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OBJECTIVE: Postoperative nausea and vomiting (PONV) occurs in up to 30% of patients and its pathophysiology and mechanisms have not been completely described. Hypotension and a decrease in cardiac output are suspected to induce nausea. The hypothesis that intraoperative hypotension might influence the incidence of PONV was investigated. MATERIAL AND METHODS: The study was conducted as a retrospective large single center cohort study. The incidence of PONV was investigated until discharge from post anesthesia care unit (PACU). Surgical patients with general anesthesia during a 2-year period between 2018 and 2019 at a university hospital in Germany were included. Groups were defined based on the lowest documented mean arterial pressure (MAP) with group H50: MAP <50mmHg; group H60: MAP <60mmHg; group H70: MAP <70mmHg, and group H0: no MAP <70mmHg. Decreases of MAP in the different groups were related to PONV. Propensity-score matching was carried out to control for overlapping risk factors. RESULTS: In the 2-year period 18.674 patients fit the inclusion criteria. The overall incidence of PONV was 11%. Patients with hypotension had a significantly increased incidence of PONV (H0 vs. H50: 11.0% vs.17.4%, Risk Ratio (RR): 1.285 (99%CI: 1.102-1.498), p < 0.001; H0 vs. H60: 10.4% vs. 13.5%, RR: 1.1852 (99%CI: 1.0665-1.3172), p < 0.001; H0 vs. H70: 9.4% vs. 11.2%, RR: 1.1236 (99%CI: 1.013 - 1.2454); p = 0.0027). CONCLUSION: The study demonstrates an association between intraoperative hypotension and early PONV. A more severe decrease of MAP had a pronounced effect.
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Hipotensión , Náusea y Vómito Posoperatorios , Humanos , Hipotensión/epidemiología , Hipotensión/etiología , Náusea y Vómito Posoperatorios/epidemiología , Femenino , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Adulto , Complicaciones Intraoperatorias/epidemiología , Complicaciones Intraoperatorias/etiología , Incidencia , Factores de Riesgo , Alemania/epidemiología , Anestesia General/efectos adversosRESUMEN
Edaravone is a mitochondrially targeted drug with a suggested capability to modify the course of diverse neurological diseases. Nevertheless, edaravone has not been tested yet in the context of spinocerebellar ataxia 1 (SCA1), an incurable neurodegenerative disease characterized mainly by cerebellar disorder, with a strong contribution of inflammation and mitochondrial dysfunction. This study aimed to address this gap, exploring the potential of edaravone to slow down SCA1 progression in a mouse knock-in SCA1 model. SCA1154Q/2Q and healthy SCA12Q/2Q mice were administered either edaravone or saline daily for more than 13 weeks. The functional impairments were assessed via a wide spectrum of behavioral assays reflecting motor and cognitive deficits and behavioral abnormalities. Moreover, we used high-resolution respirometry to explore mitochondrial function, and immunohistochemical and biochemical tools to assess the magnitude of neurodegeneration, inflammation, and neuroplasticity. Data were analyzed using (hierarchical) Bayesian regression models, combined with the methods of multivariate statistics. Our analysis pointed out various previously documented neurological and behavioral deficits of SCA1 mice. However, we did not detect any plausible therapeutic effect of edaravone on either behavioral dysfunctions or other disease hallmarks in SCA1 mice. Thus, our results did not provide support for the therapeutic potential of edaravone in SCA1.
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Disfunción Cognitiva , Ataxias Espinocerebelosas , Ratones , Animales , Edaravona/farmacología , Edaravona/uso terapéutico , Teorema de Bayes , Ataxias Espinocerebelosas/tratamiento farmacológico , Ataxias Espinocerebelosas/metabolismo , Mitocondrias , Disfunción Cognitiva/metabolismo , Cerebelo/metabolismo , Modelos Animales de Enfermedad , Ratones Transgénicos , Células de PurkinjeRESUMEN
The contribution of environmental pollutants to the obesity pandemic is still not yet fully recognized. Elucidating possible cellular and molecular mechanisms of their effects is of high importance. Our study aimed to evaluate the effect of chronic, 21-day-long, 2,2-bis (4-chlorophenyl)-1,1-dichlorethylenedichlorodiphenyldichloroethylene (p,p'-DDE) exposure of human adipose-derived mesenchymal stem cells committed to adipogenesis on mitochondrial oxygen consumption on days 4, 10, and 21. In addition, the mitochondrial membrane potential (MMP), the quality of the mitochondrial network, and lipid accumulation in maturing cells were evaluated. Compared to control differentiating adipocytes, exposure to p,p'-DDE at 1 µM concentration significantly increased basal (routine) mitochondrial respiration, ATP-linked oxygen consumption and MMP of intact cells on day 21 of adipogenesis. In contrast, higher pollutant concentration seemed to slow down the gradual increase in ATP-linked oxygen consumption typical for normal adipogenesis. Organochlorine p,p'-DDE did not alter citrate synthase activity. In conclusion, in vitro 1 µM p,p'-DDE corresponding to human exposure is able to increase the mitochondrial respiration per individual mitochondrion at the end of adipocyte maturation. Our data reveal that long-lasting exposure to p,p'-DDE could interfere with the metabolic programming of mature adipocytes.
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Adipocitos/efectos de los fármacos , Adipogénesis/efectos de los fármacos , Diclorodifenil Dicloroetileno/toxicidad , Contaminantes Ambientales/toxicidad , Células Madre Mesenquimatosas/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Adipocitos/citología , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Femenino , Humanos , Potencial de la Membrana Mitocondrial , Células Madre Mesenquimatosas/citología , Obesidad/metabolismoRESUMEN
Sarcomas are a heterogeneous group of mesenchymal tumours, with a great variability in their clinical behaviour. While our knowledge of sarcoma initiation has advanced rapidly in recent years, relatively little is known about mechanisms of sarcoma progression. JUN-murine fibrosarcoma progression series consists of four sarcoma cell lines, JUN-1, JUN-2, JUN-2fos-3, and JUN-3. JUN-1 and -2 were established from a single tumour initiated in a H2K/v-jun transgenic mouse, JUN-3 originates from a different tumour in the same animal, and JUN-2fos-3 results from a targeted in vitro transformation of the JUN-2 cell line. The JUN-1, -2, and -3 cell lines represent a linear progression from the least transformed JUN-2 to the most transformed JUN-3, with regard to all the transformation characteristics studied, while the JUN-2fos-3 cell line exhibits a unique transformation mode, with little deregulation of cell growth and proliferation, but pronounced motility and invasiveness. The invasive sarcoma sublines JUN-2fos-3 and JUN-3 show complex metabolic profiles, with activation of both mitochondrial oxidative phosphorylation and glycolysis and a significant increase in spared respiratory capacity. The specific transcriptomic profile of invasive sublines features very complex biological relationships across the identified genes and proteins, with accentuated autocrine control of motility and angiogenesis. Pharmacologic inhibition of one of the autocrine motility factors identified, Ccl8, significantly diminished both motility and invasiveness of the highly transformed fibrosarcoma cell. This progression series could be greatly valuable for deciphering crucial aspects of sarcoma progression and defining new prognostic markers and potential therapeutic targets.
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A rational infusion therapy orchestrates fluid- and volume therapy based on the individual indication and situation. The principle of fluid replacement is to substitute ongoing fluid losses such as insensible perspiration and urine output or to treat dehydration with balanced crystalloid solutions. Volume therapy in contrast is the quick restoration of intravascular losses such as an acute blood loss through application of balanced colloids or crystalloids. The goal of volume therapy is to maintain normal cardiac output and oxygen delivery by restoring intravascular normovolemia and cardiac preload. Whether colloid or crystalloid infusions are most suitable for volume therapy remains unclear. Most trials in this field are either underpowered or used colloids in inadequate situations, patients and amounts. Two major trials from the European Society of Anaesthesiology and Intensive Care (ESAIC) are underway that seem promising to provide evidence in this emotional debate.
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Fluidoterapia , Sustitutos del Plasma , Enfermedad Crítica , Soluciones Cristaloides , Humanos , Soluciones Isotónicas , Sustitutos del Plasma/uso terapéuticoRESUMEN
Porcine model of peritonitis-induced sepsis is a well-established clinically relevant model of human disease. Interindividual variability of the response often complicates the interpretation of findings. To better understand the biological basis of the disease variability, the progression of the disease was compared between animals with sepsis and septic shock. Peritonitis was induced by inoculation of autologous feces in fifteen anesthetized, mechanically ventilated and surgically instrumented pigs and continued for 24 h. Cardiovascular and biochemical parameters were collected at baseline (just before peritonitis induction), 12 h, 18 h and 24 h (end of the experiment) after induction of peritonitis. Analysis of multiple parameters revealed the earliest significant differences between sepsis and septic shock groups in the sequential organ failure assessment (SOFA) score, systemic vascular resistance, partial pressure of oxygen in mixed venous blood and body temperature. Other significant functional differences developed later in the course of the disease. The data indicate that SOFA score, hemodynamical parameters and body temperature discriminate early between sepsis and septic shock in a clinically relevant porcine model. Early pronounced alterations of these parameters may herald a progression of the disease toward irreversible septic shock.
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Inhalational anesthetics have been used for induction and maintenance of general anesthesia for more than 150 years. All of the currently used inhalational anesthetics are chlorinated and fluorinated derivatives of ether. Dosing is carried out using the minimal alveolar concentration (MAC) concept. The pharmacokinetic properties of the various inhalational anesthetics are governed by the specific distribution coefficients. Mechanisms of action include specific modulations of various receptors of the central nervous system as well as an unspecific interaction with the cell membrane. Organ toxicity of modern inhalational anesthetics is considered to be minimal. The role of inhalational anesthetics in the context of postoperative nausea and vomiting (PONV) has been reassessed in recent years. The superiority of inhalational anesthetics over intravenous hypnotics with respect to intraoperative awareness is undisputed. The organ protective mechanism of preconditioning is an exclusive property of inhalational anesthetics among all the currently available hypnotics.
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Anestésicos por Inhalación , Anestésicos , Éteres Metílicos , Anestesia General , Humanos , Náusea y Vómito PosoperatoriosRESUMEN
Spinocerebellar ataxia 1 (SCA1) is a devastating neurodegenerative disease associated with cerebellar degeneration and motor deficits. However, many patients also exhibit neuropsychiatric impairments such as depression and apathy; nevertheless, the existence of a causal link between the psychiatric symptoms and SCA1 neuropathology remains controversial. This study aimed to explore behavioral deficits in a knock-in mouse SCA1 (SCA1154Q/2Q) model and to identify the underlying neuropathology. We found that the SCA1 mice exhibit previously undescribed behavioral impairments such as increased anxiety- and depressive-like behavior and reduced prepulse inhibition and cognitive flexibility. Surprisingly, non-motor deficits characterize the early SCA1 stage in mice better than does ataxia. Moreover, the SCA1 mice exhibit significant hippocampal atrophy with decreased plasticity-related markers and markedly impaired neurogenesis. Interestingly, the hippocampal atrophy commences earlier than the cerebellar degeneration and directly reflects the individual severity of some of the behavioral deficits. Finally, mitochondrial respirometry suggests profound mitochondrial dysfunction in the hippocampus, but not in the cerebellum of the young SCA1 mice. These findings imply the essential role of hippocampal impairments, associated with profound mitochondrial dysfunction, in SCA1 behavioral deficits. Moreover, they underline the view of SCA1 as a complex neurodegenerative disease and suggest new avenues in the search for novel SCA1 therapies.
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Cerebelo/patología , Hipocampo/patología , Trastornos Mentales/patología , Mitocondrias/patología , Ataxias Espinocerebelosas/patología , Animales , Atrofia/metabolismo , Atrofia/patología , Biomarcadores/metabolismo , Cerebelo/metabolismo , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Masculino , Trastornos Mentales/metabolismo , Ratones , Mitocondrias/metabolismo , Ataxias Espinocerebelosas/metabolismoRESUMEN
The endothelial glycocalyx (EG) is the most luminal layer of the blood vessel, growing on and within the vascular wall. Shedding of the EG plays a central role in many critical illnesses. Degradation of the EG is associated with increased morbidity and mortality. Certain illnesses and iatrogenic interventions can cause degradation of the EG. It is not known whether restitution of the EG promotes the survival of the patient. First trials that focus on the reorganization and/or restitution of the EG seem promising. Nevertheless, the step "from bench to bedside" is still a big one.
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Enfermedad Crítica , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Glicocálix/metabolismo , Glicocálix/fisiología , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/fisiopatología , Permeabilidad Capilar/fisiología , Humanos , Hiperglucemia/metabolismo , Hiperglucemia/fisiopatología , Hipernatremia/metabolismo , Hipernatremia/fisiopatología , Microcirculación/fisiología , Daño por Reperfusión/metabolismo , Daño por Reperfusión/fisiopatología , Síndrome de Dificultad Respiratoria/metabolismo , Síndrome de Dificultad Respiratoria/fisiopatología , Sepsis/metabolismo , Sepsis/fisiopatología , Heridas y Lesiones/metabolismo , Heridas y Lesiones/fisiopatologíaRESUMEN
Chemokines are structurally related proteins which form a large family of chemotactic cytokines. They provide a general communication system for cells and regulate lymphocyte migration. These proteins orchestrate the formation of microenvironments in lymphoid tissue, promote lymphoid organogenesis and help foster vascular and lymphatic angiogenesis. In addition to the classical G protein-coupled chemokine receptors, many chemokines also bind to a family of nonsignaling proteins, now called interceptors (chemokine-internalizing proteins). Here we summarize recent data on the role of interceptors in chemokine biology with a focus on renal inflammation.
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Nefritis , Receptores de Quimiocina , Animales , Humanos , Quimiocinas/metabolismo , Sistema del Grupo Sanguíneo Duffy/fisiología , Riñón/metabolismo , Nefritis/fisiopatología , Receptores CCR10/fisiología , Receptores de Superficie Celular/fisiología , Receptores de Quimiocina/fisiología , Receptores CXCR/metabolismo , Receptor de Quimiocina D6RESUMEN
The Alport syndrome is a hereditary glomerular disease linked to structural abnormalities of collagen IV. In a mouse model of Alport syndrome, the interstitial lymphocyte influx was important for disease progression. CXCR3 is a chemokine receptor involved in lymphocyte recruitment to the kidney. We hypothesized that CXCR3-positive T cells might be involved in human Alport syndrome. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded biopsies from 17 patients with Alport syndrome, 10 with immunoglobulin A (IgA) nephropathy, and 11 healthy donor kidneys. We investigated the expression of the alpha5 chain of collagen IV to confirm the morphologic diagnosis, the chemokine receptor CXCR3 and CD3-positive T cells. Alport syndrome biopsies demonstrated a complete loss of the alpha5 chain of collagen IV from the glomerular basement membrane and the morphologic features consistent with Alport syndrome on electron microscopy. A prominent number of CXCR3-positive cells were found in the tubulointerstitium. Most of the CXCR3-positive cells were CD3-positive T cells, demonstrated by double-labeling in selected biopsies. The number of CXCR3-positive cells in kidneys with Alport syndrome correlated with serum creatinine (P < .05) and with morphologic features of a progressive disease (eg, interstitial fibrosis, glomerulosclerosis, and tubular atrophy). The severity of interstitial CXCR3-positive cell influx was similar in Alport syndrome as compared to immunoglobulin A nephropathy. The noninflammatory glomerular lesion of Alport syndrome is associated with prominent interstitial accumulation of CD3- and CXCR3-positive lymphocytes. The degree of infiltration correlated with renal function. We speculate that targeting T lymphocytes, for example, by CXCR3 blocking agents, might be a novel approach to inhibit disease progression in patients with Alport syndrome.