± 2.2, AA: 2.3 ± 2.2; p = 0.275) with more D‐T in CA (0.6 ± 1.0) than AA (0.3 ± 0.7; p = 0.046; caries prevalence: CA: 34%, AA: 19%; p = 0.06). Both groups had low severity of erosion (BEWE about 3.5). CA had more positive TMD screenings (43% vs. 25%; p = 0.014). In both groups, all athletes showed signs of gingival inflammation, but on average of low severity (PBI <1). More CA needed complex periodontal treatment than AA (maximum PSI = 3 in 40% vs. 12%; p < 0.001). Oral health behavior was comparable (daily tooth brushing; regular dental check‐ups in >70%). Conclusions: Young German athletes (CA and AA) generally showed signs of gingival inflammation and needed to improve their oral health behavior. CA showed slightly increased oral findings (more D‐T, periodontal and TMD screening findings) than AA, but similar oral health behavior. This may imply an increased dental care need in competitive sports. [ABSTRACT FROM AUTHOR]

Pervasive alteration of basaltic oceanic crust by heated seawater at greenschist facies conditions produces two contrasting hydrothermal rocks. "Spilites", consisting of chlorite + albite + quartz ± actinolite ± epidote, occur typically with regional extents. Locally spilites are metasomatically transformed to "epidosites" consisting of epidote + quartz + titanite + hematite or magnetite. Both alteration types have been proposed as markers of deep hydrothermal upflow in sub-seafloor convection cells, and as sources of the ore metals in basalt-hosted seafloor massive sulfide deposits. Little direct evidence is available for the chemical compositions of these fluids in their states deep in the upflow zones prior to their discharge at the seafloor. To better characterize them we have conducted a field, petrographic and fluid inclusion study of the lavas, sheeted dikes and plagiogranites in the Semail ophiolite, with supporting samples from the Troodos ophiolite. Our results show that both the spilite- and epidosite-forming fluids were single-phase aqueous liquids during the hydrothermal alteration. At some sites their salinity is 3.1–3.2 wt.% NaCl eq , which we take to represent the chlorinity of Cenomanian seawater in the Semail realm. At other sites salinities are as low as 2.4 wt.% NaCl eq or as high as 5.7 wt.% NaCl eq , attributable to liquid–vapor separation and partial remixing deep in the crust along the dew curve of seawater, prior to ascent of the fluids to the sites of fluid inclusion trapping. Hypersaline brines, often accompanied by vapor, are restricted to plagiogranites in both the Semail and Troodos ophiolites and they represent magmatic–hydrothermal fluids that pre-date and are genetically unrelated to the spilite and epidosite alteration. The volcanostratigraphic locations of the samples constrain their maximum depths to 1470–3600 m below seafloor during alteration. The range of possible fluid trapping pressures for all samples is 31–68 MPa. Trapping temperatures vary between sites from 145 to 440 °C for spilite fluids and 255 to 435 °C for epidosite fluids. Quantitative analyses of 12 elements in individual fluid inclusions by LA-ICP-MS define the chemical characters of the two alteration fluids. The Br/Cl ratio in the spilite fluid is the same as in modern seawater and the other elements fit expectations from seawater–basalt experiments at elevated temperature. Accordingly, concentrations of Li, B, Na, Cl, K, Br and Sr in the spilite fluid match those in modern black-smoker vent fluids in basaltic crust. Exceptions are Ca and Fe, which are enriched in the spilite fluid. As these elements may precipitate below or at the seafloor prior to vent sampling, we conclude that the spilite fluids are plausible feeders of basalt-hosted black-smoker vents. The epidosite fluid has broadly similar elemental concentrations to the spilite fluid, but vastly lower Fe, reflecting the highly oxidized state of epidosites. This suggests that epidosite fluids are incapabable of forming basalt-hosted seafloor massive sulfide deposits. [ABSTRACT FROM AUTHOR]

Most rare earth element deposits form from magmatic fluids, but there have also been discoveries of heavy rare earth element (HREE)- enriched hydrothermal xenotime deposits within sedimentary basins. As xenotime is notoriously insoluble, the question arises as to whether these lesser-known deposits form at typical basin temperatures or by influx of much hotter magmatic-hydrothermal fluids. The Browns Range District in northern Western Australia hosts deposits of xenotime that are enriched in HREEs and also uranium. The ore bodies consist of fault-controlled hydrothermal quartz-xenotime breccias that crosscut Archean basement rocks and overlying Paleoproterozoic sandstones. Analyses of fluid inclusions show that the xenotime precipitated at remarkably low temperatures, between 100 and 120 °C, in response to decompression boiling. The inclusions contain high excess concentrations of yttrium (10-3 mol/kg), REEs (1-7 × 10-5 mol/kg), and uranium (4 × 10-5 mol/kg) in equilibrium with xenotime at these low temperatures, showing that availability of phosphate limited the amount of xenotime precipitated. The analyses further identify SO42- and Cl- as the ligands that facilitated the elevated REE and uranium solubilities. These findings establish that significant REE transport and deposition is feasible at basin temperatures, and hence they raise the potential of unconformity settings for REE exploration. Moreover, the aqueous metal contents support a genetic link between this type of ore fluid and world-class Proterozoic unconformity-related uranium deposits elsewhere. [ABSTRACT FROM AUTHOR]

Purpose: Biomarkers are essential to implement personalized therapies in cancer treatment options. As primary liver tumors are increasing and treatment is coupled to liver function and activation of systemic cells of the immune system, we investigated blood-based cells for their ability to predict response to local ablative therapy. Methods: We analyzed peripheral blood cells in 20 patients with primary liver cancer at baseline and following brachytherapy. In addition to platelets, leukocytes, lymphocytes, monocytes, neutrophils and most common ratios PLR, LMR, NMR and NLR, we investigated T cell and NKT cell populations of 11 responders and 9 non-responders using flow cytometry. Results: We have found a peripheral blood cell signature that differed significantly between responders and non-responders treated with interstitial brachytherapy (IBT). At baseline, non-responders featured higher numbers of platelets, monocytes and neutrophils, a higher platelet-to-lymphocyte ratio and an increase in the NKT cell population with a concurrent reduction in CD16 + NKT cells. Simultaneously, a lower percentage of CD4 + T cells was present in non-responders, as also reflected in a lower CD4/8 ratio. CD45RO + memory cells were lower in both, CD4 + and CD8 + T cell populations whereas PD-1 + T cells were only present in the CD4 + T cell population. Conclusion: Baseline blood-based cell signature may function as a biomarker to predict response following brachytherapy in primary liver cancer. [ABSTRACT FROM AUTHOR]

Purpose. The case of a patient with multiple medication hypersensitivity reactions and a methicillin-resistant Staphylococcus aureus (MRSA) infection who underwent desensitization to ceftaroline is reported. Summary. A 32-year-old Caucasian woman with asthma, gastroesophageal reflux disease, heart murmur, and major depression was admitted for MRSA cellulitis with a subcutaneous abscess along the left sternomanubrial joint and clavicular osteomyelitis secondary to port placement after gastric bypass surgery. The patient had an extensive history of hypersensitivity reactions. Pertinent documented allergies were as follows: penicillin (anaphylaxis), daptomycin (anaphylaxis), vancomycin (hives), linezolid (hives), ertapenem (rash), ciprofloxacin (rash), and tigecycline (rash). The patient also reported previous reactions to aztreonam (unknown) and gentamicin (hives). The pharmacy was consulted to develop a desensitization protocol for ceftaroline. The desensitization protocol used three serial dilutions of ceftaroline to make 14 sequential infusions with escalating doses. Intramuscular epinephrine, i.v. diphenhydramine, and i.v. methylprednisolone were ordered as needed for the development of immediate hypersensitivity reactions during or after administration of ceftaroline. The cumulative dose (574.94 mg) was administered intravenously over 225 minutes with no breakthrough symptoms reported during or after the desensitization protocol. Ceftaroline fosamil 600 mg i.v. every 12 hours was continued for six weeks. Conclusion. Desensitization to ceftaroline was conducted for a patient with extensive history of hypersensitivity reactions to other drugs, including penicillin-induced anaphylaxis. Desensitization and subsequent treatment with full doses of ceftaroline were accomplished without apparent adverse effects. [ABSTRACT FROM AUTHOR]

The article discusses social impact investing in the U.S., focusing on the benefits of this type of investing on the environment, community development, and healthcare systems. It looks at the history of impact investing, which started in the 1960s, and the benefits associated with it. Other topics of the article include the differences between impact investing and government funding/grants, investing based off of community health needs assessments (CHNA), and public-private partnerships. It also discusses philanthropic organizations, such as the Kresge Foundation and the MetLife Foundation, who partner with community development financial institutions (CDFI) to aid in health, housing and environmental projects.

The therapy of cancer continues to be a challenge aggravated by the evolution of resistance against current medications. As an alternative for the traditional tripartite treatment options of surgery, radiation and chemotherapy, immunotherapy is gaining increasing attention due to the opportunity of more targeted approaches. Promising targets are antigen-presenting cells which drive innate and adaptive immune responses. The discovery and emergence of new drugs and lead structures can be inspired by natural products which comprise many highly bioactive molecules. The development of new drugs based on natural products is hampered by the current lack of guidelines for screening these structures for immune activating compounds. In this work, we describe a phenotypic preclinical screening pipeline for first-line identification of promising natural products using the mouse as a model system. Favorable compounds are defined to be non-toxic to immune target cells, to show direct anti-tumor effects and to be immunostimulatory at the same time. The presented screening pipeline constitutes a useful tool and aims to integrate immune activation in experimental approaches early on in drug discovery. It supports the selection of natural products for later chemical optimization, direct application in in vivo mouse models and clinical trials and promotes the emergence of new innovative drugs for cancer treatment. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is often characterized by the presence of specific, recurrent chromosomal abnormalities. One of the most common aberrations, inversion of chromosome 16 [inv(16)], generates the fusion oncogene CBFB-MYH11. Previously, we used a mouse knock-in model to show that Cbfb-MYH11 induces changes in gene expression and results in the accumulation of abnormal myeloid cells, a subset of which are enriched for leukemia stem cell (LSC) activity. One gene upregulated by Cbfb-MYH11 encodes the cytokine receptor IL1RL1 (ST2). IL1RL1 and its ligand IL-33 are known regulators of mature myeloid cells, but their roles in AML are not known. Here, we use Cbfb-MYH11 knock-in mice to show that IL1RL1 is expressed by cell populations with high LSC activity, and that the cell surface expression of IL1RL1 is dynamic, implying that the expression of IL1RL1 is not restricted to a specific stage of differentiation. We also show that treatment with IL-33 increased serial replating ability and expression of pro-survival proteins in vitro. Finally, we show that IL1RL1+ cells can survive chemotherapy better than IL1RL1− cells in vivo. Collectively, our results indicate that IL1RL1 is dynamically expressed in Cbfb-MYH11+ leukemia cells and promotes their survival. [ABSTRACT FROM AUTHOR]

The article presents a statement from the American Society of Health-System Pharmacists (ASHP) on precepting of students and postgraduate trainees as a professional obligation. It discusses the importance of experiential learning and outlines the value of precepting to learners, preceptors, healthcare institutions and patients. It describes the responsibilities of stakeholders, professional organizations, colleges of pharmacy and postgraduate training programs, and healthcare institutions.

Background: GD2-directed immunotherapy is highly effective in the treatment of high-risk neuroblastoma (NB), and might be an interesting target also in other high-risk tumors. Methods: The German-Austrian Retinoblastoma Registry, Essen, was searched for patients, who were treated with anti-GD2 monoclonal antibody (mAb) dinutuximab beta (Db) in order to evaluate toxicity, response and outcome in these patients. Additionally, we evaluated anti-GD2 antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in retinoblastoma cell lines in vitro. Furthermore, in vitro cytotoxicity assays directed against B7-H3 (CD276), a new identified potential target in RB, were performed. Results: We identified four patients with relapsed stage IV retinoblastoma, who were treated with Db following autologous stem cell transplantation (ASCT). Two out of two evaluable patients with detectable tumors responded to immunotherapy. One of these and another patient who received immunotherapy without residual disease relapsed 10 and 12 months after start of Db. The other patients remained in remission until last follow-up 26 and 45 months, respectively. In vitro, significant lysis of RB cell lines by ADCC and CDC with samples from patients and healthy donors and anti-GD2 and anti-CD276-mAbs were demonstrated. Conclusion: Anti-GD2-directed immunotherapy represents an additional therapeutic option in high-risk metastasized RB. Moreover, CD276 is another target of interest. [ABSTRACT FROM AUTHOR]

Arteriogenesis, the growth of natural bypass blood vessels, can compensate for the loss of arteries caused by vascular occlusive diseases. Accordingly, it is a major goal to identify the drugs promoting this innate immune system-driven process in patients aiming to save their tissues and life. Here, we studied the impact of the Cobra venom factor (CVF), which is a C3-like complement-activating protein that induces depletion of the complement in the circulation in a murine hind limb model of arteriogenesis. Arteriogenesis was induced in C57BL/6J mice by femoral artery ligation (FAL). The administration of a single dose of CVF (12.5 µg) 24 h prior to FAL significantly enhanced the perfusion recovery 7 days after FAL, as shown by Laser Doppler imaging. Immunofluorescence analyses demonstrated an elevated number of proliferating (BrdU+) vascular cells, along with an increased luminal diameter of the grown collateral vessels. Flow cytometric analyses of the blood samples isolated 3 h after FAL revealed an elevated number of neutrophils and platelet-neutrophil aggregates. Giemsa stains displayed augmented mast cell recruitment and activation in the perivascular space of the growing collaterals 8 h after FAL. Seven days after FAL, we found more CD68+/MRC-1+ M2-like polarized pro-arteriogenic macrophages around growing collaterals. These data indicate that a single dose of CVF boosts arteriogenesis by catalyzing the innate immune reactions, relevant for collateral vessel growth. [ABSTRACT FROM AUTHOR]

Introduction: Starting point of the study was the experience, that despite of a strong identification of physiotherapists and occupational therapists there is a high degree of dissatisfaction with the recognition of their occupation exists. It was examined how recognition is experienced from the subjective perspective of the therapists. Method: In a seminar on qualitative research methods for the Bachelor "Physiotherapy/Occupational Therapy", students of the Alice Salomon Hochschule (ASH) Berlin conducted fourteen semi-structured interviews with the following topic: "Satisfaction with the professional recognition among physiotherapists and occupational therapists". Subsequently the interviews were transcribed, and individual passages were coded and grouped into categories. Results: Six categories were developed: society, quality, finances, free time, experience of recognition and future. The conclusion of all six categories is that, according to the statements of the interviewees, both occupational therapists and physiotherapists were highly unsatisfied with the professional recognition of their respective occupation. The interviewees suggest that advancing the academicalisation and professionalisation of both occupational groups may ameliorate the situation. Conclusion: Providing scientific proof for the success of individual therapies should improve the political and social recognition of the two professions. Moreover, quality-increasing measures such as further vocational training may be essential deriving the best possible therapy and improving the professional recognition. [ABSTRACT FROM AUTHOR]

Cell hydration changes play a key role in the regulation of cell function and critically affect insulin sensitivity of carbohydrate- and protein metabolism. Here, the modulation of gene expression profiles by hyperosmolarity and insulin was examined in H4IIE rat hepatoma cells by cDNA/oligonucleotiode array-, Northern- and Western blot analysis. Osmosensitive expression of the insulin-like growth factor binding protein Igfbp1, the multidrug resistance protein Mrp5 (Abcc5a) and cyclin D1 (Ccnd1) was established at the mRNA and protein level. Despite a hyperosmotic increase of cyclin D1 mRNA induction by insulin, the cyclin D1 protein expression was decreased by hyperosmolarity, suggesting a hyperosmotic interference with cyclin D1 mRNA translation. Hyperosmolarity at the mRNA level blunted the insulin response of betaine homocysteine-S-methyl transferase, the multidrug resistance proteins Mdr1a (Abcb1a) and 2 (Abcb4), the Igfbp 2 and 5, cyclin G1, dual specificity phosphatase Dusp1, signal transducers and activators of transcription Stat3 and 5, catalase and the bile salt export pump Bsep (Abcb11), whereas the insulin response was increased for Mrp5, cyclin D1 and the phosphoenolpyruvate carboxykinase. Insulin effects on the mRNA expression of the eukaryotic initiation factor 4E binding protein 4e-bp1, tubulin, gene 33, growth hormone receptor, keratin18, ornithine decarboxylase and heme oxygenase 1 were largely insensitive to hyperosmolarity. The data indicate that hyperosmolarity differentially modulates insulin sensitivity at the level of gene expression. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background/Aims: Proteasome inhibitors such as MG-132 are considered as potential therapeutical tools in different clinical settings. The dual specificity MAP-kinase phosphatase MKP-1 plays a role in balancing signals mediating cell death or survival. Here the effect of cell hydration on MG-132-induced MKP-1 expression was investigated in H4IIE rat hepatoma cells. Results: Hyperosmolarity (405mosmol/l) increased MKP-1 expression by MG-132, which was accompanied by an induction of c-Fos, c-Jun, cJun Ser73 phosphorylation, and AP-1 DNA binding. MKP-1 induction by MG-132 plus hyperosmolarity was sensitive to inhibition of p38MAPK and c-Jun-N-terminal kinases (JNKs) but not extracellular signal-regulated kinases Erk-1/Erk-2, and was accompanied by a decline of MAP-kinase activities. Although hyperosmolarity increased overall protein ubiquitination in presence of MG-132, ubiquitination of MKP-1 was found under normo-, but not hyperosmotic conditions. Hyperosmolarity also enabled MG-132 to induce poly-ADP-ribose polymerase (PARP) cleavage which was sensitive to inhibition of p38MAPK and JNKs but not Erk-1/Erk-2. PARP cleavage and caspase-3 activation in H4IIE cells treated with hyperosmolarity plus MG-132 was further increased by vanadate, consistent with a contribution of MKP-1 to counterbalance proapoptotic MAP-kinase signals. Conclusion: The findings suggest that among other factors cell hydration critically determines the cellular response to proteasome inhibitors. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Targeting Ags to conventional dendritic cells can enhance Ag-specific immune responses. Although most studies have focused on the induction of T cell responses, the mechanisms by which targeting improves Ab responses are poorly understood. In this study we present data on the use of human XCL1 (hXCL1) and hXCL2 fusion vaccines in a murine model. We show that the human chemokines bound type 1 conventional dendritic cells (cDC1), and that immunization with influenza virus hemagglutinin fused to hXCL1 or hXCL2 induced full protection against influenza challenge. Surprisingly, the hXCL1- and hXCL2-fusion vaccines induced better long-term protection associated with stronger induction of neutralizing Abs, and more Ab-secreting cells in bone marrow. In contrast, murine Xcl1 fusion vaccines induced stronger CD8+ T cell responses compared with hXCL1. Further analysis revealed that although murine Xcl1 fusion vaccines induced chemotaxis and were rapidly endocytosed by cDC1, hXCL1 and hXCL2 fusion vaccines did not induce chemotaxis, were less efficiently endocytosed, and consequently, remained on the surface. This difference may explain the enhanced induction of Abs when targeting Ag to cDC1 using hXCL1 and hXCL2, and suggests that immune responses can be manipulated in directing Abs or T cells based on how efficiently the targeted Ag is endocytosed by the DC. [ABSTRACT FROM AUTHOR]

Conventional dendritic cells (cDCs) comprise a heterogeneous population of cells that are important regulators of immunity and homeostasis. CD1c+ cDCs are present in human blood and tissues, and found to efficiently activate naïve CD4+ T cells. While CD1c is thought to specifically identify this subset of human cDCs, we show here that also classical and intermediate monocytes express CD1c. Accordingly, the commercial CD1c (BDCA-1)+ Dendritic Cell Isolation Kit isolates two distinct cell populations from blood: CD1c+CD14− cDCs and CD1c+CD14+ monocytes. CD1c+ cDCs and CD1c+ monocytes exhibited strikingly different properties, including their differential regulation of surface marker expression, their levels of cytokine production, and their ability to stimulate naïve CD4+ T cells. These results demonstrate that a commercial CD1c (BDCA-1)+ Dendritic Cell Isolation Kit isolates two functionally different cell populations, which has important implications for the interpretation of previously generated data using this kit to characterize CD1c+ cDCs. [ABSTRACT FROM AUTHOR]

Summary The role of dendritic cells (DCs) in intestinal immune homeostasis remains incompletely defined. Here we show that mice lacking IRF8 transcription-factor-dependent DCs had reduced numbers of T cells in the small intestine (SI), but not large intestine (LI), including an almost complete absence of SI CD8αβ + and CD4 + CD8αα + T cells; the latter requiring β8 integrin expression by migratory IRF8 dependent CD103 + CD11b - DCs. SI homing receptor induction was impaired during T cell priming in mesenteric lymph nodes (MLN), which correlated with a reduction in aldehyde dehydrogenase activity by SI-derived MLN DCs, and inefficient T cell localization to the SI. These mice also lacked intestinal T helper 1 (Th1) cells, and failed to support Th1 cell differentiation in MLN and mount Th1 cell responses to Trichuris muris infection. Collectively these results highlight multiple non-redundant roles for IRF8 dependent DCs in the maintenance of intestinal T cell homeostasis. [ABSTRACT FROM AUTHOR]

Background/Aims: The role of bile acids for insulin resistance in cholestatic liver disease is unknown. Methods: The effect of taurolithocholic acid-3 sulfate (TLCS) on insulin signaling was studied in cultured rat hepatocytes and perfused rat liver. Results: TLCS induced insulin resistance at the level of insulin receptor (IR) β Tyr(1158) phosphorylation, phosphoinositide (PI) 3-kinase activity and protein kinase (PK)B Ser(473) phosphorylation in cultured hepatocytes. Consistently, the insulin stimulation of the PI 3-kinase-dependent K+ uptake, hepatocyte swelling and proteolysis inhibition was blunted by TLCS in perfused rat liver. The PKC inhibitor Gö6850 and tauroursodeoxycholate (TUDC) counteracted the suppression of insulin-induced IRβ and PKB phosphorylation by TLCS. Rapamycin and dibutyryl-cAMP, which inhibited basal signaling via mammalian target of rapamycin (mTOR), restored insulin-induced PKB- but not IRβ phosphorylation. In livers from 7 day bile duct-ligated rats PKB Ser(473) phosphorylation was decreased by about 50%. Conclusion: TLCS induces insulin resistance by a PKC-dependent suppression of insulin-induced IRβ phosphorylation and the PI 3-kinase/PKB path. This can in part be compensated by a decrease of mTOR activity, which may release insulin-sensitive components downstream of the insulin receptor from tonic inhibition. The data suggest that retention of hydrophobic bile acids confers insulin resistance on the cholestatic liver. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Arteriogenesis, the growth of a natural bypass from pre-existing arteriolar collaterals, is an endogenous mechanism to compensate for the loss of an artery. Mechanistically, this process relies on a locally and temporally restricted perivascular infiltration of leukocyte subpopulations, which mediate arteriogenesis by supplying growth factors and cytokines. Currently, the state-of-the-art method to identify and quantify these leukocyte subpopulations in mouse models is immunohistology. However, this is a time consuming procedure. Here, we aimed to develop an optimized protocol to identify and quantify leukocyte subpopulations by means of flow cytometry in adductor muscles containing growing collateral arteries. For that purpose, adductor muscles of murine hindlimbs were isolated at day one and three after induction of arteriogenesis, enzymatically digested, and infiltrated leukocyte subpopulations were identified and quantified by flow cytometry, as exemplary shown for neutrophils and macrophages (defined as CD45+/CD11b+/Ly6G+ and CD45+/CD11b+/F4/80+ cells, respectively). In summary, we show that flow cytometry is a suitable method to identify and quantify leukocyte subpopulations in muscle tissue, and provide a detailed protocol. Flow cytometry constitutes a timesaving tool compared to histology, which might be used in addition for precise localization of leukocytes in tissue samples. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) leading to demyelination and axonal damage. It often affects young adults and can lead to neurological disability. Interferon β (IFNβ) preparations represent widely used treatment regimens for patients with relapsing-remitting MS (RRMS) with therapeutic efficacy in reducing disease progression and frequency of acute exacerbations. In mice, IFNβ therapy has been shown to ameliorate experimental autoimmune encephalomyelitis (EAE), an animal model of MS while genetic deletion of IFNβ or its receptor augments clinical severity of disease. However, the complex mechanism of action of IFNβ in CNS autoimmunity has not been fully elucidated. Here, we review our current understanding of the origin, phenotype, and function of microglia and CNS immigrating macrophages in the pathogenesis of MS and EAE. In addition, we highlight the emerging roles of microglia as IFNβ-producing cells and vice versa the impact of IFNβ on microglia in CNS autoimmunity. We finally discuss recent progress in unraveling the underlying molecular mechanisms of IFNβ-mediated effects in EAE. [ABSTRACT FROM AUTHOR]