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2.
Proc Natl Acad Sci U S A ; 118(18)2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33931501

RESUMO

Spinal muscular atrophy (SMA) is a motoneuron disease caused by deletions of the Survival of Motoneuron 1 gene (SMN1) and low SMN protein levels. SMN restoration is the concept behind a number of recently approved drugs which result in impressive yet limited effects. Since SMN has already been enhanced in treated patients, complementary SMN-independent approaches are needed. Previously, a number of altered signaling pathways which regulate motoneuron degeneration have been identified as candidate targets. However, signaling pathways form networks, and their connectivity is still unknown in SMA. Here, we used presymptomatic SMA mice to elucidate the network of altered signaling in SMA. The SMA network is structured in two clusters with AKT and 14-3-3 ζ/δ in their centers. Both clusters are connected by B-Raf as a major signaling hub. The direct interaction of B-Raf with 14-3-3 ζ/δ is important for an efficient neurotrophic activation of the MEK/ERK pathway and crucial for motoneuron survival. Further analyses in SMA mice revealed that both proteins were down-regulated in motoneurons and the spinal cord with B-Raf being reduced at presymptomatic stages. Primary fibroblasts and iPSC-derived motoneurons from SMA patients both showed the same pattern of down-regulation. This mechanism is conserved across species since a Caenorhabditis elegans SMA model showed less expression of the B-Raf homolog lin-45 Accordingly, motoneuron survival was rescued by a cell autonomous lin-45 expression in a C. elegans SMA model resulting in improved motor functions. This rescue was effective even after the onset of motoneuron degeneration and mediated by the MEK/ERK pathway.


Assuntos
Proteínas 14-3-3/genética , Proteínas de Caenorhabditis elegans/genética , Atrofia Muscular Espinal/genética , Degeneração Neural/genética , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Quinases raf/genética , Animais , Caenorhabditis elegans/genética , Modelos Animais de Doenças , Fibroblastos , Regulação da Expressão Gênica , Humanos , Camundongos , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Atrofia Muscular Espinal/patologia , Degeneração Neural/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Transdução de Sinais/genética , Medula Espinal
3.
Z Geburtshilfe Neonatol ; 228(1): 57-64, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38330960

RESUMO

INTRODUCTION: SARS-CoV-2 is a viral disease with potentially devastating effects. Observational studies of pregnant women infected with SARS-CoV-2 report an increased risk for FGR. This study utilizes data from a prospective SARS-CoV-2 registry in pregnancy, investigating the progression of fetuses to fetal growth restriction (FGR) at birth following maternal SARS-CoV-2 and evaluating the hypothesis of whether the percentage of SGA at birth is increased after maternal SARS-CoV-2 taking into account the time interval between infection and birth. MATERIALS & METHODS: CRONOS is a prospective German registry enrolling pregnant women with confirmed SARS-CoV-2 infection during their pregnancy. SARS-CoV-2 symptoms, pregnancy- and delivery-specific information were recorded. The data evaluated in this study range from March 2020 until August 2021. Women with SARS-CoV-2 were divided into three groups according to the time of infection/symptoms to delivery: Group I<2 weeks, Group II 2-4 weeks, and Group III>4 weeks. FGR was defined as estimated and/or birth weight<10% ile, appropriate for gestational age (AGA) was within 10 and 90%ile, and large for gestational age (LGA) was defined as fetal or neonatal weight>90%ile. RESULTS: Data for a total of 2,650 SARS-CoV-2-positive pregnant women were available. The analysis was restricted to symptomatic cases that delivered after 24+0 weeks of gestation. Excluding those cases with missing values for estimated fetal weight at time of infection and/or birth weight centile, 900 datasets remained for analyses. Group I consisted of 551 women, Group II of 112 women, and Group III of 237 women. The percentage of changes from AGA to FGR did not differ between groups. However, there was a significantly higher rate of large for gestational age (LGA) newborns at the time of birth compared to the time of SARS-CoV-2 infection in Group III (p=0.0024), respectively. CONCLUSION: FGR rates did not differ between symptomatic COVID infections occurring within 2 weeks and>4 weeks before birth. On the contrary, it presented a significant increase in LGA pregnancies in Group III. However, in this study population, an increase in the percentage of LGA may be attributed to pandemic measures and a reduction in daily activity.


Assuntos
COVID-19 , SARS-CoV-2 , Gravidez , Feminino , Humanos , Recém-Nascido , Peso ao Nascer , Estudos Prospectivos , COVID-19/epidemiologia , Desenvolvimento Fetal , Retardo do Crescimento Fetal/diagnóstico , Retardo do Crescimento Fetal/epidemiologia , Idade Gestacional
4.
Am J Obstet Gynecol ; 227(3): 495.e1-495.e11, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35452651

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus type 2 infections in pregnancy have been associated with maternal morbidity, admission to intensive care, and adverse perinatal outcomes such as preterm birth, stillbirth, and hypertensive disorders of pregnancy. It is unclear whether medically assisted reproduction additionally affects maternal and neonatal outcomes in women with COVID-19. OBJECTIVE: To evaluate the effect of medically assisted reproduction on maternal and neonatal outcomes in women with COVID-19 in pregnancy. STUDY DESIGN: A total of 1485 women with COVID-19 registered in the COVID-19 Related Obstetric and Neonatal Outcome Study (a multicentric, prospective, observational cohort study) were included. The maternal and neonatal outcomes in 65 pregnancies achieved with medically assisted reproduction and in 1420 spontaneously conceived pregnancies were compared. We used univariate und multivariate (multinomial) logistic regressions to estimate the (un)adjusted odds ratios and 95% confidence intervals for adverse outcomes. RESULTS: The incidence of COVID-19-associated adverse outcomes (eg, pneumonia, admission to intensive care, and death) was not different in women after conceptions with COVID-19 than in women after medically assisted reproduction pregnancies. Yet, the risk of obstetrical and neonatal complications was higher in pregnancies achieved through medically assisted reproduction. However, medically assisted reproduction was not the primary risk factor for adverse maternal and neonatal outcomes including pregnancy-related hypertensive disorders, gestational diabetes mellitus, cervical insufficiency, peripartum hemorrhage, cesarean delivery, preterm birth, or admission to neonatal intensive care. Maternal age, multiple pregnancies, nulliparity, body mass index >30 (before pregnancy) and multiple gestation contributed differently to the increased risks of adverse pregnancy outcomes in women with COVID-19 independent of medically assisted reproduction. CONCLUSION: Although women with COVID-19 who conceived through fertility treatment experienced a higher incidence of adverse obstetrical and neonatal complications than women with spontaneous conceptions, medically assisted reproduction was not the primary risk factor.


Assuntos
COVID-19 , Nascimento Prematuro , COVID-19/epidemiologia , Feminino , Humanos , Recém-Nascido , Idade Materna , Avaliação de Resultados em Cuidados de Saúde , Gravidez , Resultado da Gravidez/epidemiologia , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/etiologia
5.
Z Geburtshilfe Neonatol ; 226(5): 343-348, 2022 10.
Artigo em Alemão | MEDLINE | ID: mdl-36228609

RESUMO

Geburtskliniken werden zunehmend mit an Covid-19 erkrankten Schwangeren konfrontiert. Dies stellt Geburtshelfer vor große Herausforderungen, da einige Fragestellungen noch nicht ausreichend wissenschaftlich erforscht sind. Über Covid-19 während der Schwangerschaft und seine Auswirkungen auf das ungeborene und neugeborene Kind ist nicht viel bekannt.


Assuntos
COVID-19 , Feminino , Humanos , Gravidez
6.
Arterioscler Thromb Vasc Biol ; 40(9): 2265-2278, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32673525

RESUMO

OBJECTIVE: Macrophages are immune cells, capable to remodel the extracellular matrix, which can harbor extracellular DNA incorporated into neutrophil extracellular traps (NETs). To study the breakdown of NETs we studied the capability of macrophage subsets to degrade these structures in vitro and in vivo in a murine thrombosis model. Furthermore, we analyzed human abdominal aortic aneurysm samples in support of our in vitro and in vivo results. Approach and Results: Macrophages were seeded onto blood clots or isolated NETs and polarized. All macrophages were capable to degrade NETs. For initial breakdown, macrophages relied on extracellular deoxyribonucleases. Proinflammatory polarization enhanced NET degradation. The boost in degradation was because of increased macropinocytosis, as inhibition by imipramine diminished their NET breakdown. Inhibition of macropinocytosis in a murine thrombosis model led to increased NET burden and reduced thrombus resolution in vivo. When analyzing abdominal aortic aneurysm samples, macrophage density furthermore corresponded negatively with the amount of local NETs in the intraluminal thrombi as well as in the vessel wall, as increased macrophage density was associated with a reduction in NET burden. CONCLUSIONS: We provide evidence that macrophages degrade NETs by extracellular predigestion and subsequent uptake. Furthermore, we show that proinflammatory macrophages increase NET degradation through enhanced macropinocytosis, priming them for NET engulfment. Based on our findings, that inhibition of macropinocytosis in mice corresponded to increased NET amounts in thrombi and that local macrophage density in human abdominal aortic aneurysm is negatively associated with surrounding NETs, we hypothesize, that macrophages are able to degrade NETs in vivo.


Assuntos
Endodesoxirribonucleases/metabolismo , Armadilhas Extracelulares/metabolismo , Ativação de Macrófagos , Macrófagos/enzimologia , Neutrófilos/metabolismo , Pinocitose , Animais , Aneurisma da Aorta Abdominal/metabolismo , Células Cultivadas , Desoxirribonuclease I/metabolismo , Desoxirribonucleases/metabolismo , Modelos Animais de Doenças , Exodesoxirribonucleases/metabolismo , Feminino , Humanos , Imipramina/farmacologia , Interferon gama/farmacologia , Interleucina-13/farmacologia , Interleucina-4/farmacologia , Cinética , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Musculares/metabolismo , Fagocitose , Fenótipo , Fosfoproteínas/metabolismo , Pinocitose/efeitos dos fármacos , Veia Cava Inferior/metabolismo , Trombose Venosa/metabolismo
7.
FASEB J ; 33(10): 10633-10647, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31262195

RESUMO

Newborn infants have a high disposition to develop systemic inflammatory response syndromes (SIRSs) upon inflammatory or infectious challenges. Moreover, there is a considerable trafficking of hematopoietic cells to tissues already under noninflammatory conditions. These age-specific characteristics suggest a hitherto unappreciated crucial role of the vascular endothelium during the neonatal period. Here, we demonstrate that healthy neonates showed already strong endothelial baseline activation, which was mediated by a constitutively increased production of TNF-α. In mice, pharmacological inhibition of TNF-α directly after birth prevented subsequent fatal SIRS but completely abrogated the recruitment of leukocytes to sites of infection. Importantly, in healthy neonates, blocking TNF-α at birth disrupted the physiologic leukocyte trafficking, which resulted in persistently altered leukocyte profiles at barrier sites. Collectively, these data suggest that constitutive TNF-α-mediated sterile endothelial activation in newborn infants contributes to the increased risk of developing SIRS but is needed to ensure the postnatal recruitment of leukocytes to organs and interfaces.-Bickes, M. S., Pirr, S., Heinemann, A. S., Fehlhaber, B., Halle, S., Völlger, L., Willers, M., Richter, M., Böhne, C., Albrecht, M., Langer, M., Pfeifer, S., Jonigk, D., Vieten, G., Ure, B., von Kaisenberg, C., Förster, R., von Köckritz-Blickwede, M., Hansen, G., Viemann, D. Constitutive TNF-α signaling in neonates is essential for the development of tissue-resident leukocyte profiles at barrier sites.


Assuntos
Recém-Nascido/sangue , Recém-Nascido/imunologia , Leucócitos/imunologia , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologia , Animais , Animais Recém-Nascidos , Estudos de Casos e Controles , Modelos Animais de Doenças , Endotélio Vascular/imunologia , Etanercepte/farmacologia , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Imunossupressores/farmacologia , Recém-Nascido Prematuro , Leucócitos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/imunologia , Transdução de Sinais/imunologia , Síndrome de Resposta Inflamatória Sistêmica/sangue , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Síndrome de Resposta Inflamatória Sistêmica/prevenção & controle , Fator de Necrose Tumoral alfa/antagonistas & inibidores
9.
J Exp Med ; 221(7)2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38753245

RESUMO

Preterm infants are at high risk of developing neonatal sepsis. γδ T cells are thought to be an important set of effector cells in neonates. Here, γδ T cells were investigated in a longitudinal cohort of preterm neonates using next-generation sequencing, flow cytometry, and functional assays. During the first year of life, the Vγ9Vδ2 T cell subset showed dynamic phenotypic changes and elevated levels of fetal-derived Vγ9Vδ2 T cells were evident in infants with sepsis. Single-cell transcriptomics identified HLA-DRhiCD83+ γδ T cells in neonatal sepsis, which expressed genes related to antigen presentation. In vitro assays showed that CD83 was expressed on activated Vγ9Vδ2 T cells in preterm and term neonates, but not in adults. In contrast, activation of adult Vγ9Vδ2 T cells enhanced CD86 expression, which was presumably the key receptor to induce CD4 T cell proliferation. Together, we provide a map of the maturation of γδ T cells after preterm birth and highlight their phenotypic diversity in infections.


Assuntos
Antígeno CD83 , Sepse Neonatal , Receptores de Antígenos de Linfócitos T gama-delta , Adulto , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Antígenos CD/metabolismo , Antígenos CD/genética , Estudos de Coortes , Recém-Nascido Prematuro/imunologia , Ativação Linfocitária/imunologia , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Sepse Neonatal/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
10.
Nat Commun ; 15(1): 1758, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38413582

RESUMO

SNURPORTIN-1, encoded by SNUPN, plays a central role in the nuclear import of spliceosomal small nuclear ribonucleoproteins. However, its physiological function remains unexplored. In this study, we investigate 18 children from 15 unrelated families who present with atypical muscular dystrophy and neurological defects. Nine hypomorphic SNUPN biallelic variants, predominantly clustered in the last coding exon, are ascertained to segregate with the disease. We demonstrate that mutant SPN1 failed to oligomerize leading to cytoplasmic aggregation in patients' primary fibroblasts and CRISPR/Cas9-mediated mutant cell lines. Additionally, mutant nuclei exhibit defective spliceosomal maturation and breakdown of Cajal bodies. Transcriptome analyses reveal splicing and mRNA expression dysregulation, particularly in sarcolemmal components, causing disruption of cytoskeletal organization in mutant cells and patient muscle tissues. Our findings establish SNUPN deficiency as the genetic etiology of a previously unrecognized subtype of muscular dystrophy and provide robust evidence of the role of SPN1 for muscle homeostasis.


Assuntos
Distrofias Musculares , Criança , Humanos , Distrofias Musculares/genética , Distrofias Musculares/metabolismo , Ribonucleoproteínas Nucleares Pequenas/metabolismo , RNA/metabolismo , Splicing de RNA/genética , Spliceossomos/genética , Spliceossomos/metabolismo
11.
Elife ; 122023 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-37395732

RESUMO

At each cell division, nanometer-scale components self-organize to build a micron-scale spindle. In mammalian spindles, microtubule bundles called kinetochore-fibers attach to chromosomes and focus into spindle poles. Despite evidence suggesting that poles can set spindle length, their role remains poorly understood. In fact, many species do not have spindle poles. Here, we probe the pole's contribution to mammalian spindle length, dynamics, and function by inhibiting dynein to generate spindles whose kinetochore-fibers do not focus into poles, yet maintain a metaphase steady-state length. We find that unfocused kinetochore-fibers have a mean length indistinguishable from control, but a broader length distribution, and reduced length coordination between sisters and neighbors. Further, we show that unfocused kinetochore-fibers, like control, can grow back to their steady-state length if acutely shortened by drug treatment or laser ablation: they recover their length by tuning their end dynamics, albeit slower due to their reduced baseline dynamics. Thus, kinetochore-fiber dynamics are regulated by their length, not just pole-focusing forces. Finally, we show that spindles with unfocused kinetochore-fibers can segregate chromosomes but fail to correctly do so. We propose that mammalian spindle length emerges locally from individual k-fibers while spindle poles globally coordinate k-fibers across space and time.


Assuntos
Cinetocoros , Microtúbulos , Animais , Metáfase , Divisão Celular , Mamíferos , Fuso Acromático
12.
Geburtshilfe Frauenheilkd ; 83(12): 1508-1518, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38046525

RESUMO

Introduction: Studies have shown that pregnant women with COVID-19 have a higher risk of intensive care unit admission and invasive mechanical ventilation support than non-pregnant women. Pregnancy-associated physiological changes in respiratory function may contribute to the elevated risk. Alteration in lung volumes and capacities are attributed to the mechanical impediment caused by the growing fetus. Multiple pregnancies may therefore compromise functional lung capacity earlier than singleton pregnancies and contribute to severe respiratory symptoms of COVID-19. Materials and Methods: A total of 5514 women with a symptomatic SARS-CoV-2 infection during pregnancy registered in the COVID-19 Related Obstetric and Neonatal Outcome Study were included. The COVID-19-related adverse maternal outcomes were compared in 165 multiple versus 5349 singleton pregnancies. Combined adverse maternal outcome was defined as presence of COVID-19-related hospitalization and/or pneumonia and/or oxygen administration and/or transfer to ICU and/or death. Multivariate logistic regression was used to estimate the odds ratios and 95% confidence intervals were calculated. Results: The frequency of dyspnea, likelihood of developing dyspnea in a defined pregnancy week and duration of the symptomatic phase of the COVID-19 infection did not differ between the two groups. On average, COVID-19-related combined adverse outcome occurred earlier during pregnancy in women expecting more than one child than in singleton pregnancies. The overall incidence of singular and combined COVID-19-associated adverse maternal outcomes was not significantly different between groups. However, regression analysis revealed that multiple gestation, preconceptional BMI > 30 kg/m 2 and gestational age correlated significantly with an increased risk of combined adverse maternal outcome. Conversely, maternal age and medically assisted reproduction were not significant risk factors for combined adverse maternal outcome. Conclusion: Our data show that multiple gestation alone is a risk factor for COVID-19-associated combined adverse maternal outcome. Moreover, severe courses of COVID-19 in women expecting more than one child are observed earlier in pregnancy than in singleton pregnancies.

14.
Biochem Pharmacol ; 190: 114634, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34058186

RESUMO

BACKGROUND: Inflammation is a key process during atherosclerotic lesion development and propagation. Recent evidence showed clearly that especially the inhibition of interleukin (IL)-1ß reduced atherosclerotic adverse events in human patients. Fatty acid oxidation (FAO) was previously demonstrated to interact with the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) pathway which is required for mature IL-1ß secretion. To understand possible anti-inflammatory properties of FAO inhibition, we tested the effect of pharmacological FAO inhibition using the inhibitor for long-chain 3-ketoacyl coenzyme A thiolase trimetazidine on atherosclerotic plaque development and inflammation. EXPERIMENTAL APPROACH: The effect of FAO inhibition was determined in LDL-R-/- male mice on a C57/BL6 background. In vitro effects of trimetazidine treatment were analyzed in human umbilical vein endothelial cells and human monocyte derived macrophages. KEY RESULTS: We were able to demonstrate that inhibition of FAO reduced atherosclerotic plaque growth. We did not find direct anti-inflammatory properties of trimetazidine in endothelial cells or macrophages in vitro. However, we found that the activation of the NLRP3 system and the secretion of IL-1ß were significantly reduced in macrophages after FAO inhibition. These results were confirmed in atherosclerotic lesions of mice treated with trimetazidine as they showed a significant reduction of IL-1ß and cleaved caspase-1 in the atherosclerotic lesion as well as of IL-1ß and IL-18 in the circulation. CONCLUSION: Overall, we therefore suggest that the main mechanism of reducing inflammation of trimetazidine and FAO inhibition is the reduction of the NLRP-3 activation leading to reduced levels of the proinflammatory cytokine IL-1ß.


Assuntos
Aterosclerose/prevenção & controle , Ácidos Graxos/metabolismo , Macrófagos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptores de LDL/metabolismo , Animais , Citocinas/genética , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Metabolismo dos Lipídeos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Oxirredução , Receptores de LDL/genética , Trimetazidina/farmacologia , Vasodilatadores/farmacologia
15.
Environ Toxicol Chem ; 27(4): 909-18, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18333693

RESUMO

A comparative hazard assessment of the antiparasitics ivermectin, albendazole, and morantel was performed, with a particular focus on bioavailability and uptake into biological membranes. The experimentally determined liposome-water distribution ratio at pH 7 (D(lipw) (pH 7)) of the positively charged morantel was 100 L/kg lipid. The D(lipw) (pH 7) of albendazole was 3,000 L/kg lipid. The membrane permeability determined with the parallel artificial membrane permeability assay was consistent with predictions from a quantitative structure-activity relationship (QSAR) for morantel but 14-fold lower than predicted for albendazole, which can be rationalized because neutral albendazole is, in fact, zwitterionic and the large dipole moment hinders permeation through hydrophobic membranes. An unusually large molecule, ivermectin was suspected to show decreased bioaccumulation because of its bulkiness, but experimental determination of solubility showed that it was 40-fold less soluble than expected from a QSAR between solubility and the octanol-water partition coefficient. In contrast, its membrane permeability appeared to be typical for a compound of the given hydrophobicity, but it was not possible to determine the membrane-water partition coefficient because of its low solubility and high affinity to the dialysis membrane of the experimental device. The D(lipw) (pH 7) for ivermectin of 2,700 L/kg lipid was calculated with a QSAR model. Morantel and albendazole were baseline toxicants in the bioluminescence inhibition test with Vibrio fischeri and a test for inhibition of photosynthesis in green algae. Only ivermectin exhibited a specific effect toward algae, but the excess toxicity was not very pronounced and might be biased by the uncertainty of the estimated hydrophobicity descriptor. Overall, we did not find any unexpected effect on nontarget endpoints.


Assuntos
Albendazol/toxicidade , Antiparasitários/toxicidade , Permeabilidade da Membrana Celular , Ivermectina/toxicidade , Morantel/toxicidade , Albendazol/química , Albendazol/farmacocinética , Animais , Antiparasitários/química , Antiparasitários/farmacocinética , Relação Dose-Resposta a Droga , Estabilidade de Medicamentos , Peixes/metabolismo , Ivermectina/química , Ivermectina/farmacocinética , Lipossomos/química , Morantel/química , Morantel/farmacocinética , Relação Quantitativa Estrutura-Atividade , Solubilidade
16.
Front Immunol ; 8: 1822, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29326708

RESUMO

Sepsis is a leading cause of perinatal mortality worldwide. Breast milk (BM) feeding is protective against neonatal sepsis, but the molecular mechanisms remain unexplained. Despite various supplementations with potential bioactive components from BM formula feeding cannot protect from sepsis. S100-alarmins are important immunoregulators in newborns preventing excessive inflammation. At high concentrations, the S100A8/A9 protein complex also has antimicrobial properties due to its metal ion chelation capacity. To assess whether BM contains S100-alarmins that might mediate the sepsis-protective effect of BM 97 human BM samples stratified for gestational age, mode of delivery and sampling after birth were collected and analyzed. S100A8/A9 levels were massively elevated after birth (p < 0.0005). They slowly decreased during the first month of life, then reaching levels comparable to normal values in adult serum. The concentration of S100A8/A9 in BM was significantly higher after term compared with preterm birth (extremely preterm, p < 0.005; moderate preterm, p < 0.05) and after vaginal delivery compared with cesarean section (p < 0.0005). In newborn s100a9-/- mice, enterally supplied S100-alarmins could be retrieved systemically in the plasma. To explore the antimicrobial activity against common causal pathogens of neonatal sepsis, purified S100-alarmins and unmodified as well as S100A8/A9-depleted BM were used in growth inhibition tests. The high amount of S100A8/A9 proved to be an important mediator of the antimicrobial activity of BM, especially inhibiting the growth of manganese (Mn) sensitive bacteria such as Staphylococcus aureus (p < 0.00005) and group B streptococci (p < 0.005). Depletion of S100A8/A9 significantly reduced this effect (p < 0.05, respectively). The growth of Escherichia coli was also inhibited by BM (p < 0.00005) as well as by S100A8/A9 in culture assays (p < 0.05). But its growth in BM remained unaffected by the removal of S100A8/A9 and was neither dependent on Mn suggesting that the antimicrobial effects of S100A8/A9 in BM are primarily mediated by its Mn chelating capacity. In summary, the enteral supply of bioavailable, antimicrobially active amounts of S100-alarmins might be a promising option to protect newborns at high risk from infections and sepsis.

17.
Front Microbiol ; 8: 2348, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29234314

RESUMO

Overuse of antibiotics is a major problem in the treatment of bovine mastitis, and antibiotic treatment is frequently non-curative, thus alternative treatments are necessary. The primary aim of this study was to evaluate the efficacy of a purified phage cocktail for treatment of bovine Staphylococcus aureus mastitis in a well-defined mouse model. Candidate phages were selected based on their in vitro performance and subsequently processed into an optimally composed phage cocktail. The highest scoring phages were further tested for efficacy and resistance suppression in broth and raw milk, with and without supplemental IgG. As these in vitro results displayed significant decreases in CFU, the cocktail was purified for testing in vivo. Lactating mice were intramammarily inoculated with S. aureus N305 (ATCC 29740), a clinical bovine mastitis isolate commonly used for experimental infection of dairy cows. The phage cocktail was applied via the same route 4 h post-inoculation. Treated mammary glands were graded for gross pathological appearance and excised for bacterial and phage load quantification as well as histopathology. Observation of gross macroscopic and histopathological changes and CFU quantification demonstrated that the phage cocktail treatment significantly improved mastitis pathology and decreased bacterial counts. Phage PFU quantification indicated that the tested phage cocktail treatment was able to maintain high intramammary phage titers without spreading systemically. The in vivo results complement the in vitro data and support our concept of phage therapy as an innovative alternative or supplementation therapy to antibiotics for the treatment of bovine mastitis.

18.
J Appl Psychol ; 101(6): 779-792, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26882444

RESUMO

Although giving bad news at work is a stressful experience, managers are often underprepared for this challenging task. As a solution, we introduce organizational bad news training that integrates (a) principles of delivering bad news from the context of health care (i.e., bad news delivery component), and (b) principles of organizational justice theory (i.e., fairness component). We argue that both the formal and fair delivery of bad news at work can be enhanced with the help of training to mitigate distress both for the messenger and the recipient. We tested the effectiveness of training for the delivery of a layoff as a typical bad news event at work. In 2 studies, we compared the performance of a training group (receiving both components of training) with that of a control group (Study 1, Study 2) and a basics group (receiving the bad news delivery component only; Study 2) during a simulated dismissal notification meeting. In general, the results supported our hypotheses: Training improved the formal delivery of bad news and predicted indicators of procedural fairness during the conversation in both studies. In Study 2, we also considered layoff victims' negativity after the layoff and found that training significantly reduced negative responses. This relationship was fully mediated by layoff victims' fairness perceptions. Despite preparation, however, giving bad news remained a challenging task in both studies. In summary, we recommend that organizations provide managers with organizational bad news training in order to promote professional and fair bad news conversations at work. (PsycINFO Database Record


Assuntos
Emprego/psicologia , Relações Interpessoais , Gestão de Recursos Humanos/métodos , Ensino , Revelação da Verdade , Adulto , Humanos , Adulto Jovem
19.
Environ Toxicol Chem ; 24(3): 750-8, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15779777

RESUMO

A test battery for identifying ecotoxicological hazards was applied to six pharmaceuticals (carbamazepine, diclofenac, ethinylestradiol, ibuprofen, propranolol, and sulfamethoxazole), to their mixtures, and to urine spiked with pharmaceuticals to test the suitability of biotests for screening urine and wastewater and for monitoring the efficiency of wastewater treatment. The test battery comprised the bioluminescence inhibition test with Vibrio fischeri, the yeast estrogen screen, and a photosynthesis inhibition assay in algae based on chlorophyll fluorescence measurements. Mixture and additional experiments with a cocktail of pharmaceuticals added to urine confirmed the applicability of the test systems as an integrated measure of the overall micropollutant burden. Because the concentration of pharmaceuticals in wastewater is low and the nutrients and salts may have a negative impact on the bioassays, urine and wastewater samples were cleaned and concentrated by solid-phase extraction (SPE). The compounds of interest ranged from polar to nonpolar and from positively charged to neutral and negatively charged. Consequently, the SPE method was optimized for universality rather than for specificity. Results of preliminary experiments with raw and treated urine and wastewater indicate the suitability of the proposed test battery for screening urine and wastewater.


Assuntos
Preparações Farmacêuticas/análise , Preparações Farmacêuticas/urina , Esgotos , Testes de Toxicidade , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/urina , Abastecimento de Água/análise , Adulto , Aliivibrio fischeri/efeitos dos fármacos , Aliivibrio fischeri/metabolismo , Clorofila/metabolismo , Clorófitas/efeitos dos fármacos , Clorófitas/metabolismo , Humanos , Concentração Inibidora 50 , Medições Luminescentes , Masculino , Receptores de Estrogênio/efeitos dos fármacos , Receptores de Estrogênio/metabolismo , Purificação da Água/normas , Abastecimento de Água/normas , Leveduras/efeitos dos fármacos , Leveduras/genética , Leveduras/metabolismo
20.
Environ Sci Technol ; 40(23): 7402-8, 2006 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-17180995

RESUMO

We analyzed nontarget effects of the beta-blockers propranolol, metoprolol, and atenolol with a screening test battery encompassing nonspecific, receptor-mediated, and reactive modes of toxic action. All beta-blockers were baseline toxicants and showed no specific effects on energy transduction nor endocrine activity in the yeast estrogen and androgen screen, and no reactive toxicity toward proteins and DNA. However, in a phytotoxicity assay based on the inhibition of the photosynthesis efficiency in green algae, all beta-blockers were 10 times more toxic than their modeled baseline toxicity. Baseline- and phytotoxicity effects increased with hydrophobicity. The beta-blockers showed concentration addition in mixture experiments, indicating a mutual specific nontarget effect on algae. Using literature data and quantitative structure-activity relationships (QSAR), we modeled the total toxic potential of mixtures of the beta-blockers and their associated human metabolites for the phytotoxicity endpoint with two scenarios. The realistic scenario (I) assumes that the metabolites lose their specific activity and act as baseline toxicants. In the worst-case scenario (II) the metabolites exhibitthe same specific mode of action as their parent drug. For scenario (II), metabolism hardly affected the overall toxicity of atenolol and metoprolol, whereas propranolol's hazard potential decreased significantly. In scenario (I), metabolism reduced the apparent EC50 of the mixture of parent drug and metabolite even further. The proposed method is a simple approach to initial hazard assessment of pharmaceuticals and can guide higher tier testing. It can be applied to other classes of pollutants, e.g., biocides, as well as to environmental transformation products of pollutants.


Assuntos
Antagonistas Adrenérgicos beta/toxicidade , Clorófitas/efeitos dos fármacos , Fotossíntese/efeitos dos fármacos , Testes de Toxicidade/métodos , Poluentes Químicos da Água/toxicidade , Antagonistas Adrenérgicos beta/metabolismo , Atenolol/toxicidade , Determinação de Ponto Final , Humanos , Lipossomos/metabolismo , Metoprolol/toxicidade , Propranolol/toxicidade , Relação Quantitativa Estrutura-Atividade , Medição de Risco
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