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1.
Front Physiol ; 13: 1041730, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36523553

RESUMEN

Background: A decade ago, it became possible to derive mean systemic filling pressure (MSFP) at the bedside using the inspiratory hold maneuver. MSFP has the potential to help guide hemodynamic care, but the estimation is not yet implemented in common clinical practice. In this study, we assessed the ability of MSFP, vascular compliance (Csys), and stressed volume (Vs) to track fluid boluses. Second, we assessed the feasibility of implementation of MSFP in the intensive care unit (ICU). Exploratory, a potential difference in MSFP response between colloids and crystalloids was assessed. Methods: This was a prospective cohort study in adult patients admitted to the ICU after cardiac surgery. The MSFP was determined using 3-4 inspiratory holds with incremental pressures (maximum 35 cm H2O) to construct a venous return curve. Two fluid boluses were administered: 100 and 500 ml, enabling to calculate Vs and Csys. Patients were randomized to crystalloid or colloid fluid administration. Trained ICU consultants acted as study supervisors, and protocol deviations were recorded. Results: A total of 20 patients completed the trial. MSFP was able to track the 500 ml bolus (p < 0.001). In 16 patients (80%), Vs and Csys could be determined. Vs had a median of 2029 ml (IQR 1605-3164), and Csys had a median of 73 ml mmHg-1 (IQR 56-133). A difference in response between crystalloids and colloids was present for the 100 ml fluid bolus (p = 0.019) and in a post hoc analysis, also for the 500 ml bolus (p = 0.010). Conclusion: MSFP can be measured at the bedside and provides insights into the hemodynamic status of a patient that are currently missing. The clinical feasibility of Vs and Csys was judged ambiguously based on the lack of required hemodynamic stability. Future studies should address the clinical obstacles found in this study, and less-invasive alternatives to determine MSFP should be further explored. Clinical Trial Registration: ClinicalTrials.gov Identifier NCT03139929.

2.
JMIR Form Res ; 6(5): e27389, 2022 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-35522477

RESUMEN

BACKGROUND: To maintain the benefits of a bariatric procedure, patients have to change their lifestyle permanently. This happens within a context of coresponsibilities of health care professionals and their social support system. However, most interventions are focused on the patient as an individual. In this explorative pilot study, behavioral, contextual, and experiential data were gathered to obtain insight on coresponsibility. OBJECTIVE: The aim of this study is to explore the use of trackers by patients who have undergone bariatric surgery in a data-enabled design approach. METHODS: Behavioral and contextual data on the households of patients who have undergone bariatric surgery were explored using a smartphone with an interactive user interface (UI), weight scale, activity bracelet, smart socket, accelerometer motion sensor, and event button to find examples of opportunities for future interventions. RESULTS: A total of 6 households were monitored. Approximately 483,000 data points were collected, and the participants engaged in 1483 conversations with the system. Examples were found using different combinations of data types, which provided the obesity team a better understanding of patient behaviors and their support system, such as a referral to a family coach instead of a dietician. Another finding regarding the partners was, for example, that the conversational UI system facilitated discussion about the support structure by asking for awareness. CONCLUSIONS: An intelligent system using a combination of quantitative data gathered by data tracking products in the home environment and qualitative data gathered by app-enhanced short conversations, as well as face-to-face interviews, is useful for an improved understanding of coresponsibilities in the households of patients who have undergone bariatric surgery. The examples found in this explorative study so far encourage research in this field.

3.
Cell Mol Gastroenterol Hepatol ; 13(2): 583-597, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34626841

RESUMEN

BACKGROUND & AIMS: Recently, novel inborn errors of metabolism were identified because of mutations in V-ATPase assembly factors TMEM199 and CCDC115. Patients are characterized by generalized protein glycosylation defects, hypercholesterolemia, and fatty liver disease. Here, we set out to characterize the lipid and fatty liver phenotype in human plasma, cell models, and a mouse model. METHODS AND RESULTS: Patients with TMEM199 and CCDC115 mutations displayed hyperlipidemia, characterized by increased levels of lipoproteins in the very low density lipoprotein range. HepG2 hepatoma cells, in which the expression of TMEM199 and CCDC115 was silenced, and induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells from patients with TMEM199 mutations showed markedly increased secretion of apolipoprotein B (apoB) compared with controls. A mouse model for TMEM199 deficiency with a CRISPR/Cas9-mediated knock-in of the human A7E mutation had marked hepatic steatosis on chow diet. Plasma N-glycans were hypogalactosylated, consistent with the patient phenotype, but no clear plasma lipid abnormalities were observed in the mouse model. In the siTMEM199 and siCCDC115 HepG2 hepatocyte models, increased numbers and size of lipid droplets were observed, including abnormally large lipid droplets, which colocalized with lysosomes. Excessive de novo lipogenesis, failing oxidative capacity, and elevated lipid uptake were not observed. Further investigation of lysosomal function revealed impaired acidification combined with impaired autophagic capacity. CONCLUSIONS: Our data suggest that the hypercholesterolemia in TMEM199 and CCDC115 deficiency is due to increased secretion of apoB-containing particles. This may in turn be secondary to the hepatic steatosis observed in these patients as well as in the mouse model. Mechanistically, we observed impaired lysosomal function characterized by reduced acidification, autophagy, and increased lysosomal lipid accumulation. These findings could explain the hepatic steatosis seen in patients and highlight the importance of lipophagy in fatty liver disease. Because this pathway remains understudied and its regulation is largely untargeted, further exploration of this pathway may offer novel strategies for therapeutic interventions to reduce lipotoxicity in fatty liver disease.


Asunto(s)
Hígado Graso , Gotas Lipídicas , Animales , Hígado Graso/genética , Hígado Graso/metabolismo , Hepatocitos/metabolismo , Humanos , Gotas Lipídicas/metabolismo , Lisosomas/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Mutación/genética , Proteínas del Tejido Nervioso/genética
4.
J Appl Physiol (1985) ; 129(2): 311-316, 2020 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-32614685

RESUMEN

Potentially, mean circulatory filling pressure (Pmcf) could aid hemodynamic management in patients admitted to the intensive care unit (ICU). However, data regarding the normal range for Pmcf do not exist challenging its clinical use. We aimed to define the range for Pmcf for ICU patients and also calculated in what percentage of cases equilibrium between arterial blood pressure (ABP) and central venous pressure (CVP) was reached. In patients in whom no equilibrium was reached, we corrected for arterial-to-venous compliance differences. Finally, we studied the influence of patient characteristics on Pmcf. We hypothesized fluid balance, the use of vasoactive medication, being on mechanical ventilation, and the level of positive end-expiratory pressure would be positively associated with Pmcf. We retrospectively studied a cohort of 311 patients that had cardiac arrest in ICU while having active recording of ABP and CVP 1 min after death. Median Pmcf was 15 mmHg [interquartile range (IQR) 12-18]. ABP and CVP reached an equilibrium state in 52% of the cases. Correction for arterial-to-venous compliances differences resulted in a maximum alteration of 1.3 mmHg in Pmcf. Fluid balance over the last 24 h, the use of vasoactive medication, and being on mechanical ventilation were associated with a higher Pmcf. Median Pmcf was 15 mmHg (IQR 12-18). When ABP remained higher than CVP, correction for arterial-to-venous compliance differences did not result in a clinically relevant alteration of Pmcf. Pmcf was affected by factors known to alter vasomotor tone and effective circulating blood volume.NEW & NOTEWORTHY In a cohort of 311 intensive care unit (ICU) patients, median mean circulatory filling pressure (Pmcf) measured after cardiac arrest was 15 mmHg (interquartile range 12-18). In 48% of cases, arterial blood pressure remained higher than central venous pressure, but correction for arterial-to-venous compliance differences did not result in clinically relevant alterations of Pmcf. Fluid balance, use of vasopressors or inotropes, and being on mechanical ventilation were associated with a higher Pmcf.


Asunto(s)
Volumen Sanguíneo , Hemodinámica , Presión Venosa Central , Humanos , Unidades de Cuidados Intensivos , Estudios Retrospectivos
5.
J Inherit Metab Dis ; 43(6): 1310-1320, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32557671

RESUMEN

Congenital disorders of glycosylation (CDG) are a rapidly expanding group of rare genetic defects in glycosylation. In a novel CDG subgroup of vacuolar-ATPase (V-ATPase) assembly defects, various degrees of hepatic injury have been described, including end-stage liver disease. However, the CDG diagnostic workflow can be complex as liver disease per se may be associated with abnormal glycosylation. Therefore, we collected serum samples of patients with a wide range of liver pathology to study the performance and yield of two CDG screening methods. Our aim was to identify glycosylation patterns that could help to differentiate between primary and secondary glycosylation defects in liver disease. To this end, we analyzed serum samples of 1042 adult liver disease patients. This cohort consisted of 567 liver transplant candidates and 475 chronic liver disease patients. Our workflow consisted of screening for abnormal glycosylation by transferrin isoelectric focusing (tIEF), followed by in-depth analysis of the abnormal samples with quadruple time-of-flight mass spectrometry (QTOF-MS). Screening with tIEF resulted in identification of 247 (26%) abnormal samples. QTOF-MS analysis of 110 of those did not reveal glycosylation abnormalities comparable with those seen in V-ATPase assembly factor defects. However, two patients presented with isolated sialylation deficiency. Fucosylation was significantly increased in liver transplant candidates compared to healthy controls and patients with chronic liver disease. In conclusion, a significant percentage of patients with liver disease presented with abnormal CDG screening results. However, the glycosylation pattern was not indicative for a V-ATPase assembly factor defect. Advanced glycoanalytical techniques assist in the dissection of secondary and primary glycosylation defects.


Asunto(s)
Trastornos Congénitos de Glicosilación/metabolismo , Enfermedad Hepática en Estado Terminal/metabolismo , Espectrometría de Masas/métodos , Transferrina/análisis , Adulto , Anciano , Estudios de Casos y Controles , Estudios de Cohortes , Trastornos Congénitos de Glicosilación/diagnóstico , Femenino , Glicosilación , Humanos , Hígado/metabolismo , Masculino , Persona de Mediana Edad , Transferrina/metabolismo
6.
Hepatology ; 72(6): 1968-1986, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32145091

RESUMEN

BACKGROUND AND AIMS: Vacuolar H+-ATP complex (V-ATPase) is a multisubunit protein complex required for acidification of intracellular compartments. At least five different factors are known to be essential for its assembly in the endoplasmic reticulum (ER). Genetic defects in four of these V-ATPase assembly factors show overlapping clinical features, including steatotic liver disease and mild hypercholesterolemia. An exception is the assembly factor vacuolar ATPase assembly integral membrane protein (VMA21), whose X-linked mutations lead to autophagic myopathy. APPROACH AND RESULTS: Here, we report pathogenic variants in VMA21 in male patients with abnormal protein glycosylation that result in mild cholestasis, chronic elevation of aminotransferases, elevation of (low-density lipoprotein) cholesterol and steatosis in hepatocytes. We also show that the VMA21 variants lead to V-ATPase misassembly and dysfunction. As a consequence, lysosomal acidification and degradation of phagocytosed materials are impaired, causing lipid droplet (LD) accumulation in autolysosomes. Moreover, VMA21 deficiency triggers ER stress and sequestration of unesterified cholesterol in lysosomes, thereby activating the sterol response element-binding protein-mediated cholesterol synthesis pathways. CONCLUSIONS: Together, our data suggest that impaired lipophagy, ER stress, and increased cholesterol synthesis lead to LD accumulation and hepatic steatosis. V-ATPase assembly defects are thus a form of hereditary liver disease with implications for the pathogenesis of nonalcoholic fatty liver disease.


Asunto(s)
Autofagia/genética , Trastornos Congénitos de Glicosilación/genética , Hepatopatías/genética , ATPasas de Translocación de Protón Vacuolares/genética , Adulto , Biopsia , Células Cultivadas , Trastornos Congénitos de Glicosilación/sangre , Trastornos Congénitos de Glicosilación/diagnóstico , Trastornos Congénitos de Glicosilación/patología , Análisis Mutacional de ADN , Fibroblastos , Humanos , Hígado/citología , Hígado/patología , Hepatopatías/sangre , Hepatopatías/diagnóstico , Hepatopatías/patología , Masculino , Mutación Missense , Linaje , Cultivo Primario de Células
7.
J Clin Monit Comput ; 34(2): 233-243, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31089844

RESUMEN

Evaluation of a new Windkessel model based pulse contour method (WKflow) to calculate stroke volume in patients undergoing intra-aortic balloon pumping (IABP). Preload changes were induced by vena cava occlusions (VCO) in twelve patients undergoing cardiac surgery to vary stroke volume (SV), which was measured by left ventricular conductance volume method (SVlv) and WKflow (SVwf). Twelve VCO series were carried out during IABP assist at a 1:2 ratio and seven VCO series were performed with IABP switched off. Additionally, SVwf was evaluated during nine episodes of severe arrhythmia. VCO's produced marked changes in SV over 10-20 beats. 198 paired data sets of SVlv and SVwf were obtained. Bland-Altman analysis for the difference between SVlv and SVwf during IABP in 1:2 mode showed a bias (accuracy) of 1.04 ± 3.99 ml, precision 10.9% and limits of agreement (LOA) of - 6.94 to 9.02 ml. Without IABP bias was 0.48 ± 4.36 ml, precision 11.6% and LOA of - 8.24 to 9.20 ml. After one thermodilution calibration of SVwf per patient, during IABP the accuracy improved to 0.14 ± 3.07 ml, precision to 8.3% and LOA to - 6.00 to + 6.28 ml. Without IABP the accuracy improved to 0.01 ± 2.71 ml, precision to 7.5% and LOA to - 5.41 to + 5.43 ml. Changes in SVlv and SVwf were directionally concordant in response to VCO's and during severe arrhythmia. (R2 = 0.868). The SVwf and SVlv methods are interchangeable with respect to measuring absolute stroke volume as well as tracking changes in stroke volume. The precision of the non-calibrated WKflow method is about 10% which improved to 7.5% after one calibration per patient.


Asunto(s)
Presión Arterial , Gasto Cardíaco , Monitorización Hemodinámica/métodos , Contrapulsador Intraaórtico , Anciano , Arritmias Cardíacas/fisiopatología , Simulación por Computador , Femenino , Monitorización Hemodinámica/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Modelos Cardiovasculares , Análisis de Regresión , Volumen Sistólico , Venas Cavas/fisiopatología
8.
Ann Intensive Care ; 8(1): 73, 2018 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-29926230

RESUMEN

The bedside hemodynamic assessment of the critically ill remains challenging since blood volume, arterial-venous interaction and compliance are not measured directly. Mean circulatory filling pressure (Pmcf) is the blood pressure throughout the vascular system at zero flow. Animal studies have shown Pmcf provides information on vascular compliance, volume responsiveness and enables the calculation of stressed volume. It is now possible to measure Pmcf at the bedside. We performed a systematic review of the current Pmcf measurement techniques and compared their clinical applicability, precision, accuracy and limitations. A comprehensive search strategy was performed in PubMed, Embase and the Cochrane databases. Studies measuring Pmcf in heart-beating patients at the bedside were included. Data were extracted from the articles into predefined forms. Quality assessment was based on the Newcastle-Ottawa Scale for cohort studies. A total of 17 prospective cohort studies were included. Three techniques were described: Pmcf hold, based on inspiratory hold-derived venous return curves, Pmcf arm, based on arterial and venous pressure equilibration in the arm as a model for the entire circulation, and Pmcf analogue, based on a Guytonian mathematical model of the circulation. The included studies show Pmcf to accurately follow intravascular fluid administration and vascular compliance following drug-induced hemodynamic changes. Bedside Pmcf measures allow for more direct assessment of circulating blood volume, venous return and compliance. However, studies are needed to determine normative Pmcf values and their expected changes to therapies if they are to be used to guide clinical practice.

10.
J Clin Anesth ; 46: 17-22, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29367093

RESUMEN

STUDY OBJECTIVE: The mini-fluid challenge may predict fluid responsiveness with minimum risk of fluid overloading. However, the amount of fluid as well as the best manner to evaluate the effect is unclear. In this prospective observational pilot study, the value of changes in pulse contour cardiac output (CO) measurements during mini-fluid challenges is investigated. DESIGN: Prospective observational study. SETTING: Intensive Care Unit of a university hospital. PATIENTS: Twenty-one patients directly after elective cardiac surgery on mechanical ventilation. INTERVENTIONS: The patients were subsequently given 10 intravenous boluses of 50mL of hydroxyethyl starch with a total of 500mL per patient while measuring pulse contour CO. MEASUREMENTS: We measured CO by minimal invasive ModelflowR (COm) and PulseCOR (COli), before and one minute after each fluid bolus. We analyzed the smallest volume that was predictive of fluid responsiveness. A positive fluid response was defined as an increase in CO of >10% after 500mL fluid infusion. MAIN RESULTS: Fifteen patients (71%) were COm responders and 13 patients (62%) COli responders. An increase in COm after 150mL of fluid >5.0% yielded a positive and negative predictive value (+PV and -PV) of 100% with an area under the curve (AUC) of 1.00 (P<0.001). An increase in COli >6.3% after 200mL was able to predict a fluid response in COli after 500mL with a +PV of 100% and -PV of 73%, with an AUC of 0.88 (P<0.001). CONCLUSION: The use of minimal invasive ModelflowR pulse contour CO measurements following a mini-fluid challenge of 150mL can predict fluid responsiveness and may help to improve fluid management.


Asunto(s)
Gasto Cardíaco , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Fluidoterapia/efectos adversos , Monitoreo Fisiológico/instrumentación , Sustitutos del Plasma/administración & dosificación , Anciano , Presión Sanguínea , Dióxido de Carbono/análisis , Dióxido de Carbono/sangre , Femenino , Fluidoterapia/métodos , Humanos , Derivados de Hidroxietil Almidón/administración & dosificación , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Monitoreo Fisiológico/métodos , Proyectos Piloto , Estudios Prospectivos , Curva ROC , Respiración Artificial/efectos adversos
11.
Ann Intensive Care ; 7(1): 20, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28233196

RESUMEN

BACKGROUND: Although oxygen is generally administered in a liberal manner in the perioperative setting, the effects of oxygen administration on dynamic cardiovascular parameters, filling status and cerebral perfusion have not been fully unraveled. Our aim was to study the acute hemodynamic and microcirculatory changes before, during and after arterial hyperoxia in mechanically ventilated patients after coronary artery bypass grafting (CABG) surgery. METHODS: This was a single-center physiological study in a tertiary care ICU in the Netherlands. Twenty-two patients scheduled for ICU admission after elective CABG were enrolled in the study between September 2014 and September 2015. In the ICU, patients were exposed to a fraction of inspired oxygen (FiO2) of 90% allowing a 15-min wash-in period. Various hemodynamic parameters were measured using direct pressure signals and continuous arterial waveform analysis at three sequential time points: before, during and after hyperoxia. RESULTS: During a 15-min exposure to a fraction of inspired oxygen (FiO2) of 90%, the partial pressure of arterial oxygen (PaO2) and arterial oxygen saturation (SaO2) were significantly higher. The systemic resistance increased (P < 0.0001), without altering the heart rate. Stroke volume variation and pulse pressure variation decreased slightly. The cardiac output did not significantly decrease (P = 0.08). Mean systemic filling pressure and arterial critical closing pressure increased (P < 0.01whereas the percentage of perfused microcirculatory vessels decreased (P < 0.01). Other microcirculatory parameters and cerebral blood flow velocity showed only slight changes. CONCLUSIONS: We found that short-term hyperoxia affects hemodynamics in ICU patients after CABG. This was translated in several changes in central circulatory variables, but had only slight effects on cardiac output, cerebral blood flow and the microcirculation. Clinical trial registration Netherlands Trial Register: NTR5064.

12.
Am J Hum Genet ; 98(2): 322-30, 2016 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-26833330

RESUMEN

Congenital disorders of glycosylation (CDGs) form a genetically and clinically heterogeneous group of diseases with aberrant protein glycosylation as a hallmark. A subgroup of CDGs can be attributed to disturbed Golgi homeostasis. However, identification of pathogenic variants is seriously complicated by the large number of proteins involved. As part of a strategy to identify human homologs of yeast proteins that are known to be involved in Golgi homeostasis, we identified uncharacterized transmembrane protein 199 (TMEM199, previously called C17orf32) as a human homolog of yeast V-ATPase assembly factor Vph2p (also known as Vma12p). Subsequently, we analyzed raw exome-sequencing data from families affected by genetically unsolved CDGs and identified four individuals with different mutations in TMEM199. The adolescent individuals presented with a mild phenotype of hepatic steatosis, elevated aminotransferases and alkaline phosphatase, and hypercholesterolemia, as well as low serum ceruloplasmin. Affected individuals showed abnormal N- and mucin-type O-glycosylation, and mass spectrometry indicated reduced incorporation of galactose and sialic acid, as seen in other Golgi homeostasis defects. Metabolic labeling of sialic acids in fibroblasts confirmed deficient Golgi glycosylation, which was restored by lentiviral transduction with wild-type TMEM199. V5-tagged TMEM199 localized with ERGIC and COPI markers in HeLa cells, and electron microscopy of a liver biopsy showed dilated organelles suggestive of the endoplasmic reticulum and Golgi apparatus. In conclusion, we have identified TMEM199 as a protein involved in Golgi homeostasis and show that TMEM199 deficiency results in a hepatic phenotype with abnormal glycosylation.


Asunto(s)
Fosfatasa Alcalina/metabolismo , Colesterol/metabolismo , Aparato de Golgi/genética , Homeostasis , Proteínas de la Membrana/deficiencia , Transaminasas/metabolismo , Adulto , Secuencia de Aminoácidos , Ceruloplasmina/metabolismo , Retículo Endoplásmico/metabolismo , Exoma , Fibroblastos/metabolismo , Genotipo , Glicosilación , Aparato de Golgi/metabolismo , Humanos , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Datos de Secuencia Molecular , Mutación , Fenotipo , Adulto Joven
13.
Am J Hum Genet ; 98(2): 310-21, 2016 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-26833332

RESUMEN

Disorders of Golgi homeostasis form an emerging group of genetic defects. The highly heterogeneous clinical spectrum is not explained by our current understanding of the underlying cell-biological processes in the Golgi. Therefore, uncovering genetic defects and annotating gene function are challenging. Exome sequencing in a family with three siblings affected by abnormal Golgi glycosylation revealed a homozygous missense mutation, c.92T>C (p.Leu31Ser), in coiled-coil domain containing 115 (CCDC115), the function of which is unknown. The same mutation was identified in three unrelated families, and in one family it was compound heterozygous in combination with a heterozygous deletion of CCDC115. An additional homozygous missense mutation, c.31G>T (p.Asp11Tyr), was found in a family with two affected siblings. All individuals displayed a storage-disease-like phenotype involving hepatosplenomegaly, which regressed with age, highly elevated bone-derived alkaline phosphatase, elevated aminotransferases, and elevated cholesterol, in combination with abnormal copper metabolism and neurological symptoms. Two individuals died of liver failure, and one individual was successfully treated by liver transplantation. Abnormal N- and mucin type O-glycosylation was found on serum proteins, and reduced metabolic labeling of sialic acids was found in fibroblasts, which was restored after complementation with wild-type CCDC115. PSI-BLAST homology detection revealed reciprocal homology with Vma22p, the yeast V-ATPase assembly factor located in the endoplasmic reticulum (ER). Human CCDC115 mainly localized to the ERGIC and to COPI vesicles, but not to the ER. These data, in combination with the phenotypic spectrum, which is distinct from that associated with defects in V-ATPase core subunits, suggest a more general role for CCDC115 in Golgi trafficking. Our study reveals CCDC115 deficiency as a disorder of Golgi homeostasis that can be readily identified via screening for abnormal glycosylation in plasma.


Asunto(s)
Aparato de Golgi/genética , Homeostasis , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/genética , Secuencia de Aminoácidos , Niño , Preescolar , Clonación Molecular , Retículo Endoplásmico/metabolismo , Exoma , Femenino , Fibroblastos/citología , Glicosilación , Aparato de Golgi/metabolismo , Células HeLa , Heterocigoto , Humanos , Lactante , Masculino , Datos de Secuencia Molecular , Linaje , Fenotipo , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción
14.
Ned Tijdschr Geneeskd ; 157(35): A6374, 2013.
Artículo en Holandés | MEDLINE | ID: mdl-23985243

RESUMEN

BACKGROUND: Boerhaave's syndrome is a spontaneous oesophageal rupture caused by excessive vomiting. Left untreated the mortality rate is high. Surgical intervention was always the treatment of first choice, but increasingly a minimally invasive approach involving the endoscopic placement of an oesophageal stent is being carried out. CASE STUDY: A 55-year-old man with no previous history presented at the Emergency Department complaining of pain in the upper abdomen that had come on suddenly after excessive vomiting. On CT scan Boerhaave's syndrome was diagnosed. An oesophageal stent was placed. The postoperative course was complicated by mediastinal and pleural abscesses for which surgical debridement was required. After 2 months the patient was discharged to a rehabilitation centre. CONCLUSION: Surgical intervention is indicated if a patient with Boerhaave's syndrome is haemodynamically unstable or has sepsis, and the diagnosis is made within 24 hours. In all other cases a minimally invasive approach involving antibiotics, pleural drainage and endoscopic stent placement should be considered.


Asunto(s)
Enfermedades del Esófago/cirugía , Stents , Vómitos/complicaciones , Enfermedad Aguda , Enfermedades del Esófago/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Procedimientos Quirúrgicos Mínimamente Invasivos , Complicaciones Posoperatorias , Rotura Espontánea/diagnóstico , Rotura Espontánea/cirugía , Síndrome , Resultado del Tratamiento
15.
Crit Care Med ; 41(1): 143-50, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23128382

RESUMEN

OBJECTIVE: We studied the variable effects of norepinephrine infusion on cardiac output in postoperative cardiac surgical patients in whom norepinephrine increased mean arterial pressure. We hypothesized that the directional change in cardiac output would be determined by baseline cardiac function, as quantified by stroke volume variation, and the subsequent changes in mean systemic filling pressure and vasomotor tone. DESIGN: Intervention study. SETTING: ICU of a university hospital. PATIENTS: Sixteen mechanically ventilated postoperative cardiac surgery patients. INTERVENTIONS: Inspiratory holds were performed at baseline-1, during increased norepinephrine infusion, and baseline-2 conditions. MEASUREMENTS AND MAIN RESULTS: We measured mean arterial pressure, heart rate, central venous pressure, cardiac output, stroke volume variation and, with use of inspiratory hold maneuvers, mean systemic filling pressure, then calculated resistance for venous return and systemic vascular resistance. Increasing norepinephrine by 0.04 ± 0.02 µg·kg·min increased mean arterial pressure 20 mm Hg in all patients. Cardiac output decreased in ten and increased in six patients. In all patients mean systemic filling pressure, systemic vascular resistance and resistance for venous return increased and stroke volume variation decreased. Resistance for venous return and systemic vascular resistance increased more (p = 0.019 and p = 0.002) in the patients with a cardiac output decrease. Heart rate decreased in the patients with a cardiac output decrease (p = 0.002) and was unchanged in the patients with a cardiac output increase. Baseline stroke volume variation was higher in those in whom cardiac output increased (14.4 ± 4.2% vs. 9.1 ± 2.4%, p = 0.012). Stroke volume variation >8.7% predicted the increase in cardiac output to norepinephrine (area under the receiver operating characteristic curve 0.900). CONCLUSIONS: The change in cardiac output induced by norepinephrine is determined by the balance of volume recruitment (increase in mean systemic filling pressure), change in resistance for venous return, and baseline heart function. Furthermore, the response of cardiac output on norepinephrine can be predicted by baseline stroke volume variation.


Asunto(s)
Gasto Cardíaco/efectos de los fármacos , Norepinefrina/farmacología , Vasoconstrictores/farmacología , Procedimientos Quirúrgicos Cardíacos , Presión Venosa Central , Femenino , Humanos , Infusiones Intravenosas , Análisis de los Mínimos Cuadrados , Masculino , Persona de Mediana Edad , Norepinefrina/administración & dosificación , Cuidados Posoperatorios , Volumen Sistólico , Resistencia Vascular , Vasoconstrictores/administración & dosificación , Venas
16.
J Clin Monit Comput ; 27(2): 163-70, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23143501

RESUMEN

External leg compression (ELC) may increase cardiac output (CO) in fluid-responsive patients like passive leg raising (PLR). We compared the hemodynamic effects of two methods of ELC and PLR measured by thermodilution (COtd), pressure curve analysis Modelflow™ (COmf) and ultra-sound HemoSonic™ (COhs), to evaluate the method with the greatest hemodynamic effect and the most accurate less invasive method to measure that effect. We compared hemodynamic effects of two different ELC methods (circular, A (n = 16), vs. wide, B (n = 13), bandages inflated to 30 cm H2O for 15 min) with PLR prior to each ELC method, in 29 post-operative cardiac surgical patients. Hemodynamic responses were measured with COtd, COmf and COhs. PLR A increased COtd from 6.1 ± 1.7 to 6.3 ± 1.8 L·min(-1) (P = 0.016), and increased COhs from 4.9 ± 1.5 to 5.3 ± 1.6 L·min(-1) (P = 0.001), but did not increase COmf. ELC A increased COtd from 6.4 ± 1.8 to 6.7 ± 1.9 L·min(-1) (P = 0.001) and COmf from 6.9 ± 1.7 to 7.1 ± 1.8 L·min(-1) (P = 0.021), but did not increase COhs. ELC A increased COtd and COmf as in PLR A. PLR B increased COtd from 5.4 ± 1.3 to 5.8 ± 1.4 L·min(-1) (P < 0.001), and COhs from 5.0 ± 1.0 to 5.4 ± 1.0 L·min(-1) (P = 0.013), but not COmf. ELC B increased COtd from 5.2 ± 1.2 to 5.4 ± 1.1 L·min(-1) (P = 0.003), but less than during PLR B (P = 0.012), while COmf and COhs did not change. Bland-Altman and polar plots showed lower limits of agreement with changes in COtd for COmf than for COhs. The circular leg compression increases CO more than bandage compression, and is able to increase CO as in PLR. The less invasive Modelflow™ can detect these changes reasonably well.


Asunto(s)
Gasto Cardíaco/fisiología , Vendajes de Compresión , Hemodinámica , Monitoreo Fisiológico/instrumentación , Presión Sanguínea , Procedimientos Quirúrgicos Cardíacos , Diseño de Equipo , Femenino , Humanos , Pierna , Masculino , Persona de Mediana Edad , Monitoreo Fisiológico/métodos , Presión , Termodilución
17.
J Clin Anesth ; 24(8): 668-74, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23228872

RESUMEN

Hypovolemia is a common clinical problem. The Trendelenburg position and passive leg raising (PLR) are routinely used in the initial treatment while awaiting fluid resuscitation. In this meta-analysis, we evaluated the hemodynamic effects of PLR and Trendelenburg positioning to determine which position had the most optimal effect on cardiac output (CO). Databases were searched for prospective studies published between 1960 and 2010 in normovolemic or hypovolemic humans; these studies had to investigate the hemodynamic effects within 10 minutes of a postural change from supine. Twenty-one studies were included for PLR (n=431) and 13 studies for Trendelenburg position (n=246). Trendelenburg position increased mean arterial pressure (MAP). Cardiac output increased 9%, or 0.35 L/min, at one minute of head-down tilt. Between 2 and 10 minutes, this increase in CO decreased to 4%, or 0.14 L/min, from baseline. Cardiac output increased at one minute of leg elevation by 6%, or 0.19 L/min. The effect persisted after this period by 6%, or 0.17 L/min. Both Trendelenburg and PLR significantly increased CO, but only PLR seemed to sustain this effect after one minute. Although the Trendelenberg position is a common maneuver for nurses and doctors, PLR may be the better intervention in the initial treatment of hypovolemia.


Asunto(s)
Inclinación de Cabeza/fisiología , Hipovolemia/terapia , Postura/fisiología , Presión Sanguínea/fisiología , Gasto Cardíaco/fisiología , Hemodinámica/fisiología , Humanos , Pierna , Posicionamiento del Paciente , Factores de Tiempo
18.
Anesth Analg ; 115(4): 880-7, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22763909

RESUMEN

BACKGROUND: Mean systemic filling pressure (Pmsf) can be measured at the bedside with minimally invasive monitoring in ventilator-dependent patients using inspiratory hold maneuvers (Pmsf(hold)) as the zero flow intercept of cardiac output (CO) to central venous pressure (CVP) relation. We compared Pmsf(hold) with arm vascular equilibrium pressure during vascular occlusion (Pmsf(arm)) and their ability to assess systemic vascular compliance (Csys) and stressed volume by intravascular fluid administration. METHODS: In mechanically ventilated postoperative cardiac surgery patients, inspiratory holds at varying airway pressures and arm stop-flow maneuvers were performed during normovolemia and after each of 10 sequential 50-mL bolus colloid infusions. We measured CVP, Pmsf(arm), stroke volume, and CO during fluid administration steps to construct CVP to CO (cardiac function) curves and Δvolume/ΔPmsf (compliance) curves. Pmsf(hold) was measured before and after fluid administration. Stressed volume was determined by extrapolating the Pmsf-volume curve to zero pressure intercept. RESULTS: Fifteen patients were included. Pmsf(hold) and Pmsf(arm) were closely correlated. Csys was linear (64.3 ± 32.7 mL · mm Hg(-1), 0.97 ± 0.49 mL · mm Hg(-1) · kg(-1) predicted body weight). Stressed volume was estimated to be 1265 ± 541 mL (28.5% ± 15% predicted total blood volume). Cardiac function curves of patients with an increase of >12% to 500 mL volume extension (volume responsive) were steep, whereas the cardiac function curves of the remaining patients were flat. CONCLUSIONS: Csys, stressed volume, and cardiac function curves can be determined at the bedside and can be used to characterize patients' hemodynamic status.


Asunto(s)
Presión Sanguínea/fisiología , Inhalación/fisiología , Unidades de Cuidados Intensivos , Sistemas de Atención de Punto , Volumen Sistólico/fisiología , Resistencia Vascular/fisiología , Anciano , Determinación de la Presión Sanguínea/métodos , Femenino , Pruebas de Función Cardíaca/métodos , Humanos , Masculino , Persona de Mediana Edad , Respiración Artificial/métodos
19.
Intensive Care Med ; 38(9): 1452-60, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22584797

RESUMEN

PURPOSE: To assess the level of agreement between different bedside estimates of effective circulating blood volume-mean systemic filling pressure (Pmsf), arm equilibrium pressure (Parm) and model analog (Pmsa)-in ICU patients. METHODS: Eleven mechanically ventilated postoperative cardiac surgery patients were studied. Sequential measures were made in the supine position, rotating the bed to a 30° head-up tilt and after fluid loading (500 ml colloid). During each condition four inspiratory hold maneuvers were done to determine Pmsf; arm stop-flow was created by inflating a cuff around the upper arm for 30 s to measure Parm, and Pmsa was estimated from a Guytonian model of the systemic circulation. RESULTS: Mean Pmsf, Parm and Pmsa across all three states were 20.9 ± 5.6, 19.8 ± 5.7 and 14.9 ± 4.0 mmHg, respectively. Bland-Altman analysis for the difference between Parm and Pmsf showed a non-significant bias of -1.0 ± 3.08 mmHg (p = 0.062), a coefficient of variation (COV) of 15 %, and limits of agreement (LOA) of -7.3 and 5.2 mmHg. For the difference between Pmsf and Pmsa we found a bias of -6.0 ± 3.1 mmHg (p < 0.001), COV 17 % and LOA -12.4 and 0.3 mmHg. Changes in Pmsf and Parm and in Pmsf and Pmsa were directionally concordant in response to head-up tilt and volume loading. CONCLUSIONS: Parm and Pmsf are interchangeable in mechanically ventilated postoperative cardiac surgery patients. Changes in effective circulatory volume are tracked well by changes in Parm and Pmsa.


Asunto(s)
Presión Sanguínea/fisiología , Gasto Cardíaco , Procedimientos Quirúrgicos Cardíacos , Hemodinámica , Anciano , Anciano de 80 o más Años , Enfermedad de la Arteria Coronaria/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Periodo Posoperatorio , Estadísticas no Paramétricas , Factores de Tiempo , Presión Venosa
20.
Anesth Analg ; 114(4): 803-10, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22344243

RESUMEN

BACKGROUND: Mean systemic filling pressure (Pmsf) can be determined at the bedside by measuring central venous pressure (Pcv) and cardiac output (CO) during inspiratory hold maneuvers. Critical closing pressure (Pcc) can be determined using the same method measuring arterial pressure (Pa) and CO. If Pcc > Pmsf, there is then a vascular waterfall. In this study, we assessed the existence of a waterfall and its implications for the calculation of vascular resistances by determining Pmsf and Pcc at the bedside. METHODS: In 10 mechanically ventilated postcardiac surgery patients, inspiratory hold maneuvers were performed, transiently increasing Pcv and decreasing Pa and CO to 4 different steady-state levels. For each patient, values of Pcv and CO were plotted in a venous return curve to determine Pmsf. Similarly, Pcc was determined with a ventricular output curve plotted for Pa and CO. Measurements were performed in each patient before and after volume expansion with 0.5 L colloid, and vascular resistances were calculated. RESULTS: For every patient, the relationship between the 4 measurements of Pcv and CO and of Pa and CO was linear. Baseline Pmsf was 18.7 ± 4.0 mm Hg (mean ± SD) and differed significantly from Pcc 45.5 ± 11.1 mm Hg (P < 0.0001). The difference of Pcc and Pmsf was 26.8 ± 10.7 mm Hg, indicating the presence of a systemic vascular waterfall. Volume expansion increased Pmsf (26.3 ± 3.2 mm Hg), Pcc (51.5 ± 9.0 mm Hg), and CO (5.5 ± 1.8 to 6.8 ± 1.8 L · min(-1)). Arterial (upstream of Pcc) and venous (downstream of Pmsf) vascular resistance were 8.27 ± 4.45 and 2.75 ± 1.23 mm Hg · min · L(-1); the sum of both (11.01 mm Hg · min · L(-1)) was significantly different from total systemic vascular resistance (16.56 ± 8.57 mm Hg · min · L(-1); P = 0.005). Arterial resistance was related to total resistance. CONCLUSIONS: Vascular pressure gradients in cardiac surgery patients suggest the presence of a vascular waterfall phenomenon, which is not affected by CO. Thus, measures of total systemic vascular resistance may become irrelevant in assessing systemic vasomotor tone.


Asunto(s)
Presión Sanguínea , Gasto Cardíaco , Anciano , Anciano de 80 o más Años , Procedimientos Quirúrgicos Cardíacos , Presión Venosa Central , Femenino , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Resistencia Vascular
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