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We measured the Coulomb dissociation of 16O into 4He and 12C within the FAIR Phase-0 program at GSI Helmholtzzentrum für Schwerionenforschung Darmstadt, Germany. From this we will extract the photon dissociation cross section 16O(α,γ)12C, which is the time reversed reaction to 12C(α,γ)16O. With this indirect method, we aim to improve on the accuracy of the experimental data at lower energies than measured so far. The expected low cross section for the Coulomb dissociation reaction and close magnetic rigidity of beam and fragments demand a high precision measurement. Hence, new detector systems were built and radical changes to the R3B setup were necessary to cope with the high-intensity 16O beam. All tracking detectors were designed to let the unreacted 16O ions pass, while detecting the 12C and 4He.

Abstract Background Gene knockouts are a critical resource for functional genomics. In Arabidopsis, comprehensive knockout collections were generated by amplifying and sequencing genomic DNA flanking insertion mutants. These Flanking Sequence Tags (FSTs) map each mutant to a specific locus within the genome. In maize, FSTs have been generated using DNA transposons. Transposable elements can generate unstable insertions that are difficult to analyze for simple knockout phenotypes. Transposons can also generate somatic insertions that fail to segregate in subsequent generations. Results Transposon insertion sites from 106 UniformMu FSTs were tested for inheritance by locus-specific PCR. We confirmed 89% of the FSTs to be germinal transposon insertions. We found no evidence for somatic insertions within the 11% of insertion sites that were not confirmed. Instead, this subset of insertion sites had errors in locus-specific primer design due to incomplete or low-quality genomic sequences. The locus-specific PCR assays identified a knockout of a 6-phosphogluconate dehydrogenase gene that co-segregates with a seed mutant phenotype. The mutant phenotype linked to this knockout generates novel hypotheses about the role for the plastid-localized oxidative pentose phosphate pathway during grain-fill. Conclusion We show that FSTs from the UniformMu population identify stable, germinal insertion sites in maize. Moreover, we show that these sequence-indexed mutations can be readily used for reverse genetic analysis. We conclude from these data that the current collection of 1,882 non-redundant insertion sites from UniformMu provide a genome-wide resource for reverse genetics.

Abstract Background Hypercortisolism as a sign of hypothamamus-pituitary-adrenocortical (HPA) axis overactivity and sleep EEG changes are frequently observed in depression. Closely related to the HPA axis is the renin-angiotensin-aldosterone system (RAAS) as 1. adrenocorticotropic hormone (ACTH) is a common stimulus for cortisol and aldosterone, 2. cortisol release is suppressed by mineralocorticoid receptor (MR) agonists 3. angiotensin II (ATII) releases CRH and vasopressin from the hypothalamus. Furthermore renin and aldosterone secretion are synchronized to the rapid eyed movement (REM)-nonREM cycle. Methods Here we focus on the difference of sleep related activity of the RAAS between depressed patients and healthy controls. We studied the nocturnal plasma concentration of ACTH, cortisol, renin and aldosterone, and sleep EEG in 7 medication free patients with depression (1 male, 6 females, age: (mean +/-SD) 53.3 ± 14.4 yr.) and 7 age matched controls (2 males, 5 females, age: 54.7 ± 19.5 yr.). After one night of accommodation a polysomnography was performed between 23.00 h and 7.00 h. During examination nights blood samples were taken every 20 min between 23.00 h and 7.00 h. Area under the curve (AUC) for the hormones separated for the halves of the night (23.00 h to 3.00 h and 3.00 h to 7.00 h) were used for statistical analysis, with analysis of co variance being performed with age as a covariate. Results No differences in ACTH and renin concentrations were found. For cortisol, a trend to an increase was found in the first half of the night in patients compared to controls (p < 0.06). Aldosterone was largely increased in the first (p < 0.05) and second (p < 0.01) half of the night. Cross correlations between hormone concentrations revealed that in contrast to earlier findings, which included only male subjects, in our primarily female sample, renin and aldosterone secretion were not coupled and no difference between patients and controls could be found, suggesting a gender difference in RAAS regulation. No difference in conventional sleep EEG parameters were found in our sample. Conclusion Hyperaldosteronism could be a sensitive marker for depression. Further our findings point to an altered renal mineralocorticoid sensitivity in patients with depression.

OBJECTIVE: To develop clinical practice guidelines for application of palliative care consultation, quality-of-life measurements, and appropriate bereavement activities for patients with lung cancer. METHODS: To review the pertinent medical literature on palliative care consultation, quality-of-life measurements, and bereavement for patients with lung cancer, developing multidisciplinary discussions with authorities in these areas, and evolving written guidelines for end-of-life care of these patients. RESULTS: Palliative care consultation has developed into a new specialty with credentialing of experts in this field based on extensive experience with patients in end-of-life circumstances including those with lung cancer. Bereavement studies of the physical and emotional morbidity of family members and caregivers before, during, and after the death of a cancer patient have supported truthful communication, consideration of psychological problems, effective palliative care, understanding of the patient's spiritual and cultural background, and sufficient forewarning of impending death. CONCLUSION: Multidisciplinary investigations and experiences, with emphasis on consultation and delivery of palliative care, timely use of quality-of-life measurements for morbidities of treatment modalities and prognosis, and an understanding of the multifaceted complexities of the bereavement process, have clarified additional responsibilities of the attending physician. [ABSTRACT FROM AUTHOR]

Evidence-based practice guidelines for end-of-life care for patients with lung cancer have been previously available only from the British health-care system. Currently in this setting, there has been increasing concern in attaining control of the physical, psychological, social, and spiritual distress of the patient and family. This American College of Chest Physicians'-sponsored multidisciplinary panel has generated recommendations for improving quality of life after examining the English-language literature for answers to some of the most important questions in end-of-life care. Communication between the doctor, patient, and family is central to the active total care of patients with disease that is not responsive to curative treatment. The advance care directive, which has been slowly evolving and is presently limited in application and often circumstantially ineffective, better protects patient autonomy. The problem-solving capability of the hospital ethics committee has been poorly utilized, often due to a lack of understanding of its composition and function. Cost considerations and a sense of futility have confused caregivers as to the potentially important role of the critical care specialist in this scenario. Symptomatic and supportive care provided in a timely and consistent fashion in the hospice environment, which treats the patient and family at home, has been increasingly used, and at this time is the best model for end-of-life care in the United States. [ABSTRACT FROM AUTHOR]

Background: Matrix-induced autologous chondrocyte implantation (MACI), the third-generation of the technique, is an established procedure for the treatment of focal cartilage defects in the knee. However, the literature lacks long-term results of MACI with good statistical power., Purpose: To determine long-term survival and patient-reported outcomes (PROs) in a representative cohort and to identify patient- and surgery-related parameters that may influence long-term clinical outcomes., Study Design: Case series; Level of evidence, 4., Methods: A total of 103 patients were clinically evaluated at the current follow-up of 8.1 years (range, 5-11.9 years). PRO measures (PROMs) included the Knee injury and Osteoarthritis Outcome Score (KOOS), EQ-5D, visual analog scale for pain, and Tegner Activity Scale. Magnetic resonance imaging results were evaluated by using the AMADEUS (area measurement and depth and underlying structures) and MOCART (magnetic resonance observation of cartilage repair tissue) 2.0 knee score classification systems. Potential factors influencing PROs were first identified univariately and investigated in a multivariate regression model., Results: The defects had a mean size of 4.8 cm 2 (range, 1.2-12 cm 2 ) and were predominantly femorotibial (66%). The mean Kaplan-Meier survival rate of revision for any reason was 97.2% ± 1.6% at 10 years. In comparison to preoperative values, all PROMs were significantly improved at the current follow-up ( P < .05). The MOCART 2.0 score peaked at 12 months (mean, 80.2 ± 15.3 months) and showed no significant change at 96 months (mean, 76.1 ± 19.5 months; P = .142). The linear multivariate regression model identified an association of body mass index (BMI), MOCART 2.0 score, and number of previous knee surgeries with KOOS ( R 2 = 0.41; f 2 = 0.69). Further analysis of the individual determinants revealed an optimal BMI range of 20 to 29 for favorable PROs at 96 months. Significant correlations of MOCART subscores with the overall KOOS were found for graft surface and structure, bony reaction, and subchondral detectable changes. Only 30% of patients with 2 previous surgeries and 20% of patients with 3 previous surgeries achieved a Patient Acceptable Symptom State ( χ 2 = 10.93; P = .012)., Conclusion: The present study shows consistently good long-term clinical outcomes after MACI with a low revision rate and high patient satisfaction. BMI and number of previous knee surgeries may influence clinical outcomes and should be considered in patient selection and education. There is a correlation between graft structure, subchondral bone changes on magnetic resonance imaging, and long-term PROMs., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: T.R. has received research funding at personal disposal from DePuy, Zimmer, Aesculap, German Federal Ministry of Education and Research, Deutsche Arthrose-Hilfe, OttoBock-Stiftung, German Federal Ministry of Economic and Development, Oskar-Helene-Heim Foundation in Berlin, Vielberth Foundation, and Deutsche Forschungsgemeinschaft (DFG); and reimbursement of costs from DePuy, Zimmer, and Aesculap. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Purpose: The aim of this study was to evaluate the role of leg alignment on long-term clinical outcome after matrix-associated autologous chondrocyte implantation (M-ACI) and to define an individualized target range to optimize clinical outcome., Methods: The present study examined patients who underwent M-ACI of the femoral condyle. The Knee Injury and Osteoarthritis Outcome Score (KOOS) and Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) were used to assess the results. Clinical outcomes were related to Patient Acceptable Symptomatic State (PASS). For intra- and interobserver reliability of mechanical tibiofemoral angle, mechanical medial proximal tibial angle and mechanical lateral distal femoral angle, we calculated intraclass correlation coefficients using a two-way mixed model with absolute agreement. A regression model and receiver-operating characteristics curve were used to identify an individual range of alignment where a favourable clinical outcome could be expected in the long term., Results: Additional osteotomy was performed in 50% of patients with similar clinical outcomes as physiologically aligned patients (p > 0.05). The curve-fitting regression model identified a target range of -2.5° valgus to 4.5° varus for ideal postoperative alignment (R 2  = 0.12, p = 0.01). Patients within this range were more likely to achieve PASS (70% vs. 27%, p = 0.001). In medially treated defects, a refined range of -2.5° valgus to 4° varus alignment was found (R 2  = 0.15, p = 0.01). These patients were more likely to achieve PASS (67% vs. 30%, p = 0.01) and showed favourable postoperative KOOS and MOCART scores (p = 0.02). Patients with lateral defects were more likely to achieve PASS within a range of -2° valgus and 0.5° varus (90% vs. 45%, p = 0.03) and showed favourable postoperative KOOS and MOCART scores (p = not significant)., Conclusions: An individual range of leg alignment-whether achieved by osteotomy or physiologic alignment-should be respected in M-ACI treatment. A neutral to slightly undercorrected alignment favours the postoperative outcome after M-ACI. When planning surgery for patients with focal cartilage defects of the femoral condyle, these ranges should be recognized as critical factors., Level of Evidence: Level III., (© 2024 The Authors. Knee Surgery, Sports Traumatology, Arthroscopy published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Purpose: The purpose of this study was to evaluate long-term survival, patient-reported outcomes (PROs) and radiographic results of matrix-associated autologous chondrocyte implantation (M-ACI) in adolescents with immature cartilage and compare them to adult controls., Methods: A retrospective matched-pair analysis was performed comparing the PRO after M-ACI for focal cartilage defect of the knee in cartilaginous immature adolescents to mature adults. Groups were matched for sex, body mass index, defect site and size, symptom duration and the number of previous knee surgeries. Knee Injury and Osteoarthritis Outcome Score (KOOS) and the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART 2.0) scores were assessed at least 60 months postoperatively. Patient acceptable symptomatic state (PASS) and clinical response rate in KOOS and KOOS subscores were calculated., Results: A total of 54 patients were matched. At a mean of 96 months (65-144 months), no surgical complications, graft hypertrophy or reoperations were noted in the cohorts studied. Adolescents showed superior PROs at the final follow-up (76.9 ± 14.1 vs. 66.4 ± 15.0, p = 0.03) and were significantly more likely to achieve PASS (74.1% vs. 55.6%; p = 0.02) compared to the adult cohort. The KOOS subscale analysis showed long-term benefits for adolescents in terms of symptom improvement, pain reduction, activities of daily living, sports and quality of life (p < 0.05). None of the patients in the adolescent group showed graft hypertrophy on magnet resonance imaging or signs of osteoarthritis on radiographs at long-term follow-ups., Conclusions: M-ACI is an effective treatment for chondral defects of the knee in patients with immature cartilage with low revision rates and high patient satisfaction over the long term. Adolescents showed comparable clinical and radiographic results in the short and medium term, with slightly more favourable, clinically relevant functional results in adolescents in the long term. M-ACI can be safely used in adolescents, and consideration should be given to expanding the indication to include these patients., Level of Evidence: Level III., (© 2024 The Author(s). Knee Surgery, Sports Traumatology, Arthroscopy published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Luminescence quenching by hole transport layers (HTLs) is one of the major issues in developing efficient perovskite light-emitting diodes (PeLEDs), which is particularly prominent in blue-emitting devices. While a variety of material systems have been used as interfacial layers, the origin of such quenching and the type of interactions between perovskites and HTLs are still ambiguous. Here, we present a systematic investigation of the luminescence quenching of CsPbBr 3 by a commonly employed hole transport polymer, poly[(9,9-dioctylfluorenyl-2,7diyl)-co-(4,4'-(N-(4-sec-butylphenyl) diphenylamine)] (TFB), in LEDs. Strong and weak quantum-confined CsPbBr 3 (nanoplatelets (NPLs)/nanocrystals (NCs)) are rationally selected to study the quenching mechanism by considering the differences in their morphology, energy level alignments, and quantum confinement. The steady-state and time-resolved Stern-Volmer plots unravel the dominance of dynamic and static quenching at lower and higher concentrations of TFB, respectively, with a maximum quenching efficiency of 98%. The quenching rate in NCs is faster than that in NPLs owing to their longer PL lifetimes and weak quantum confinement. The ultrafast transient absorption results support these dynamics and rule out the involvement of Forster or Dexter energy transfer. Finally, the 1D 1 H and 2D nuclear overhauser effect spectroscopy nuclear magnetic resonance (NOESY NMR) study confirms the exchange of native ligands at the NCs surface with TFB, leading to dark CsPbBr 3 -TFB ensemble formation accountable for luminescence quenching. This highlights the critical role of the triarylamine functional group on TFB (also the backbone of many HTLs) in the quenching process. These results shed light on the underlying reasons for the luminescence quenching in PeLEDs and will help to rationally choose the interfacial layers for developing efficient LEDs., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Quantum-dot (QD) solids are being widely exploited as a solution-processable technology to develop photovoltaic, light-emission, and photodetection devices. Charge transport in these materials is the result of a compromise between confinement at the individual QD level and electronic coupling among the different nanocrystals in the ensemble. While this is commonly achieved by ligand engineering in colloidal-based systems, ligand-free QD assemblies have recently emerged as an exciting alternative where nanostructures can be directly grown into porous matrices with optical quality as well as control over their connectivity and, hence, charge transport properties. In this context, we present a complete photophysical study comprising fluence- and temperature-dependent time-resolved spectroscopy to study carrier dynamics in ligand-free QD networks with gradually varying degrees of interconnectivity, which we achieve by changing the average distance between the QDs. Analysis of the photoluminescence and absorption properties of the QD assemblies, involving both static and time-resolved measurements, allows us to identify the weight of the different recombination mechanisms, both radiative and nonradiative, as a function of QD connectivity. We propose a picture where carrier diffusion, which is needed for any optoelectronic application and implies interparticle transport, gives rise to the exposure of carriers to a larger defect landscape than in the case of isolated QDs. The use of a broad range of fluences permits extracting valuable information for applications demanding either low- or high-carrier-injection levels and highlighting the relevance of a judicious design to balance recombination and diffusion.

Introduction: The aim of the current study was to demonstrate short- to mid-term survivorship as well as clinical outcome of lateral unicompartmental knee replacement (UKR) with a fixed-bearing (FB) design from a non-designer center using the Oxford Fixed Lateral prosthesis., Materials and Methods: This single-center retrospective cohort study reports the results of 133 consecutive lateral FB-UKR. Survivorship analysis was performed with different endpoints and clinical outcome was measured using the Oxford-Knee-Score (OKS), American-Knee-Society-Score (AKSS-O), range-of-motion (ROM) and visual-analog-scale for pain (VAS)., Results: There were two revision surgeries with conversion to total knee replacements (TKR) due to persistent pain resulting in a survival rate of 98.5% (95% CI 93.5-99.6) with a mean follow-up (FU) of 3.3 ± 1.8 years (range 1-8.5). All outcome scores, VAS and ROM showed a significant improvement at final FU (p < 0.001). The OKS improved from 26 ± 7.8 (range 11-45) preoperatively to 39 ± 8.3 (range 13-48), the AKSS-O from 49.2 ± 14.6 (range 18-90) to 81.8 ± 15.1 (range 40-100), the AKSS-F from 53 ± 23.7 (range 0-100) to 80.4 ± 21.4 (range 5-100) and the ROM from 118 ± 17 (range 90-160) to 134 ± 9.5 (range 100-155)., Conclusions: The short- to mid-term results following lateral FB-UKR demonstrate a high survivorship and good clinical outcome from an independent series. We, therefore, suggest that FB-UKR is a safe treatment option for isolated lateral OA if sufficient surgical experience is provided., Level of Evidence: Retrospective cohort study, level IV., (© 2023. The Author(s).)

(1) Background: In the treatment of periprosthetic joint infection (PJI), the individual host status and previous surgical procedures appear to have a relevant influence on success rates and clinical outcome of knee revision surgery. Current data about the predictive value are limited in this subgroup of patients. (2) Methods: Retrospectively, 107 patients (109 knees) undergoing two-stage exchange knee arthroplasty for PJI using a rotating-hinge design with at least two years follow-up. The cumulative incidence (CI) for different endpoints was estimated with death as competing risk. Univariate and multivariate analyses for potential predictive factors were performed. Patient-related outcome measures (PROMs) for clinical outcome were evaluated. (3) Results: At 8 years, the CI of any revision was 29.6%, and of any reoperation was 38.9%. Significant predictors for risk of re-revision were the Charlson Comorbidity Index (CCI) and the number of previous surgical procedures prior to explanation of the infected implant. The functional and clinical outcome demonstrated acceptable results in the present cohort with a high comorbidity level. (4) Conclusions: A compromised host status and multiple previous surgical procedures were identified as negative predictors for re-revision knee surgery in the treatment of PJI. Reinfection remained the major reason for re-revision. Overall mortality was high.

Background: Organ fibrosis due to excessive production of extracellular matrix by resident fibroblasts is estimated to contribute to >45% of deaths in the Western world, including those due to cardiovascular diseases such as heart failure. Here, we screened for small molecule inhibitors with a common ability to suppress activation of fibroblasts across organ systems., Methods: High-content imaging of cultured cardiac, pulmonary, and renal fibroblasts was used to identify nontoxic compounds that blocked induction of markers of activation in response to the profibrotic stimulus, transforming growth factor-β1. SW033291, which inhibits the eicosanoid-degrading enzyme, 15-hydroxyprostaglandin dehydrogenase, was chosen for follow-up studies with cultured adult rat ventricular fibroblasts and human cardiac fibroblasts (CF), and for evaluation in mouse models of cardiac fibrosis and diastolic dysfunction. Additional mechanistic studies were performed with CFs treated with exogenous eicosanoids., Results: Nine compounds, including SW033291, shared a common ability to suppress transforming growth factor-β1-mediated activation of cardiac, pulmonary, and renal fibroblasts. SW033291 dose-dependently inhibited transforming growth factor-β1-induced expression of activation markers (eg, α-smooth muscle actin and periostin) in adult rat ventricular fibroblasts and normal human CFs, and reduced contractile capacity of the cells. Remarkably, the 15-hydroxyprostaglandin dehydrogenase inhibitor also reversed constitutive activation of fibroblasts obtained from explanted hearts from patients with heart failure. SW033291 blocked cardiac fibrosis induced by angiotensin II infusion and ameliorated diastolic dysfunction in an alternative model of systemic hypertension driven by combined uninephrectomy and deoxycorticosterone acetate administration. Mechanistically, SW033291-mediated stimulation of extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase signaling was required for the compound to block CF activation. Of the 12 exogenous eicosanoids that were tested, only 12(S)-hydroxyeicosatetraenoic acid, which signals through the G protein-coupled receptor, GPR31, recapitulated the suppressive effects of SW033291 on CF activation., Conclusions: Inhibition of degradation of eicosanoids, arachidonic acid-derived fatty acids that signal through G protein-coupled receptors, is a potential therapeutic strategy for suppression of pathological organ fibrosis. In the heart, we propose that 15-hydroxyprostaglandin dehydrogenase inhibition triggers CF-derived autocrine/paracrine signaling by eicosanoids, including 12(S)-hydroxyeicosatetraenoic acid, to stimulate extracellular signal-regulated kinase 1/2 and block conversion of fibroblasts into activated cells that secrete excessive amounts of extracellular matrix and contribute to heart failure pathogenesis.

Background: The indications and outcomes of semi- or fully-constrained knee implants in primary total knee arthroplasty (TKA) are still controversially discussed. The present study aims to evaluate the mid-term results and complications of a modular/non-modular rotating-hinge implant in complex primary TKA., Methods: Eighty-two patients (86 knees) following primary TKA were retrospectively evaluated with a mean follow-up of 63 months. The functional outcome was assessed using the American Knee Society Score (AKSS) and the Oxford Knee Score (OKS). A Visual Analog Scale (VAS) was used to determine pain levels. Implant survival and reoperation rateswere estimated using competing risk analysis. Cox regression analysis wasperformed to evaluate the influence of modularity on implant survival., Results: The survival rate with the endpoint implant revision was 90% (95 %CI:83-98%) and the survival rate with the endpoint all reoperations was 84% (95 %CI:75-94%) at 7 years. The AKSS improved significantly from 24 (SD 14.9, range:0-69) preoperatively to 83 (SD 14.3, range:57-100) postoperatively (p < 0.001); functional AKSS improved significantly from 27 (SD 24.3, range:0-100) to 46 (SD: 32.9, range 0-100) (p = 0.003), and OKS from 19 (SD: 8.3, range:5-43) to 29 (SD: 10.7, range:6-48), respectively (p < 0.0001). VAS decreased significantly from 8 (SD: 2.6, range:0-10) preoperatively to 3 (SD: 2.9, range:0-9) postoperatively (p < 0.0001). There was no significant influence of modularity on revision rates comparing modular to non-modular implants (p = 0.072)., Conclusions: The present rotating-hinge implant provides substantial improvement in function and reduction of pain with good implant survival in the mid-term. Modularity was not associated with higher rates of revision., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors DS, KK, PH and TR declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article. Author C.M. report research funding and speaker fees from Zimmer Biomet and consultant fees from from DePuy Synthes outside the submitted work. Author TG report personal fees and institutional research support from Zimmer Biomet, DePuy Synthes and Peter Brehm outside the submitted work., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Heart failure is the one of the leading causes of death in the United States. Heart failure is a complex syndrome caused by numerous diseases, including severe myocardial infarction (MI). MI occurs after an occlusion of a cardiac artery causing downstream ischemia. MI is followed by cardiac remodeling involving extensive remodeling and fibrosis, which, if the original insult is severe or prolonged, can ultimately progress into heart failure. There is no "cure" for heart failure because therapies to regenerate dead tissue are not yet available. Previous studies have shown that in both post-MI and post-ischemia-reperfusion (I/R) models of heart failure, administration of cortical bone stem cell (CBSC) treatment leads to a reduction in scar size and improved cardiac function. Our first study investigated the ability of mouse CBSC-derived exosomes (mCBSC-dEXO) to recapitulate mouse CBSCs (mCBSC) therapeutic effects in a 24-h post-I/R model. This study showed that injection of mCBSCs and mCBSC-dEXOs into the ischemic region of an infarct had a protective effect against I/R injury. mCBSC-dEXOs recapitulated the effects of CBSC treatment post-I/R, indicating exosomes are partly responsible for CBSC's beneficial effects. To examine if exosomes decrease fibrotic activation, adult rat ventricular fibroblasts (ARVFs) and adult human cardiac fibroblasts (NHCFs) were treated with transforming growth factor β (TGFβ) to activate fibrotic signaling before treatment with mCBSC- and human CBSC (hCBSC)-dEXOs. hCBSC-dEXOs caused a 100-fold decrease in human fibroblast activation. To further understand the signaling mechanisms regulating the protective decrease in fibrosis, we performed RNA sequencing on the NHCFs after hCBSC-dEXO treatment. The group treated with both TGFβ and exosomes showed a decrease in small nucleolar RNA (snoRNA), known to be involved with ribosome stability. NEW & NOTEWORTHY Our work is noteworthy due to the identification of factors within stem cell-derived exosomes (dEXOs) that alter fibroblast activation through the hereto-unknown mechanism of decreasing small nucleolar RNA (snoRNA) signaling within cardiac fibroblasts. The study also shows that the injection of stem cells or a stem-cell-derived exosome therapy at the onset of reperfusion elicits cardioprotection, emphasizing the importance of early treatment in the post-ischemia-reperfusion (I/R) wounded heart.

Acute damage to the heart, as in the case of myocardial infarction (MI), triggers a robust inflammatory response to the sterile injury that is part of a complex and highly organized wound-healing process. Cortical bone stem cell (CBSC) therapy after MI has been shown to reduce adverse structural and functional remodeling of the heart after MI in both mouse and swine models. The basis for these CBSC treatment effects on wound healing are unknown. The present experiments show that CBSCs secrete paracrine factors known to have immunomodulatory properties, most notably macrophage colony-stimulating factor (M-CSF) and transforming growth factor-β, but not IL-4. CBSC therapy increased the number of galectin-3 + macrophages, CD4 + T cells, and fibroblasts in the heart while decreasing apoptosis in an in vivo swine model of MI. Macrophages treated with CBSC medium in vitro polarized to a proreparative phenotype are characterized by increased CD206 expression, increased efferocytic ability, increased IL-10, TGF-β, and IL-1RA secretion, and increased mitochondrial respiration. Next generation sequencing revealed a transcriptome significantly different from M2a or M2c macrophage phenotypes. Paracrine factors from CBSC-treated macrophages increased proliferation, decreased α-smooth muscle actin expression, and decreased contraction by fibroblasts in vitro. These data support the idea that CBSCs are modulating the immune response to MI to favor cardiac repair through a unique macrophage polarization that ultimately reduces cell death and alters fibroblast populations that may result in smaller scar size and preserved cardiac geometry and function. NEW & NOTEWORTHY Cortical bone stem cell (CBSC) therapy after myocardial infarction alters the inflammatory response to cardiac injury. We found that cortical bone stem cell therapy induces a unique macrophage phenotype in vitro and can modulate macrophage/fibroblast cross talk.

Objective: Our recent work demonstrates that PTEN (phosphatase and tensin homolog) is an important regulator of smooth muscle cell (SMC) phenotype. SMC-specific PTEN deletion promotes spontaneous vascular remodeling and PTEN loss correlates with increased atherosclerotic lesion severity in human coronary arteries. In mice, PTEN overexpression reduces plaque area and preserves SMC contractile protein expression in atherosclerosis and blunts Ang II (angiotensin II)-induced pathological vascular remodeling, suggesting that pharmacological PTEN upregulation could be a novel therapeutic approach to treat vascular disease. Approach and Results: To identify novel PTEN activators, we conducted a high-throughput screen using a fluorescence based PTEN promoter-reporter assay. After screening ≈3400 compounds, 11 hit compounds were chosen based on level of activity and mechanism of action. Following in vitro confirmation, we focused on 5-azacytidine, a DNMT1 (DNA methyltransferase-1) inhibitor, for further analysis. In addition to PTEN upregulation, 5-azacytidine treatment increased expression of genes associated with a differentiated SMC phenotype. 5-Azacytidine treatment also maintained contractile gene expression and reduced inflammatory cytokine expression after PDGF (platelet-derived growth factor) stimulation, suggesting 5-azacytidine blocks PDGF-induced SMC de-differentiation. However, these protective effects were lost in PTEN-deficient SMCs. These findings were confirmed in vivo using carotid ligation in SMC-specific PTEN knockout mice treated with 5-azacytidine. In wild type controls, 5-azacytidine reduced neointimal formation and inflammation while maintaining contractile protein expression. In contrast, 5-azacytidine was ineffective in PTEN knockout mice, indicating that the protective effects of 5-azacytidine are mediated through SMC PTEN upregulation., Conclusions: Our data indicates 5-azacytidine upregulates PTEN expression in SMCs, promoting maintenance of SMC differentiation and reducing pathological vascular remodeling in a PTEN-dependent manner.

Objective: Evaluate an established scribe program on throughput and revenue capture in an Emergency Department (ED) undergoing an EMR transition., Methods: A prospective cohort design comparing patients managed with and without scribes in an academic ED. Throughput metrics (medians, min) and relative value units (RVUs, means) were collected. Data was evaluated in its entirety (three months), as well as in two subsets: go live (immediate two weeks) and adoption (two weeks post implementation to end)., Results: All patients: There was no significant difference in throughput or RVUs during the three month period. During go-live, scribes showed improvement in total RVUs per patient (4.63 vs 4.40, p = 0.048). During adoption, scribed patients had decreased length of stay (LOS, 221 vs 231, p = 0.023). Adults: Door to provider (28 vs 37, p = 0.014) and total RVUs (5.20 vs 4.92, p = 0.042) were improved with scribes in the go-live period. Scribes improved go-live morning and overnight shifts, while lengthening provider to disposition during afternoon shifts. No significant differences were seen in the adoption period, except for increased provider to disposition time overnight with scribes (154 vs 146, p = 0.030). Pediatrics: When all pediatric patients were compared, scribe patients had a decreased professional RVU charge (2.78 vs 2.90, p = 0.037). During go live and adoption, no significant differences were found in any other parameter or subgrouping., Conclusions: A scribe's ability to mitigate operational inefficiencies introduced by an EMR transition seems limited in an academic hospital. Previous research highlighting the impact of scribes on revenue was not replicated during this study., Competing Interests: Declaration of competing interest None., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Emergency Medicine Telehealth (TeleEM) represents an opportunity to work directly with referral centres, rural facilities and underserved areas to mitigate unnecessary testing, optimise resource utilisation and facilitate patient transfers across health systems. To optimise the impact of a TeleEM programme, a tool is needed to remotely monitor patient activity in multiple emergency department facilities, concurrently., Methods: After identifying data sources for activation criteria put forth by the TeleEM operations group, rules were constructed within the electronic health record to facilitate data checks and ultimately produce a yes/no response if the category's conditions were met. Responses were organised into a table, with functionality allowing end users to drill into the different sites to see patient-specific information for patients meeting activation criteria., Conclusions: The TeleEM dashboard allows for proactive engagement by the TeleEM physician and strengthens the team-based approach of critically ill., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: Small molecule inhibitors of the acetyl-histone binding protein BRD4 have been shown to block cardiac fibrosis in preclinical models of heart failure (HF). However, since the inhibitors target BRD4 ubiquitously, it is unclear whether this chromatin reader protein functions in cell type-specific manner to control pathological myocardial fibrosis. Furthermore, the molecular mechanisms by which BRD4 stimulates the transcriptional program for cardiac fibrosis remain unknown., Objective: We sought to test the hypothesis that BRD4 functions in a cell-autonomous and signal-responsive manner to control activation of cardiac fibroblasts, which are the major extracellular matrix-producing cells of the heart., Methods and Results: RNA-sequencing, mass spectrometry, and cell-based assays employing primary adult rat ventricular fibroblasts demonstrated that BRD4 functions as an effector of TGF-β (transforming growth factor-β) signaling to stimulate conversion of quiescent cardiac fibroblasts into Periostin ( Postn )-positive cells that express high levels of extracellular matrix. These findings were confirmed in vivo through whole-transcriptome analysis of cardiac fibroblasts from mice subjected to transverse aortic constriction and treated with the small molecule BRD4 inhibitor, JQ1. Chromatin immunoprecipitation-sequencing revealed that BRD4 undergoes stimulus-dependent, genome-wide redistribution in cardiac fibroblasts, becoming enriched on a subset of enhancers and super-enhancers, and leading to RNA polymerase II activation and expression of downstream target genes. Employing the Sertad4 (SERTA domain-containing protein 4) locus as a prototype, we demonstrate that dynamic chromatin targeting of BRD4 is controlled, in part, by p38 MAPK (mitogen-activated protein kinase) and provide evidence of a critical function for Sertad4 in TGF-β-mediated cardiac fibroblast activation., Conclusions: These findings define BRD4 as a central regulator of the pro-fibrotic cardiac fibroblast phenotype, establish a p38-dependent signaling circuit for epigenetic reprogramming in heart failure, and uncover a novel role for Sertad4 . The work provides a mechanistic foundation for the development of BRD4 inhibitors as targeted anti-fibrotic therapies for the heart.

Oxidative stress is an underlying component of acute and chronic kidney disease. Apoptosis signal-regulating kinase 1 (ASK1) is a widely expressed redox-sensitive serine threonine kinase that activates p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase kinases, and induces apoptotic, inflammatory, and fibrotic signaling in settings of oxidative stress. We describe the discovery and characterization of a potent and selective small-molecule inhibitor of ASK1, GS-444217, and demonstrate the therapeutic potential of ASK1 inhibition to reduce kidney injury and fibrosis. Activation of the ASK1 pathway in glomerular and tubular compartments was confirmed in renal biopsies from patients with diabetic kidney disease (DKD) and was decreased by GS-444217 in several rodent models of kidney injury and fibrosis that collectively represented the hallmarks of DKD pathology. Treatment with GS-444217 reduced progressive inflammation and fibrosis in the kidney and halted glomerular filtration rate decline. Combination of GS-444217 with enalapril, an angiotensin-converting enzyme inhibitor, led to a greater reduction in proteinuria and regression of glomerulosclerosis. These results identify ASK1 as an important target for renal disease and support the clinical development of an ASK1 inhibitor for the treatment of DKD.

Background: We aimed to evaluate factors associated with prolonged emergency department (ED) length of stay (LOS) among psychiatric patients and to develop a multivariable predictive model to guide future interventions to reduce ED LOS., Methods: Electronic health records of ED patients receiving a psychiatric consultation and providing research authorization were reviewed from September 14, 2010, through September 13, 2013, at an academic hospital with approximately 73000 visits annually. Prolonged LOS was defined as ≥8 hours., Results: We identified 9247 visits among 6335 patients; median LOS was 4.1 hours, with 1424 visits (15%) with prolonged LOS. In the multivariable model, characteristics associated with an increased risk of a prolonged LOS included patient age 12 to 17 years (odds ratio [OR], 2.43; P<.001) or ≥65 years (OR, 1.46; P=.007); male gender (OR, 1.24; P=.002); Medicare insurance coverage (OR, 1.34; P=.008); use of restraints (OR, 2.25; P=.006); diagnoses of cognitive disorder (OR, 4.62; P<.001) or personality disorder (OR, 3.45; P<.001); transfer to an unaffiliated psychiatric hospital (OR, 22.82; P<.001); ED arrival from 11 pm through 6:59 am (OR, 1.53; P<.001) or on a Sunday (OR, 1.76; P<.001); or ED evaluation in February (OR, 1.59; P=.006), April (OR, 1.66; P=.002), and May (OR, 1.54; P=.007)., Conclusions: Many psychiatric patients had a prolonged ED LOS. Understanding the multiple, patient-specific, ED operational, and seasonal factors that predict an increased LOS will help guide allocation of resources to improve overall ED processes and patient care., (Copyright © 2015 Elsevier Inc. All rights reserved.)

We describe a boy with developmental delay, speech delay, and minor dysmorphic features with a heterozygous de novo ∼460 kb deletion at 2p13.2 involving only parts of EXOC6B present in about 50% of lymphocytes. This widely expressed gene encodes the exocyst component 6B, which is part of a multiprotein complex required for targeted exocytosis. Little is known about the effect of EXOC6B haploinsufficiency. In 2008, a patient with a complex syndromic phenotype, including left renal agenesis, neutropenia, recurrent pulmonary infections, long bone diaphysis broadening, growth retardation, and developmental delay (DD) was found to carry a de novo translocation t(2;7) involving TSN3 and EXOC6B. Further characterization of the translocation indicated that disruption of TSN3 may be responsible for the skeletal phenotype. Recently, a heterozygous deletion of EXOC6B along with a deletion of the CYP26B1 gene has been reported in a boy with intellectual disability, speech delay, hyperactivity, facial asymmetry, a dysplastic ear, brachycephaly, and mild joint contractures. Additionally, disruption of EXOC6B by a de novo balanced translocation t(2;8) has been described in a patient with developmental delay, epilepsy, autistic and aggressive behavior. This is the first report of a de novo deletion affecting only EXOC6B in an individual with developmental delay. In conclusion, based on our findings and recent data from the literature, there is evidence that EXOC6B and the exocyst complex might play an important role in the molecular pathogenesis of intellectual disability., (© 2014 Wiley Periodicals, Inc.)

The metabolic enhancer piracetam is used in many countries to treat cognitive impairment in aging, brain injuries, as well as dementia such as AD (Alzheimer's disease). As a specific feature of piracetam, beneficial effects are usually associated with mitochondrial dysfunction. In previous studies we were able to show that piracetam enhanced ATP production, mitochondrial membrane potential as well as neurite outgrowth in cell and animal models for aging and AD. To investigate further the effects of piracetam on mitochondrial function, especially mitochondrial fission and fusion events, we decided to assess mitochondrial morphology. Human neuroblastoma cells were treated with the drug under normal conditions and under conditions imitating aging and the occurrence of ROS (reactive oxygen species) as well as in stably transfected cells with the human wild-type APP (amyloid precursor protein) gene. This AD model is characterized by expressing only 2-fold more human Aβ (amyloid β-peptide) compared with control cells and therefore representing very early stages of AD when Aβ levels gradually increase over decades. Interestingly, these cells exhibit an impaired mitochondrial function and morphology under baseline conditions. Piracetam is able to restore this impairment and shifts mitochondrial morphology back to elongated forms, whereas there is no effect in control cells. After addition of a complex I inhibitor, mitochondrial morphology is distinctly shifted to punctate forms in both cell lines. Under these conditions piracetam is able to ameliorate morphology in cells suffering from the mild Aβ load, as well as mitochondrial dynamics in control cells.

Bilobalide, an active constituent of Ginkgo biloba, has neuroprotective properties in experimental stroke models, but nearly all published studies were carried out in young animals. As ischemic strokes in humans are much more frequent in old age, we investigated bilobalide's effects in aged mice (age 18-22 month) using a model of transient ischemia induced by occlusion of the middle cerebral artery (MCAO) for 60 min. When bilobalide was administered locally into the striatum via microdialysis, a significant reduction of infarct size by almost 70% was observed. Concomitantly, the extensive, twelve-fold increase of extracellular glutamate which was observed in untreated animals was strongly reduced during the infusion of bilobalide. Glucose levels, in contrast, were not affected by bilobalide. In further experiments, bilobalide was given as an intraperitoneal injection (10/mg/kg) 1h before MCAO onset. ATP levels (measured in brain homogenates) were significantly reduced by transient MCAO but pretreatment with bilobalide prevented this loss. In ex vivo experiments with isolated mitochondria from aged mice, we found that the activity of the mitochondrial respiratory chain was only slightly impaired after 60 min of ischemia, and bilobalide showed no benefit in this experiment. However, aged mitochondria proved to be very sensitive to calcium-induced swelling which was significantly increased after ischemia. In this assay, pretreatment with bilobalide lowered the extent of swelling nearly to control levels. In behavioural tests, pretreatment of aged mice with bilobalide significantly improved the outcome in the Rotarod and the Corner test. In conclusion, aged mice show some differences in their response to transient ischemia when compared with young mice. Bilobalide has prominent neuroprotective properties in mice of all ages., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: In the United States, lung cancer is a major health problem that is associated with significant patient distress and often limited survival, with some exceptions. The purpose of this article is to address the role of palliative and end-of-life care in the management of patients with lung cancer and to address the need for good communication skills to provide support to patients and families., Methods: This article is based on an extensive review of the medical literature up to April 2012, with some articles as recent as August 2012. The authors used the PubMed and Cochrane databases, as well as EBESCO Host search, for articles addressing palliative care, supportive care, lung neoplasm, and quality of life in cancer or neoplasm, with no limitation on dates. The research was limited to human studies and the English language., Results: There was no "definitive" work in this area, most of it being concurrence based rather than evidence based. Several randomized controlled trials were identified, which are reviewed in the text. The article focuses on the assessment and treatment of suffering in patients with lung cancer, as well as the importance of communication in the care of these patients over the course of the disease. The aim of medical care for patients with terminal lung cancer is to decrease symptom burden, enhance the quality of remaining life, and increase survival benefit. A second objective is to emphasize the importance of good communication skills when addressing the needs of the patient and his or her family, starting at the time of diagnosis, which in itself is a life-changing event. Too often we do it poorly, but by using patient-centered communication skills, the outcome can be more satisfactory. Finally, the article addresses the importance of advance care planning for patients with lung cancer, from the time of diagnosis until the last phase of the illness, and it is designed to enhance the physician's role in facilitating this planning process., Conclusions: This article provides guidance on how to reduce patient distress and avoid nonbeneficial treatment in patients with lung cancer. The goal is to decrease symptom burden, enhance quality of life, and increase survival benefit. Good communication and advance care planning are vital to the process.

Transient myeloproliferative disorder (TMD) of the newborn and acute megakaryoblastic leukaemia (AMKL) in children with Down syndrome (DS) represent paradigmatic models of leukaemogenesis. Chromosome 21 gene dosage effects and truncating mutations of the X-chromosomal transcription factor GATA1 synergize to trigger TMD and AMKL in most patients. Here, we report the occurrence of TMD, which spontaneously remitted and later progressed to AMKL in a patient without DS but with a distinct dysmorphic syndrome. Genetic analysis of the leukaemic clone revealed somatic trisomy 21 and a truncating GATA1 mutation. The analysis of the patient's normal blood cell DNA on a genomic single nucleotide polymorphism (SNP) array revealed a de novo germ line 2·58 Mb 15q24 microdeletion including 41 known genes encompassing the tumour suppressor PML. Genomic context analysis of proteins encoded by genes that are included in the microdeletion, chromosome 21-encoded proteins and GATA1 suggests that the microdeletion may trigger leukaemogenesis by disturbing the balance of a hypothetical regulatory network of normal megakaryopoiesis involving PML, SUMO3 and GATA1. The 15q24 microdeletion may thus represent the first genetic hit to initiate leukaemogenesis and implicates PML and SUMO3 as novel components of the leukaemogenic network in TMD/AMKL., (© 2012 Blackwell Publishing Ltd.)

Since the introduction of soybean aphid, Aphis glycines Matsumura, from Asia, insecticide use in soybean has increased substantially in the north central United States. Insecticide seed treatments and aphid resistant soybean varieties are management tactics that may reduce reliance on foliar applications of broad-spectrum insecticides. Exploring potential nontarget impacts of these technologies will be an important step in incorporating them into aphid management programs. We investigated impacts of thiamethoxam seed treatment and Rag1 aphid resistant soybean on a fungal pathogen of soybean aphid, Pandora neoaphidis (Remaudière & Hennebert) Humber, via open plot and cage studies. We found that although thiamethoxam seed treatment did significantly lower aphid pressure in open plots compared with an untreated control, this reduction in aphid density translated into nonsignificant decreases in fungal disease prevalence in aphids. Furthermore, when aphid densities were approximately equal in seed treated and untreated soybean, no impact on aphid fungal disease was observed. In open plots, Rag1 resistant soybean experienced lower aphid pressure and aphid disease prevalence compared with a nonresistant isoline. However, in cages when aphid densities were equivalent in both resistant and susceptible soybean, resistance had no impact on aphid disease prevalence. The addition of thiamethoxam seed treatment to resistant soybean yielded aphid densities and aphid disease prevalence similar to untreated, resistant soybean. These studies provide evidence that thiamethoxam seed treatments and Rag1 resistance can impact P. neoaphidis via decreased aphid densities; however, this impact is minimal, implying use of seed treatments and host plant resistance are compatible with P. neoaphidis.

Transforming growth factor β (TGF-β) type I receptor (activin receptor-like kinase 5, ALK5) has been identified as a promising target for fibrotic diseases. To find a novel inhibitor of ALK5, the authors performed a high-throughput screen of a library of 420,000 compounds using dephosphorylated ALK5. From primary hits of 1521 compounds, 555 compounds were confirmed. In total, 124 compounds were then selected for follow-up based on their unique structures and other properties. Repeated concentration-response testing and final interference assays of the above compounds resulted in the discovery of a structurally novel ALK5 inhibitor (compound 8) (N-(thiophen 2-ylmethyl)-3-(3,4,5 trimethoxyphenyl)imidazo[1,2β]pyridazin 6-amine) with a low IC(50) value of 0.7 µM. Compound 8 also inhibited the TGF-β-induced nuclear translocation of SMAD with an EC(50) value of 0.8 µM. Kinetic analysis revealed that compound 8 inhibited ALK5 via mixed-type inhibition, suggesting that it may bind to ALK5 differently than other published adenosine triphosphate site inhibitors.

The synthesis and preliminary studies of the SAR of novel 3,5-diarylazole inhibitors of Protein Kinase D (PKD) are reported. Notably, optimized compounds in this class have been found to be active in cellular assays of phosphorylation-dependant HDAC5 nuclear export, orally bioavailable, and highly selective versus a panel of additional putative histone deacetylase (HDAC) kinases. Therefore these compounds could provide attractive tools for the further study of PKD/HDAC5 signaling., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The machineable representation and execution of clinical guidelines has been the focus of research efforts for some time, however there is less examination of whether the methods and techniques for guidelines are sufficient for clinical protocols. The objective of this study was to test the feasibility of using the Guideline Elements Model II (GEM II) and GEM Cutter for the representation of clinical protocols, specifically clinical protocols commonly used by nurses. After downloading the GEM Cutter 2.5, we decomposed a set of clinical protocols and analyzed the completeness in which elemental protocol data was represented. One of the most complicated of these protocols (extravasations of infused medication) is presented as an example. While GEM II adequately represents core elements of clinical protocols at the high level, it was not possible to adequately represent sequence and associated role based permissions via use of conditional criteria at branching and procedural levels. Functionality of the tool would also be enhanced with more robust terminology management and support for multi-authoring.

The synthesis and biological evaluation of potent and selective PKD inhibitors are described herein. The compounds described in the present study selectively inhibit PKD among other putative HDAC kinases. The PKD inhibitors of the present study blunt phosphorylation and subsequent nuclear export of HDAC4/5 in response to diverse agonists. These compounds further establish the central role of PKD as an HDAC4/5 kinase and enhance the current understanding of cardiac myocyte signal transduction. The in vivo efficacy of a representative example compound on heart morphology is reported herein.

Soybean aphid, Aphis glycines, has caused serious economic damage to soybean across the North Central US since its introduction to North America in 2000. The management of another invasive soybean pest, Asian soybean rust, Phakopsora pachyrhizi, using foliar fungicide applications has the potential to impact soybean aphid populations by suppressing beneficial fungal entomopathogens. In 2005 and 2006, we applied recommended soybean rust fungicide treatments, consisting of strobilurin and triazole fungicides, to small soybean plots in two locations to assess if such applications might suppress aphid fungal epizootics. In Lamberton, MN, in 2005, during the epizootic, fungicide-treated plots averaged 2.0+/-0.7% (mean+/-SE) disease prevalence while untreated plots averaged 14.2+/-5.6%. In 2007, we applied strobilurin and strobilurin-triazole mix fungicides to single-plant microplots either before or after release of Pandora neoaphidis, the most commonly observed aphid pathogen in 2005 and 2006. Treatments that contained a mixture of two active ingredients significantly lowered peak and cumulative aphid disease prevalence in both early and late reproductive stage soybeans indicating that fungicide mixtures used to manage soybean rust can negatively impact an aphid-specific fungal pathogen. However, no consistent soybean aphid population response was observed in these studies of low levels of aphid fungal infection., (Copyright (c) 2009 Elsevier Inc. All rights reserved.)

Class IIa histone deacetylases (HDACs) repress genes involved in pathological cardiac hypertrophy. The anti-hypertrophic action of class IIa HDACs is overcome by signals that promote their phosphorylation-dependent nuclear export. Several kinases have been shown to phosphorylate class IIa HDACs, including calcium/calmodulin-dependent protein kinase (CaMK), protein kinase D (PKD) and G protein-coupled receptor kinase (GRK). However, the identity of the kinase(s) responsible for phosphorylating class IIa HDACs during cardiac hypertrophy has remained controversial. We describe a novel and selective small molecule inhibitor of PKD, bipyridyl PKD inhibitor (BPKDi). BPKDi blocks signal-dependent phosphorylation and nuclear export of class IIa HDACs in cardiomyocytes and concomitantly suppresses hypertrophy of these cells. These studies define PKD as a principal cardiac class IIa HDAC kinase., (2009 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Histone deacetylase 5 (HDAC5) represses expression of nuclear genes that promote cardiac hypertrophy. Agonism of a variety of G protein coupled receptors (GPCRs) triggers phosphorylation-dependent nuclear export of HDAC5 via the CRM1 nuclear export receptor, resulting in derepression of pro-hypertrophic genes. A cell-based high-throughput screen of a commercial compound collection was employed to identify compounds with the ability to preserve the nuclear fraction of GFP-HDAC5 in primary cardiomyocytes exposed to GPCR agonists. A hit compound potently inhibited agonist-induced GFP-HDAC5 nuclear export in cultured neonatal rat ventricular myocytes (NRVMs). A small set of related compounds was designed and synthesized to evaluate structure-activity relationship (SAR). The results demonstrated that inhibition of HDAC5 nuclear export was a result of compounds irreversibly reacting with a key cysteine residue in CRM1 that is required for its function. CRM1 inhibition by the compounds also resulted in potent suppression of cardiomyocyte hypertrophy. These studies define a novel class of anti-hypertrophic compounds that function through irreversible inhibition of CRM1-dependent nuclear export.

Calcium-sensing receptor (CaR) activation decreases serum parathyroid hormone (PTH) and Ca2+ and, despite long-term reductions in mean arterial blood pressure (MAP), may produce acute hypertension in rats, an effect we hypothesized was mediated by constriction of multiple vascular beds. Rats were subjected to 5/6 nephrectomy (NX) or no surgery (Normal); at 7 to 8 weeks, uremia animals were anesthetized and instrumented to record MAP and regional blood flow (carotid, mesenteric, and hindlimb). Cinacalcet [N-(1-naphthalen-1-ylethyl)-3-[3-(trifluoromethyl)phenyl]-propan-1-amine; 1, 3, and 10 mg/kg; 30 min/dose] was infused over 90 min. In NX rats, cinacalcet dose-dependently decreased ionized calcium (iCa2+), elicited a 90% reduction in PTH, and produced dose-dependent self-limiting increases in MAP (from 119 +/- 6 to 129 +/- 5, 142 +/- 4, and 145 +/- 3 mm Hg at the end of each infusion). At 1 mg/kg, carotid vascular resistance (CVR) and mesenteric vascular resistance (MVR) increased to 16 +/- 6 and 18 +/- 6% above baseline, respectively. Hindlimb vascular resistance (HVR) also trended upward (13 +/- 8%). At 3 mg/kg, increases in CVR (38 +/- 10%), MVR (40 +/- 8%), and HVR (39 +/- 14%) were exacerbated; at 10 mg/kg, values remained at or near these levels. The effects of cinacalcet in Normal rats were similar to NX and were attenuated by ganglionic blockade with hexamethonium at low doses but remained significantly elevated at higher doses. Thus, CaR activation acutely increases MAP in uremic and nonuremic rats, responses that occur in parallel to vasoconstriction in multiple vascular beds through both a central and peripheral mechanism of action. Moreover, subsequent mechanistic studies suggest that increases in MAP produced by cinacalcet may be mediated by reduced tonic NO synthase-dependent NO production subsequent to reductions in blood iCa2+.

Background/aims: Vitamin D receptor activators (VDRAs) may suppress renin expression and VDR-mediated renin inhibitors may offer a novel mechanism to control the RAS., Methods: We delineated the effects of paricalcitol and calcitriol on PTH, renin, and iCa(2+) in C57/BL6 mice administered vehicle, paricalcitol, or calcitriol (0.01, 0.03, 0.10, 0.33, 1.0 microg/kg s.c.) 3 days/week for 9 days., Results: Paricalcitol produced PTH suppression from 0.03 to 1.0 microg/kg (values between 9.7 +/- 3.3 and 20.7 +/- 4.7 pg/ml; vehicle = 88.0 +/- 16.9) and elicited dose-dependent reductions in renin/GAPDH expression at 0.33 and 1.0 microg/kg (0.037 +/- 0.002, 0.027 +/- 0.003; vehicle = 0.054 +/- 0.003) but produced no increases iCa(2+) at any dose tested. Calcitrol produced PTH suppression at all doses tested (between 6.4 +/- 1.2 and 29.5 +/- 17.2 pg/ml) and renin suppression at 0.10, 0.33, and 1.0 microg/kg (0.029 +/- 0.002, 0.031 +/- 0.003, and 0.038 +/- 0.02). However, at 0.33 and 1.0 mg/kg, calcitriol produced increases iCa(2+) (1.31 +/- 0.03 and 1.48 +/- 0.02 mmol/l; vehicle = 1.23 +/- 0.02 mmol/l)., Conclusions: Paricalcitol produces significant, dose-dependent suppression of renin expression in the absence of hypercalcemia at doses 10-fold above those necessary for PTH suppression. Calcitriol also produced suppression of renin at doses at least 10-fold above those required for PTH suppression, but increases in iCa(2+) were observed at doses only 3-fold above those necessary to elicit renin suppression., (Copyright 2007 S. Karger AG, Basel.)