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1.
Proteomics ; 19(5): e1800319, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30637940

RESUMO

Oviductal fluid (ODF) proteins modulate and support reproductive processes in the oviduct. In the present study, proteins involved in the biological events that precede fertilization have been identified in the rabbit ODF proteome, isolated from the ampulla and isthmus of the oviduct at different time points within 8 h after intrauterine insemination. A workflow is used that integrates lectin affinity capture with stable-isotope dimethyl labeling prior to nanoLC-MS/MS analysis. In total, over 400 ODF proteins, including 214 lectin enriched glycoproteins, are identified and quantified. Selected data are validated by Western blot analysis. Spatiotemporal alterations in the abundance of ODF proteins in response to insemination are detected by global analysis. A subset of 63 potentially biologically relevant ODF proteins is identified, including extracellular matrix components, chaperones, oxidoreductases, and immunity proteins. Functional enrichment analysis reveals an altered peptidase regulator activity upon insemination. In addition to protein identification and abundance changes, N-glycopeptide analysis further identifies 281 glycosites on 199 proteins. Taken together, these results show, for the first time, the evolving oviductal milieu early upon insemination. The identified proteins are likely those that modulate in vitro processes, including spermatozoa function.


Assuntos
Tubas Uterinas/química , Proteínas/análise , Proteômica/métodos , Coelhos , Animais , Secreções Corporais/química , Secreções Corporais/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Tubas Uterinas/fisiologia , Feminino , Fertilização , Glicosilação , Inseminação , Masculino , Proteínas/metabolismo , Coelhos/fisiologia , Espectrometria de Massas em Tandem/métodos
2.
BMC Public Health ; 18(1): 817, 2018 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-29970077

RESUMO

BACKGROUND: Food system function is vulnerable to disruption from a variety of sources. Disruption of the processes required for food provision may result in decreases in food security in affected communities. Currently, there are few tools that quantitatively predict or analyze food system vulnerabilities to contribute to food system resilience analysis. This work presents a prototype version of one such tool, a fault tree, which can be used conceptually and for future modeling work. Fault tree analysis is an engineering tool used to illustrate basic and intermediate factors that can cause overall system failures. METHODS: The fault tree defines food system functioning as food security at the community level and maps the components of the food system onto three main tenets of food security - accessibility, availability, and acceptability. Subtrees were populated using a top down approach guided by expertise, extant literature, and 36 stakeholder interviews. RESULTS: The food system is complex, requiring 12 subtrees to elaborate potential failures. Subtrees comprising accessibility include physical accessibility of the vending point and economic accessibility among community members. Food availability depends on the functioning of the food supply chain, or, in the case of individuals who rely on donated food, the food donation system. The food supply chain includes processing, wholesale operations, distribution systems, and retail center subtrees. Elements of acceptability include the medical appropriateness, nutritional adequacy, and cultural acceptability of food. Case studies of the effects of Winter Storm Jonas of 2016 and the 2013-2017 California drought in Baltimore City illustrate the utility of the fault tree model. CONCLUSION: FTA of potential routes to food system failure provides a tool that allows for consideration of the entirety of the food system; has potential to provide a quantitative assessment of food system failure and recovery; and is able to capture short-term and long-term hazards in a single framework. This systems modeling approach highlights an extensive list of vulnerability points throughout the food system, and underscores the message that reducing food system vulnerabilities requires action at all levels to protect communities from the risks of short-term and long-term threats to food security.


Assuntos
Árvores de Decisões , Abastecimento de Alimentos/métodos , California , Humanos , Estações do Ano , Análise de Sistemas
3.
Proteomics ; 16(23): 2962-2966, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27678138

RESUMO

The analysis of glycoproteins in body fluids represents a central task in the study of vital processes. Herein, we assessed the combined use of Concanavalin A and Wheat Germ Agglutinin as ligands to fractionate and enrich glycoproteins from oviductal fluid (OF), which is a source of molecules involved in fertilization. First, the selectivity was corroborated by a gel-based approach using glycoprotein staining and enzymatic deglycosylation. Nanoliquid chromatography-tandem mass spectrometry (nLC-ESI-MS/MS) further allowed the reliable identification of 134 nonbound as well as 130 lectin-bound OF proteins. Enrichment analysis revealed that 77% of the annotated proteins in the lectin-bound fraction were known glycoproteins (p-value [FDR] = 1.45E-31). The low variance of the number of peptide spectrum matches for each protein within replicates indicated a consistent reproducibility of the whole workflow (median CV 17.3% for technical replicates and 20.7% for biological replicates). Taken together, this study highlights the applicability of a lectin-based workflow for the comprehensive analysis of OF proteins and gives for the first time an insight into the broad glycoprotein content of OF.


Assuntos
Líquidos Corporais/química , Glicoproteínas/análise , Proteoma/análise , Animais , Concanavalina A/metabolismo , Tubas Uterinas/química , Feminino , Glicoproteínas/metabolismo , Masculino , Proteoma/metabolismo , Coelhos , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray/métodos , Aglutininas do Germe de Trigo/metabolismo , Fluxo de Trabalho
4.
J Pers Med ; 14(5)2024 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-38793055

RESUMO

BACKGROUND: Understanding the dynamics of conduction velocity (CV) and voltage amplitude (VA) is crucial in cardiac electrophysiology, particularly for substrate-based catheter ablations targeting slow conduction zones and low voltage areas. This study utilizes ultra-high-density mapping to investigate the impact of heart rate and pacing location on changes in the wavefront direction, CV, and VA of healthy pig hearts. METHODS: We conducted in vivo electrophysiological studies on four healthy juvenile pigs, involving various pacing locations and heart rates. High-resolution electroanatomic mapping was performed during intrinsic normal sinus rhythm (NSR) and electrical pacing. The study encompassed detailed analyses at three levels: entire heart cavities, subregions, and localized 5-mm-diameter circular areas. Linear mixed-effects models were used to analyze the influence of heart rate and pacing location on CV and VA in different regions. RESULTS: An increase in heart rate correlated with an increase in conduction velocity and a decrease in voltage amplitude. Pacing influenced conduction velocity and voltage amplitude. Pacing also influenced conduction velocity and voltage amplitude, with varying effects observed based on the pacing location within different heart cavities. Pacing from the right atrium (RA) decreased CV in all heart cavities. The overall CV and VA changes in the whole heart cavities were not uniformly reflected in all subregions and subregional CV and VA changes were not always reflected in the overall analysis. Overall, there was a notable variability in absolute CV and VA changes attributed to pacing. CONCLUSIONS: Heart rate and pacing location influence CV and VA within healthy juvenile pig hearts. Subregion analysis suggests that specific regions of the heart cavities are more susceptible to pacing. High-resolution mapping aids in detecting regional changes, emphasizing the substantial physiological variations in CV and VA.

5.
EBioMedicine ; 100: 104982, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38306899

RESUMO

BACKGROUND: Inflammatory demyelinating diseases of the central nervous system, such as multiple sclerosis, are significant sources of morbidity in young adults despite therapeutic advances. Current murine models of remyelination have limited applicability due to the low white matter content of their brains, which restricts the spatial resolution of diagnostic imaging. Large animal models might be more suitable but pose significant technological, ethical and logistical challenges. METHODS: We induced targeted cerebral demyelinating lesions by serially repeated injections of lysophosphatidylcholine in the minipig brain. Lesions were amenable to follow-up using the same clinical imaging modalities (3T magnetic resonance imaging, 11C-PIB positron emission tomography) and standard histopathology protocols as for human diagnostics (myelin, glia and neuronal cell markers), as well as electron microscopy (EM), to compare against biopsy data from two patients. FINDINGS: We demonstrate controlled, clinically unapparent, reversible and multimodally trackable brain white matter demyelination in a large animal model. De-/remyelination dynamics were slower than reported for rodent models and paralleled by a degree of secondary axonal pathology. Regression modelling of ultrastructural parameters (g-ratio, axon thickness) predicted EM features of cerebral de- and remyelination in human data. INTERPRETATION: We validated our minipig model of demyelinating brain diseases by employing human diagnostic tools and comparing it with biopsy data from patients with cerebral demyelination. FUNDING: This work was supported by the DFG under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy, ID 390857198) and TRR 274/1 2020, 408885537 (projects B03 and Z01).


Assuntos
Doenças Desmielinizantes , Esclerose Múltipla , Substância Branca , Suínos , Humanos , Animais , Camundongos , Doenças Desmielinizantes/diagnóstico por imagem , Doenças Desmielinizantes/patologia , Cuprizona , Porco Miniatura , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia , Bainha de Mielina/patologia , Substância Branca/patologia , Microscopia Eletrônica , Modelos Animais de Doenças
6.
Am J Vet Res ; 84(9)2023 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-37429569

RESUMO

OBJECTIVE: This study assessed the use of a topical anesthetic as a feasible approach to reduce pain during piglet castration using a minimal anesthesia protocol. ANIMALS: 18 male piglets, aged 3-6 days, were included in this study. METHODS: A minimal anesthetic state was induced with isoflurane administered by facemask, with anesthetic depth individually adjusted based on responses to interdigital pinch. To desensitize the scrotal skin, a vapocoolant was applied 3 times. Scrotal incisions were made subsequently and Tri-Solfen (TS) or Placebo (P) was administered in both incisional gaps. After 30 seconds, the spermatic cords were severed followed by a further application of TS/P to both incision edges. Nociception-related variables, such as mean arterial blood pressure (MAP), heart rate (HR), and nocifensive movements, were assessed. RESULTS: Significant differences in MAP changes were assessed between the TS (14 ± 4 mmHg) and the P group (36 ± 8 mmHg) for cutting the spermatic cords. Furthermore, significantly fewer nocifensive movement score points appeared in the TS than in the P group (0; IQR = 0 vs 5; IQR = 6). CLINICAL RELEVANCE: In this anesthesia model, the application of TS after skin incision significantly reduced MAP responses and nocifensive movements with spermatic cord transection compared with the application of P. However, the waiting period between TS-application and spermatic cord transection might limit the benefit of the method in conscious piglets, as pain during castration is reduced but additional stress is caused by the prolonged handling. Furthermore, using a vapocoolant did not provide anesthesia for skin incisions.


Assuntos
Anestésicos Locais , Dor , Cordão Espermático , Animais , Masculino , Suínos , Anestésicos Locais/farmacologia , Anestésicos Locais/uso terapêutico , Dor/tratamento farmacológico , Dor/veterinária , Anestesia Local/efeitos adversos , Anestesia Local/métodos , Anestesia Local/veterinária , Orquiectomia/efeitos adversos , Orquiectomia/veterinária , Orquiectomia/métodos
7.
Animals (Basel) ; 13(17)2023 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-37684974

RESUMO

Although it is assumed that chicken embryos acquire the capacity for nociception while developing in the egg, an exact time point has not yet been specified. The present research was an exploratory study aiming to determine when the capacity of nociception emerges during embryonic development in chickens. Changes in blood pressure and heart rate (HR) in response to a noxious mechanical stimulus at the base of the beak versus a light touch on the beak were examined in chicken embryos between embryonic days (EDs) 7 and 18. Mean arterial pressure (MAP) was the most sensitive parameter for assessing cardiovascular responses. Significant changes in MAP in response to a noxious stimulus were detected in embryos at ED16 to ED18, whereas significant changes in HR were observed at ED17 and ED18. Infiltration anesthesia with the local anesthetic lidocaine significantly reduced the response of MAP on ED18, so the measured cardiovascular changes may be interpreted as nociceptive responses.

8.
J Clin Med ; 12(17)2023 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-37685665

RESUMO

BACKGROUND: Ultra-high-density mapping systems allow more precise measurement of the heart chambers at corresponding conduction velocities (CVs) and voltage amplitudes (VAs). Our aim for this study was to define and compare a basic value set for unipolar CV and VA in all four heart chambers and their separate walls in healthy, juvenile porcine hearts using ultra-high-density mapping. METHODS: We used the Rhythmia Mapping System to create electroanatomical maps of four pig hearts in sinus rhythm. CVs and VAs were calculated for chambers and wall segments with overlapping circular areas (radius of 5 mm). RESULTS: We analysed 21 maps with a resolution of 1.4 points/mm2. CVs were highest in the left atrium (LA), followed by the left ventricle (LV), right ventricle (RV), and right atrium (RA). As for VA, LV was highest, followed by RV, LA, and RA. The left chambers had a higher overall CV and VA than the right. Within the chambers, CV varied more in the right than in the left chambers, and VA varied in the ventricles but not in the atria. There was a slightly positive correlation between CVs and VAs at velocity values of <1.5 m/s. CONCLUSIONS: In healthy porcine hearts, the left chambers showed higher VAs and CVs than the right. CV differs mainly within the right chambers and VA differs only within the ventricles. A slightly positive linear correlation was found between slow CVs and low VAs.

9.
Animals (Basel) ; 13(18)2023 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-37760239

RESUMO

Chicken culling has been forbidden in Germany since 2022; male/female selection and male elimination must be brought to an embryonic status prior to the onset of nociception. The present study evaluated the ontogenetic point at which noxious stimuli could potentially be perceived/processed in the brain in ovo. EEG recordings from randomized hyperpallial brain sites were recorded in ovo and noxious stimuli were applied. Temporal and spectral analyses of the EEG were performed. The onset of physiological neuronal signals could be determined at developmental day 13. ERP/ERSP/ITC analysis did not reveal phase-locked nociceptive responses. Although no central nociceptive responses were documented, adequate EEG responses to noxious stimuli from other brain areas cannot be excluded. The extreme stress impact on the embryo during the recording may overwrite the perception of noniceptive stimuli. The results suggest developmental day 13 as the earliest embryonal stage being able to receive and process nociceptive stimuli.

10.
Animals (Basel) ; 13(3)2023 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-36766418

RESUMO

Surgical castration of piglets is generally recognized as a painful procedure, but there is currently no gold standard for the assessment of pain behavior in piglets. However, pain assessment is essential for evaluating the effectiveness of local anesthetics. In this study, we investigated the efficacy of four local anesthetics in terms of pain relief during and after surgical castration in three sequential study parts. To do so, we filmed 178 piglets before the applied procedures, after injection of the local anesthetic, and up to 24 h after castration (five observation times in total) in an observation arena and compared their behavior before and after castration and between treatments and control groups. The results showed significant differences in the behavior of the piglets before and after castration and between the sham-castrated control group and the control group castrated without anesthesia. The different local anesthesia treatment groups showed diverging differences to the control groups. The most frequently shown pain-associated behaviors of the piglets were changes in tail position and hunched back posture. We observed a reduction but no complete elimination of the expressed pain-associated behaviors after local anesthesia. Several behavioral changes-such as changes in tail position, hunched back posture or tail wagging-persisted until the day after castration. Owing to the limited duration of the effects of the local anesthetics, local anesthesia did not influence long-term pain.

11.
Animals (Basel) ; 13(18)2023 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-37760259

RESUMO

Many potentially noxious interventions are performed on chicken embryos in research and in the poultry industry. It is therefore essential and in the interest of animal welfare to be able to precisely define the point at which a chicken embryo is capable of nociception in ovo. The present part III of a comprehensive study examined the movements of developing chicken embryos with the aim of identifying behavioral responses to a noxious stimulus. For this purpose, a noxious mechanical stimulus and a control stimulus were applied in a randomized order. The recorded movements of the embryos were evaluated using the markerless pose estimation software DeepLabCut and manual observations. After the application of the mechanical stimulus, a significant increase in beak movement was identified in 15- to 18-day-old embryos. In younger embryos, no behavioral changes related to the noxious stimulus were observed. The presented results indicate that noxious mechanical stimuli at the beak base evoke a nocifensive reaction in chicken embryos starting at embryonic day 15.

12.
J Thorac Cardiovasc Surg ; 166(4): 1119-1129.e1, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-35379474

RESUMO

OBJECTIVE: Due to severely limited donor heart availability, durable mechanical circulatory support remains the only treatment option for many patients with end-stage heart failure. However, treatment complexity persists due to its univentricular support modality and continuous contact with blood. We investigated the function and safety of reBEAT (AdjuCor GmbH), a novel, minimal invasive mechanical circulatory support device that completely avoids blood contact and provides pulsatile, biventricular support. METHODS: For each animal tested, an accurately sized cardiac implant was manufactured from computed tomography scan analyses. The implant consists of a cardiac sleeve with three inflatable cushions, 6 epicardial electrodes and driveline connecting to an electro-pneumatic, extracorporeal portable driver. Continuous epicardial electrocardiogram signal analysis allows for systolic and diastolic synchronization of biventricular mechanical support. In 7 pigs (weight, 50-80 kg), data were analyzed acutely (under beta-blockade, n = 5) and in a 30-day long-term survival model (n = 2). Acquisition of intracardiac pressures and aortic and pulmonary flow data were used to determine left ventricle and right ventricle stroke work and stroke volume, respectively. RESULTS: Each implant was successfully positioned around the ventricles. Automatic algorithm electrocardiogram signal annotations resulted in precise, real-time mechanical support synchronization with each cardiac cycle. Consequently, progressive improvements in cardiac hemodynamic parameters in acute animals were achieved. Long-term survival demonstrated safe device integration, and clear and stable electrocardiogram signal detection over time. CONCLUSIONS: The present study demonstrates biventricular cardiac support with reBEAT. Various demonstrated features are essential for realistic translation into the clinical setting, including safe implantation, anatomical fit, safe device-tissue integration, and real-time electrocardiogram synchronized mechanical support, result in effective device function and long-term safety.


Assuntos
Insuficiência Cardíaca , Transplante de Coração , Coração Auxiliar , Animais , Suínos , Humanos , Doadores de Tecidos , Hemodinâmica
14.
Animals (Basel) ; 12(8)2022 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-35454274

RESUMO

The present study evaluated the effects of two injection techniques in combination with lidocaine or mepivacaine for piglets undergoing castration. To improve ease of use, a cannula with side holes (one-step fenestrated (F)) was invented to simultaneously deliver a local anesthetic into the testis and scrotum and was compared to a two-step injection technique. The distribution of a lidocaine/contrast agent mixture using the two methods was examined using computed tomography. Piglets were randomly divided into treatment groups: handling, castration without pain relief and castration after lidocaine or mepivacaine injection using the one-step F or two-step method. Acute physiological responses to noxious stimuli were evaluated by measuring the mean arterial blood pressure (MAP), heart rate (HR) and nocifensive movements. Fos protein expression in the spinal dorsal cord was semi-quantitatively analyzed. Both injection techniques achieved similar distribution patterns. The one-step F method was faster and easier. Injection was not associated with significant changes in MAP or HR, but Mepi1 and NaCl elicited significantly increased nocifensive movements. Both techniques significantly reduced MAP and nocifensive movements when the spermatic cords were cut, regardless of the local anesthetic type. Compared to NaCl, only the lidocaine treatments significantly reduced HR during skin incision. Lido2 significantly reduced Fos protein expression.

15.
Animals (Basel) ; 12(18)2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36139169

RESUMO

The objective of this study was to investigate the electroencephalographic reaction pattern and FOS protein expression in male piglets undergoing surgical castration under light isoflurane anaesthesia with or without local anaesthesia. The experiment was conducted under isoflurane anaesthesia to exclude the effect of the affective components of pain on the measurements. Changes in the oscillatory activity of the cerebral cortex over a 90 s period after noxious stimulation or simulated interventions were analysed. FOS expression was determined postmortem by performing immunohistochemistry in the dorsal horn of the spinal cord. The analysis of the response to an interdigital pinch revealed a biphasic reaction pattern in the electroencephalogram (EEG) that similarly was observed for the surgical stimuli during the castration procedure in the group without analgesia. This EEG response was attenuated or altered by the application of local anaesthetics. Immunohistochemical staining for FOS indicated a lower expression in the handling and in three local anaesthetic groups than in the animals castrated without pain relief. The findings indicate that EEG and FOS expression may serve as indicators for nociception in piglets under light isoflurane anaesthesia. A lower activation of nociceptive pathways occurs during castration after the application of local anaesthetics. However, EEG and FOS analyses should be combined with additional parameters to assess nociception, e.g., haemodynamic monitoring.

16.
Am J Respir Cell Mol Biol ; 45(1): 163-71, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20870896

RESUMO

We showed that nitric oxide (NO) signaling is decreased in the pulmonary vasculature before the development of endothelial dysfunction in a lamb model of congenital heart disease and increased pulmonary blood flow (Shunt). The elucidation of the molecular mechanism by which this occurs was the purpose of this study. Here, we demonstrate that concentrations of the endogenous NO synthase (NOS) inhibitor, asymmetric dimethylarginine (ADMA), are elevated, whereas the NOS cofactor tetrahydrobiopterin (BH(4)) is decreased in Shunt lambs. Our previous studies demonstrated that ADMA decreases heat shock protein-90 (Hsp90) chaperone activity, whereas other studies suggest that guanosine-5'-triphosphate cyclohydrolase 1 (GCH1), the rate-limiting enzyme in the generation of BH(4), may be a client protein for Hsp90. Thus, we determined whether increases in ADMA could alter GCH1 protein and activity. Our data demonstrate that ADMA decreased GCH1 protein, but not mRNA concentrations, in pulmonary arterial endothelial cells (PAECs) because of the ubiquitination and proteasome-dependent degradation of GCH1. We also found that Hsp90-GCH1 interactions were reduced, whereas the association of GCH1 with Hsp70 and the C-terminus of Hsp70-interacting protein (CHIP) increased in ADMA-exposed PAECs. The overexpression of CHIP potentiated, whereas a CHIP U-box domain mutant attenuated, ADMA-induced GCH1 degradation and reductions in cellular BH(4) concentrations. We also found in vivo that Hsp90/GCH1 interactions are decreased, whereas GCH1-Hsp70 and GCH1-CHIP interactions and GCH1 ubiquitination are increased. Finally, we found that supplementation with l-arginine restored Hsp90-GCH1 interactions and increased both BH(4) and NO(x) concentrations in Shunt lambs. In conclusion, increased concentrations of ADMA can indirectly alter NO signaling through decreased cellular BH(4) concentrations, secondary to the disruption of Hsp90-GCH1 interactions and the CHIP-dependent proteasomal degradation of GCH1.


Assuntos
GTP Cicloidrolase/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Cardiopatias Congênitas/metabolismo , Pulmão/irrigação sanguínea , Pulmão/metabolismo , Animais , Antracenos/farmacologia , Arginina/análogos & derivados , Arginina/farmacologia , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Cardiopatias Congênitas/patologia , Cardiopatias Congênitas/fisiopatologia , Pulmão/patologia , Pulmão/fisiopatologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Propano/análogos & derivados , Propano/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Ovinos
17.
JCI Insight ; 6(15)2021 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-34185710

RESUMO

Abdominal aortic aneurysm (AAA) is a disease with high morbidity and mortality, especially when ruptured. The rationale of this study was to evaluate the repurposing of lenvatinib, a multi-tyrosine kinase inhibitor, in limiting experimental AAA growth targeting vascular smooth muscle cells (VSMCs) and angiogenesis. We applied systemic and local lenvatinib treatment to elastase-induced murine aortic aneurysms, and RNA profiling identified myosin heavy chain 11 (Myh11) as the most deregulated transcript. Daily oral treatment substantially reduced aneurysm formation in 2 independent mouse models. In addition, a large animal aneurysm model in hypercholesterolemic low-density lipoprotein receptor-knockout (LDLR-/-) Yucatan minipigs was applied to endovascularly deliver lenvatinib via drug-eluting balloons (DEBs). Here, a single local endovascular delivery blocked AAA progression successfully compared with a DEB-delivered control treatment. Reduced VSMC proliferation and a restored contractile phenotype were observed in animal tissues (murine and porcine), as well as AAA patient-derived cells. Apart from increasing MYH11 levels, lenvatinib reduced downstream ERK signaling. Hence, lenvatinib is a promising therapy to limit aortic aneurysm expansion upon local endovascular delivery. The tyrosine kinase inhibitor was able to positively affect pathways of key relevance to human AAA disease, even in a potentially new local delivery using DEBs.


Assuntos
Aneurisma da Aorta Abdominal , Sistemas de Liberação de Medicamentos/métodos , Procedimentos Endovasculares/métodos , Músculo Liso Vascular/efeitos dos fármacos , Cadeias Pesadas de Miosina/metabolismo , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Indutores da Angiogênese/metabolismo , Animais , Aneurisma da Aorta Abdominal/tratamento farmacológico , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Modelos Animais de Doenças , Reposicionamento de Medicamentos , Perfilação da Expressão Gênica , Camundongos , Camundongos Knockout
18.
Nat Commun ; 11(1): 4325, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32859917

RESUMO

Hospital systems play a critical role in treating injuries during disaster emergency responses. Simultaneously, natural disasters hinder their ability to operate at full capacity. Thus, cities must develop strategies that enable hospitals' effective disaster operations. Here, we present a methodology to evaluate emergency response based on a model that assesses the loss of hospital functions and quantifies multiseverity injuries as a result of earthquake damage. The proposed methodology can design effective plans for patient transfers and allocation of ambulances and mobile operating rooms. This methodology is applied to Lima, Peru, subjected to a disaster scenario following a magnitude 8.0 earthquake. Our results show that the spatial distribution of healthcare demands mismatches the post-earthquake capacities of hospitals, leaving large zones on the periphery significantly underserved. This study demonstrates how plans that leverage hospital-system coordination can address this demand-capacity mismatch, reducing waiting times of critically injured patients by factors larger than two.


Assuntos
Planejamento em Desastres/métodos , Terremotos , Emergências , Hospitais , Planejamento em Desastres/organização & administração , Desastres , Serviços Médicos de Emergência , Instalações de Saúde , Serviços de Saúde , Necessidades e Demandas de Serviços de Saúde , Humanos , Modelos Teóricos , Peru , Administração em Saúde Pública
19.
PLoS One ; 15(7): e0236742, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32730302

RESUMO

Surgical castration of male piglets without analgesia is a painful procedure. This prospective, randomized and double-blinded study aimed to evaluate the analgesic effects of four different local anesthetics for piglet castration during the first week of life. In total, 54 piglets aged 3 to 7 days were distributed into 6 treatment groups: handling (H); castration without pain relief (sodium chloride, NaCl); and castration with a local anesthetic: 4% procaine (P), 2% lidocaine (L), 0.5% bupivacaine (B) or 20 mg/ml mepivacaine (M). By excluding stress and fear as disruptive factors via a minimum anesthesia model, all piglets received individual minimum alveolar concentration (MAC) isoflurane anesthesia. Twenty minutes before castration, all treatment groups except group H received one injection per testis. Then, 0.5 ml of a local anesthetic or NaCl was injected intratesticularly (i.t.), and 0.5 ml was administered subscrotally. Acute physiological responses to noxious stimuli at injection and castration were evaluated by measuring blood pressure (BP), heart rate (HR), cortisol, epinephrine, norepinephrine and chromogranin A (CgA); limb movements were quantified. The results confirm that castration without analgesia is highly painful. Surgical castration without pain relief revealed significant changes in mean arterial blood pressure (MAP) and HR. Local anesthetic administration significantly reduced changes in BP and HR associated with castration. Piglets receiving a preoperative local anesthetic exhibited the fewest limb movements during castration, while the NaCl group exhibited the most. Injection itself was not associated with significant changes in MAP or HR. However, many piglets exhibited limb movements during injection, indicating that the injection itself causes nociceptive pain. No significant differences were found between groups regarding parameters of plasma cortisol, catecholamines and CgA. In conclusion, all four local anesthetics administered are highly effective at reducing signs of nociception during castration under light isoflurane anesthesia. However, injection of a local anesthetic seems to be painful.


Assuntos
Anestesia Geral/veterinária , Anestésicos Locais/administração & dosagem , Pressão Sanguínea , Castração/veterinária , Extremidades/fisiologia , Movimento , Animais , Animais Recém-Nascidos , Castração/métodos , Catecolaminas/sangue , Frequência Cardíaca , Hidrocortisona/sangue , Masculino , Suínos
20.
Animals (Basel) ; 10(10)2020 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-32993118

RESUMO

The aim of the present study was to investigate the effect of four local anesthetics on pain relief during surgical castration under standardized conditions in conscious piglets. Therefore, 71 male piglets (three to seven days) were distributed into control groups (handling, castration without anesthesia or analgesia) and local anesthetic trial groups (procaine, lidocaine, bupivacaine, mepivacaine). Then, 20 min prior to castration, animals of the treatment groups, except piglets in the handling group, received an injection of a local anesthetic or sodium chloride of 0.5 mL intratesticularly and 0.5 mL subscrotally. During injection and castration, defensive behavior was evaluated. Locomotor activity, as well as postoperative bleeding, wound healing and average daily weight gain were assessed to detect side effects. The injection caused increased defensive movements, significantly in the bupivacaine group. Lidocaine and mepivacaine significantly reduced defensive movements during castration, and procaine and bupivacaine only during severing of the spermatic cord. Impairments of locomotor activity were found in piglets injected with lidocaine, bupivacaine or sodium chloride. Considering healing, bleeding and weight gain, no negative impacts were observed. In conclusion, lidocaine and mepivacaine were able to achieve significant pain relief during the castration procedure, whereas procaine and bupivacaine only during the severing of the spermatic cord. Moreover, the injection of bupivacaine seemed to be painful itself.

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