RESUMEN
Mutations in the human desmin gene cause autosomal-dominant and recessive cardiomyopathies and myopathies with marked phenotypic variability. Here, we investigated the effects of adeno-associated virus (AAV)-mediated cardiac wild-type desmin expression in homozygous desmin knockout (DKO) and homozygous R349P desmin knockin (DKI) mice. These mice serve as disease models for two subforms of autosomal-recessive desminopathies, the former for the one with a complete lack of desmin protein and the latter for the one with solely mutant desmin protein expression in conjunction with protein aggregation pathology in striated muscle. Two-month-old mice were injected with either a single dose of 5 × 1012 AAV9-hTNT2-mDes (AAV-Des) vector genomes or NaCl as control. One week after injection, mice were subjected to a forced swimming exercise protocol for 4 weeks. Cardiac function was monitored over a period of 15 month after injection and before the mice were sacrificed for biochemical and morphological analysis. AAV-mediated cardiac expression of wild-type desmin in both the homozygous DKO and DKI backgrounds reached levels seen in wild-type mice. Notably, AAV-Des treated DKO mice showed a regular subcellular distribution of desmin as well as a normalization of functional and morphological cardiac parameters. Treated DKI mice, however, showed an aberrant subcellular localization of desmin, unchanged functional cardiac parameters, and a trend toward an increased cardiac fibrosis. In conclusion, the effect of a high-dose AAV9-based desmin gene therapy is highly beneficial for the heart in DKO animals, but not in DKI mice.
Asunto(s)
Cardiomiopatías , Dependovirus , Animales , Cardiomiopatías/genética , Cardiomiopatías/terapia , Dependovirus/genética , Desmina/genética , Modelos Animales de Enfermedad , Terapia Genética , Humanos , RatonesRESUMEN
BACKGROUND: As early as pregnancy, maternal mental stress impinges on the child's development and health. Thus, this may cause enhanced risk for premature birth, lowered fetal growth, and lower fetal birth weight as well as enhanced levels of the stress hormone cortisol and lowered levels of the bonding hormone oxytocin. Maternal stress further reduces maternal sensitivity for the child's needs which impairs the mother-child-interaction and bonding. Therefore, prevention and intervention studies on mental stress are necessary, beginning prenatally and applying rigorous research methodology, such as randomized controlled trials, to ensure high validity. METHODS: A randomized controlled trial is used to assess the impact of psychotherapy and telemedicine on maternal mental stress and the child's mental and physical health. Mentally stressed pregnant women are randomized to an intervention (IG) and a not intervened control group. The IG receives an individualized psychotherapy starting prenatal and lasting for 10 months. Afterwards, a second randomization is used to investigate whether the use of telemedicine can stabilize the therapeutic effects. Using ecological momentary assessments and video recordings, the transfer into daily life, maternal sensitivity and mother-child-bonding are assessed. Psycho-biologically, the synchronicity of cortisol and oxytocin levels between mother and child are assessed as well as the peptidome of the colostrum and breast milk, which are assumed to be essential for the adaptation to the extra-uterine environment. All assessments are compared to an additional control group of healthy women. Finally, the results of the study will lead to the development of a qualification measure for health professionals to detect mental stress, to treat it with low-level interventions and to refer those women with high stress levels to mental health professionals. DISCUSSION: The study aims to prevent the transgenerational transfer of psychiatric and somatic disorders from the mother to her child. The effects of the psychotherapy will be stabilized through telemedicine and long-term impacts on the child's and mothers' mental health are enhanced. The combination of psychotherapy, telemedicine and methodologies of ecological momentary assessment, video recording and bio banking are new in content-related and methodological manner. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00017065. Registered 02 May 2019. World Health Organization, Universal Trial Number: U1111-1230-9826. Registered 01 April 2019.
Asunto(s)
Madres/psicología , Complicaciones del Embarazo/terapia , Atención Prenatal/métodos , Psicoterapia/métodos , Estrés Psicológico/terapia , Telemedicina/métodos , Adulto , Niño , Femenino , Humanos , Exposición Materna/efectos adversos , Embarazo , Complicaciones del Embarazo/psicología , Efectos Tardíos de la Exposición Prenatal/prevención & control , Efectos Tardíos de la Exposición Prenatal/psicología , Ensayos Clínicos Controlados Aleatorios como Asunto , Estrés Psicológico/psicología , Resultado del Tratamiento , Adulto JovenRESUMEN
The downregulation of ß-adrenergic receptors (ß-AR) and decreased cAMP-dependent protein kinase activity in failing hearts results in decreased phosphorylation and inactivation of phosphatase-inhibitor-1 (I-1), a distal amplifier element of ß-adrenergic signaling, leading to increased protein phosphatase 1 activity and dephosphorylation of key phosphoproteins, including phospholamban. Downregulated and hypophosphorylated I-1 likely contributes to ß-AR desensitization; therefore its modulation is a promising approach in heart failure treatment. Aim of our study was to assess the effects of adeno-associated virus serotype 9 (AAV9) - mediated cardiac-specific expression of constitutively active inhibitor-1 (I-1c) and to investigate whether I-1c is able to attenuate the development of heart failure in mice subjected to transverse aortic constriction (TAC). 6-8 week old C57BL/6 N wild-type mice were subjected to banding of the transverse aorta (TAC). Two days later 2.8 × 1012 AAV-9 vector particles harbouring I-1c cDNA under transcriptional control of a human troponin T-promoter (AAV9/I-1c) were intravenously injected into the tail vein of these mice (n=12). AAV9 containing a Renilla luciferase reporter (AAV9/hRluc) was used as a control vector (n=12). Echocardiographic analyses were performed weekly to evaluate cardiac morphology and function. 4 weeks after TAC pressure- volume measurements were performed and animals were sacrificed for histological and molecular analyses. Both groups exhibited progressive contractile dysfunction and myocardial remodeling. Surprisingly, echocardiographic assessment and histological analyses showed significantly increased left ventricular hypertrophy in AAV9/I-1c treated mice compared to AAV9/hRluc treated controls as well as reduced contractility. Pressure-volume loops revealed significantly impaired contractility after AAV9/I-1c treatment. At the molecular level, hearts of AAV9/I-1c treated TAC mice showed a hyperphosphorylation of the SR Ca2+-ATPase inhibitor phospholamban. In contrast, expression of AAV9/I-1c in unchallenged animals resulted in selective enhancement of phospholamban phosphorylation and augmented cardiac contractility. Our data suggest that AAV9-mediated cardiac-specific overexpression of I-1c, previously associated with enhanced calcium cycling, improves cardiac contractile function in unchallenged animals but failed to protect against cardiac remodeling induced by hemodynamic stress questioning the use of I-1c as a potential strategy to treat heart failure in conditions with increased afterload.
Asunto(s)
Dependovirus , Terapia Genética/métodos , Insuficiencia Cardíaca/terapia , Péptidos y Proteínas de Señalización Intracelular/genética , Contracción Miocárdica/genética , Animales , Proteínas de Unión al Calcio/metabolismo , Modelos Animales de Enfermedad , Ecocardiografía , Expresión Génica , Vectores Genéticos , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones Endogámicos C57BL , Ratones Transgénicos , Fosforilación , Regiones Promotoras Genéticas , Troponina T/genéticaRESUMEN
BACKGROUND: Some etiological factors involved in developmental dysplasia of the hip (DDH) occur in the last trimester of pregnancy, which could result in a decreased incidence of DDH in preterm infants. The aim of this study was to compare the incidence of DDH between preterm and term infants. METHODS: Ultrasound of the hip joint was performed in 2,534 term infants and 376 preterm infants within the population-based Survey of Neonates in Pomerania (SNiP) study. RESULTS: A total of 42 (1.66%) term infants had DDH (Graf type II c, 0.8%; type D, 0.3% left and 0.4% right; type III a, 0.2% left). Eighteen infants had bilateral findings. Hip dysplasia occurred more frequently in female neonates (32/1,182 vs. 10/1,302, p < 0.023; 95% CI 0.012-0.022, χ 2 test). A familial disposition for DDH was found in 169 (6.7%) term infants and 181 (7.1%) infants in the overall population. In preterm infants, dysplasia of the hip was found in only three late preterm infants with gestational age between 36 and 37 weeks (n = 97) and not in preterm infants <36 weeks gestational age (n = 279). Regression analysis revealed a narrowly significant association between gestational week of birth and DDH (relative risk = 1.17; 95% confidence interval 0.99-1.37; p = 0.065). CONCLUSION: Our study suggests that preterm infants <36 weeks gestational age have a decreased risk of DDH.
Asunto(s)
Luxación Congénita de la Cadera/epidemiología , Enfermedades del Prematuro/epidemiología , Femenino , Alemania/epidemiología , Edad Gestacional , Encuestas Epidemiológicas , Humanos , Incidencia , Recién Nacido , Recien Nacido Prematuro , Masculino , Embarazo , Estudios Prospectivos , Factores de Riesgo , Nacimiento a TérminoRESUMEN
Mutations of the human desmin (DES) gene cause autosomal dominant and recessive myopathies affecting skeletal and cardiac muscle tissue. Desmin knockout mice (DES-KO), which develop progressive myopathy and cardiomyopathy, mirror rare human recessive desminopathies in which mutations on both DES alleles lead to a complete ablation of desmin protein expression. Here, we investigated whether an adeno-associated virus-mediated gene transfer of wild-type desmin cDNA (AAV-DES) attenuates cardiomyopathy in these mice. Our approach leads to a partial reconstitution of desmin protein expression and the de novo formation of the extrasarcomeric desmin-syncoilin network in cardiomyocytes of treated animals. This finding was accompanied by reduced fibrosis and heart weights and improved systolic left-ventricular function when compared with control vector-treated DES-KO mice. Since the re-expression of desmin protein in cardiomyocytes of DES-KO mice restores the extrasarcomeric desmin-syncoilin cytoskeleton, attenuates the degree of cardiac hypertrophy and fibrosis, and improves contractile function, AAV-mediated desmin gene transfer may be a novel and promising therapeutic approach for patients with cardiomyopathy due to the complete lack of desmin protein expression.
Asunto(s)
Cardiomiopatías/terapia , Dependovirus/genética , Desmina/genética , Terapia Genética , Citoesqueleto de Actina/metabolismo , Animales , Cardiomiopatías/genética , Desmina/metabolismo , Vectores Genéticos/genética , Proteínas de Filamentos Intermediarios/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Musculares/metabolismo , Contracción Miocárdica , Miocitos Cardíacos/metabolismo , Función Ventricular IzquierdaRESUMEN
BACKGROUND: Congenital toxoplasmosis is associated with severe complications. German state health insurance covers rubella, but not toxoplasmosis, immunity screening. We analysed the effect of socioeconomic factors on the efficiency of private toxoplasmosis screening during pregnancy. METHODS: Toxoplasmosis and rubella screening data (n = 5402 mothers) were collected within the population-based Survey of Neonates in Pomerania (SNiP). RESULTS: At the first-trimester screening, 34.4 % (88.1 %) of expecting mothers were immune to toxoplasmosis (rubella). Susceptibility for toxoplasmosis (rubella) was observed in 39.6 % (8.9 %) and 25.8 % (2.95 %) were not tested. Data on a 2(nd) screening were available in a subgroup of women with negative immunity showing less than 45 % participation rate. Active toxoplasmosis (no rubella) infection was observed in 0.3 % (n = 17) of pregnant women. A multiple logistic regression model (AIC = 719.67; AUC = 0.725) revealed that the likelihood of participating in a second toxoplasmosis screening increased among women with a good level of education and a steady partnership and decreased with paternal unemployment and the absence of breastfeeding. The highest probability of non-participation in toxoplasmosis screening was found among women with temporal burden and family responsibilities. A cost-benefit analysis showed that covering general screening for toxoplasmosis with health insurance saved costs. CONCLUSION: Toxoplasmosis carried a substantial risk of infection during pregnancy. Although increased socioeconomic status was positively associated with the participation in toxoplasmosis screening, this was not the case when pregnant women had strong temporal burden and family responsibilities. This data supports the need for toxoplasmosis screening among pregnant women as a general healthcare benefit covered by insurance.
Asunto(s)
Tamizaje Masivo/economía , Aceptación de la Atención de Salud/estadística & datos numéricos , Complicaciones Parasitarias del Embarazo/diagnóstico , Diagnóstico Prenatal/economía , Factores Socioeconómicos , Toxoplasmosis/diagnóstico , Adulto , Femenino , Alemania , Humanos , Cobertura del Seguro/economía , Tamizaje Masivo/métodos , Tamizaje Masivo/psicología , Aceptación de la Atención de Salud/psicología , Embarazo , Complicaciones Parasitarias del Embarazo/economía , Complicaciones Parasitarias del Embarazo/psicología , Diagnóstico Prenatal/métodos , Diagnóstico Prenatal/psicología , Toxoplasma , Toxoplasmosis/economía , Toxoplasmosis/psicología , Adulto JovenRESUMEN
Adeno-associated viral (AAV) vectors yield high potential for clinical gene therapy but, like for other vectors systems, they frequently do not sufficiently transduce the target tissue and their unspecific tropism prevents their application for multifocal diseases such as disseminated cancer. Targeted AAV vectors have been obtained from random AAV display peptide libraries but so far, all vector variants selected from AAV libraries upon systemic administration in vivo retained some collateral tropism, frequently the heart. Here we explored, if this impediment can be overcome by microRNA-regulated transgene cassettes as the combination of library-derived capsid targeting and micro-RNA control has not been evaluated so far. We used a tumor-targeted AAV capsid variant (ESGLSQS) selected from random AAV-display peptide libraries in vivo with remaining off-target tropism toward the heart and regulated targeted transgene expression in vivo by complementary target elements for heart-specific microRNA (miRT-1d). Although this vector still maintained its strong transduction capacity for tumor target tissue after intravenous injection, transgene expression in the heart was almost completely abrogated. This strong and completely tumor-specific transgene expression was used for therapeutic gene transfer in an aggressive multifocal, transgenic, polyoma middle T-induced, murine breast cancer model. A therapeutic suicide gene, delivered systemically by this dual-targeted AAV vector to multifocal breast cancer, significantly inhibited tumor growth after one single vector administration while avoiding side effects compared with untargeted vectors.
Asunto(s)
Dependovirus , Genes Transgénicos Suicidas , Terapia Genética , Vectores Genéticos , Neoplasias Mamarias Experimentales/terapia , Animales , Femenino , Neoplasias Mamarias Experimentales/genética , Ratones , MicroARNs/administración & dosificaciónRESUMEN
Parvovirus B19 (B19V) infection during pregnancy can lead to fetal damage and even fetal loss. In some cases a severe fetal anemia with hydrops fetalis occurs. An intrauterine red blood cell transfusion can reduce the mortality rate. Neurodevelopmental outcome after fetal B19V infection is affected by fetal anemia and presumably direct infection of the CNS. There are only a few studies on long-term neurodevelopmental outcome after B19V infection induced hydrops fetalis. There are hardly any long-term data especially in preterm infants. We report on the long-term outcomes of 2 extremely preterm children after non-immune hydrops fetalis due to intrauterine B19V Infection.
Asunto(s)
Hidropesía Fetal/etiología , Hidropesía Fetal/terapia , Trastornos del Neurodesarrollo/prevención & control , Infecciones por Parvoviridae/terapia , Parvovirus B19 Humano , Atención Perinatal/métodos , Adulto , Femenino , Humanos , Hidropesía Fetal/diagnóstico , Recien Nacido Extremadamente Prematuro , Estudios Longitudinales , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/etiología , Infecciones por Parvoviridae/complicaciones , Infecciones por Parvoviridae/diagnóstico , Embarazo , Resultado del TratamientoRESUMEN
We examined the hypothesis that major cardiac surgery triggers a more intense adrenal stress response than less intensive noncardiac surgery, which then alters cortisol inactivation. Urinary excretion rates of glucocorticoid metabolites were determined before and after surgery using gas chromatography-mass spectrometry in 29 children undergoing scheduled major cardiac surgery and 17 control children undergoing conventional noncardiac surgery in a prospective observational study. Excretion rates of glucocorticoid metabolites were summed and corrected for creatinine excretion to calculate cortisol production rates (mg/mmol creatinine/m(2) body surface area). Precursor/product ratios from individual metabolites were calculated to characterize cortisol inactivation (11ß-hydroxysteroid dehydrogenase). Postoperatively, median cortisol production rates increased in both groups ( MCS: from 2.7 to 9.3; controls: from 2.7 to 5.8; p<0.001) with no significant difference between groups (p=0.12). Ratios of cortisol to cortisone metabolites, indicating the overall activity of 11ß-hydroxysteroid dehydrogenase, increased postoperatively in both groups (p<0.001). In conclusion, surgery resulted in a distinct postoperative increase in cortisol production. In contrast to our hypothesis, children undergoing major cardiac surgery did not show an increased adrenal stress response compared to children undergoing conventional surgery. Furthermore, the reduction in cortisol inactivation appears to be an essential part of the stress response to pediatric surgery in general.
Asunto(s)
Glándulas Suprarrenales/metabolismo , Procedimientos Quirúrgicos Cardíacos/métodos , Cortisona/orina , Glucocorticoides/sangre , Glucocorticoides/orina , Cardiopatías/cirugía , Hidrocortisona/orina , 11-beta-Hidroxiesteroide Deshidrogenasas/metabolismo , Niño , Preescolar , Regulación hacia Abajo , Femenino , Cromatografía de Gases y Espectrometría de Masas , Cardiopatías/congénito , Cardiopatías/orina , Humanos , Lactante , Masculino , Estudios ProspectivosRESUMEN
Neonatal mysthenia gravis (NMG) is a rare cause of arthrogryposis multiplex congenita (AMC) due to diaplacental transfer of maternal acetylcholine receptors (AChR) antibodies. 2 cases of severe NMG complicated by chronic lung disease and pulmonary arterial hypertension are reported. With respect to the severe course of the index patient, prenatal diagnosis and immunomodulation treatment were offered during the 2nd pregnancy. The combination of prenatal immunoadsorption (IA) therapy, administration of intravenous immunoglobulin (IVIG) and prednisolone failed. Failure may be partly explained by immaturity of the infant. However, considering the successful treatment of fetal/neonatal alloimmune thrombocytopenia (AIT) reported in literature, a treatment approach with IVIG doses up to 1-2 g/kg per week plus prednisone/prednisolone at a higher dose up to 1 mg/kg/d might be more effective.
Asunto(s)
Artrogriposis/embriología , Artrogriposis/prevención & control , Factores Inmunológicos/uso terapéutico , Miastenia Gravis Neonatal/tratamiento farmacológico , Miastenia Gravis Neonatal/embriología , Prednisona/uso terapéutico , Atención Prenatal/métodos , Artrogriposis/diagnóstico , Resultado Fatal , Femenino , Humanos , Miastenia Gravis Neonatal/diagnóstico , Embarazo , Resultado del Embarazo , Diagnóstico Prenatal , Resultado del Tratamiento , Adulto JovenRESUMEN
The primarily anuric very low birth weight infant (VLBWI) is an ethical challenge for the attending doctor as well as for the parents. Long term peritoneal dialysis (PD) might provide an acceptable way in treating a primarily anuric VLBWI prior to kidney transplantation without endangering the child's neurologic development. We report a case of a VLBWI born at 30 weeks gestational age after anhydramnion for 5 weeks. Postnatally the neonate had persisting anuria and was successfully treated with peritonealdialysis for 31 months followed by hemodialysis for 12 months and eventually received a renal transplantion at the age of 43 months.
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Anuria/terapia , Enfermedades del Prematuro/terapia , Recién Nacido de muy Bajo Peso , Inutilidad Médica , Diálisis Peritoneal/métodos , Preescolar , Terapia Combinada , Discapacidades del Desarrollo/diagnóstico , Nutrición Enteral , Femenino , Estudios de Seguimiento , Rechazo de Injerto/terapia , Humanos , Recién Nacido , Pruebas de Función Renal , Trasplante de Riñón , Cuidados a Largo Plazo , Embarazo , Diálisis Renal , ResucitaciónRESUMEN
Neonatal haemochromatosis (NH) is a connatal hepatopathy that is lethal in 32% and necessitates liver transplantation in 63% of the survivors. The classical diagnostic criteria of extrahepatic siderosis do not apply in all patients who are suspected to have NH. The hypothesis of NH as an alloimmune disease is supported by the quantitative immunohistochemical proof of C5b-9 complement complexes on the hepatocytes of liver biopsy material. This has opened a new perspective in the therapy and prophylaxis for this severe disease. Prophylactic therapy with intravenous immunoglobulins (IVIG) for mothers at risk can prevent a relevant NH in most cases.
Asunto(s)
Hemocromatosis/prevención & control , Inmunoglobulinas Intravenosas/administración & dosificación , Humanos , Factores Inmunológicos/administración & dosificación , Recién Nacido , Inyecciones Intravenosas , Masculino , Factores de Riesgo , Prevención Secundaria/métodos , Resultado del TratamientoRESUMEN
Walker-Warburg syndrome is a very rare autosomal recessive disorder with congenital muscular dystrophy, brain malformations on the basis of a neuronal migration defect and ocular abnormalities. We report our experience in treating two cases of Walker-Warburg syndrome complicated by hydrocephalus with shunting and endoscopic techniques.
Asunto(s)
Anomalías Múltiples , Encéfalo/anomalías , Hidrocefalia , Distrofias Musculares/complicaciones , Síndrome , Derivación Ventriculoperitoneal , Encéfalo/patología , Endoscopía , Femenino , Estudios de Seguimiento , Humanos , Hidrocefalia/complicaciones , Hidrocefalia/patología , Hidrocefalia/cirugía , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Distrofias Musculares/congénito , Procedimientos NeuroquirúrgicosRESUMEN
BACKGROUND: A genomic region on chromosome 6p21.3, including HLA-DPB1, has been linked to Wegener's granulomatosis (WG). The basis of this association is difficult to evaluate because of the complex haplotype block architecture of this region. OBJECTIVE: To identify the causative molecular genetic variation(s) using a detailed HapMap based fine-mapping approach. METHODS: 282 patients with WG and 380 healthy controls were genotyped for HLA-DPB1 as well as for 35 informative single nucleotide polymorphisms (SNPs) within the respective region. 25 of these SNPs have been selected as tagging SNPs for another 219 associated SNPs. Allele and genotype frequencies were analysed separately by contingency tables and logistic regression. Finally, the coding region of RING1 was directly sequenced in subjects who carried haplotypes that were correlated with contrasting WG risks. RESULTS: The previously reported strong association of WG with the HLA-DPB1*0401 allele was confirmed in an independent WG sample (n = 108, p(c) = 6.4 x 10(-8)). When the complete cohort (n = 282) was considered, the association remained highly significant in ANCA-positive (p(c) = 1.26 x 10(-22)), but not in ANCA-negative patients. An SNP 3' of HLA-DPB1 yielded the smallest p value and was associated with WG partly independently from the HLA-DPB1 alleles. Another informative SNP in the vicinity of RING1 showed significant WG association that was also partly independent of HLA-DPB1. RING1 sequencing, however, did not show any variation potentially predisposing to WG. CONCLUSIONS: The HLA-DPB1/RING1 region is strongly associated with WG in ANCA-positive subjects. Further analyses of potential cis regulatory sequences of candidate genes HLA-DPB1, RING1 and RXRB appear warranted.
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Cromosomas Humanos Par 6/genética , Granulomatosis con Poliangitis/genética , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Anticuerpos Anticitoplasma de Neutrófilos/sangre , Proteínas de Unión al ADN/genética , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Granulomatosis con Poliangitis/inmunología , Antígenos HLA-DP/genética , Cadenas beta de HLA-DP , Haplotipos , Prueba de Histocompatibilidad/métodos , Humanos , Complejo Represivo Polycomb 1Asunto(s)
Encefalomielitis Aguda Diseminada/terapia , Técnicas de Inmunoadsorción , Encéfalo/patología , Niño , Terapia Combinada , Encefalomielitis Aguda Diseminada/diagnóstico , Escala de Coma de Glasgow , Humanos , Aumento de la Imagen , Interpretación de Imagen Asistida por Computador , Inmunización Pasiva , Leucomalacia Periventricular/diagnóstico , Leucomalacia Periventricular/terapia , Imagen por Resonancia Magnética , Masculino , RecurrenciaRESUMEN
Retinopathy of prematurity (ROP) is a vascular disease of the eye unique to preterm infants. The distinctive feature of ROP is that is an illness of the still-maturing organism. Thus, an understanding of the normal fetal development of the retina is fundamental to understanding the pathogenesis of ROP. Animal models of ROP differ in important attributes, a fact that is important for interpretation of results. However, all models have in common the finding that ROP is a biphasic disease. In the first phase, relative hyperoxia results in vaso-obliteration and vessel loss. The second phase is characterized by hypoxia-induced neovascularization resulting in retinal detachment and blindness. Oxygen-dependent vascular endothelial growth factor (VEGF) and oxygen-independent insulin-like growth factor (IGF-1) have been identified as important factors in the pathogenesis of ROP. These findings suggest new therapeutic approaches. Substitution of IGF-1 during the first phase of the disease may help prevent vessel loss, and administration of anti-angiogenic substances during the second phase may prevent pathological neovascularization.
Asunto(s)
Retinopatía de la Prematuridad/etiología , Animales , Modelos Animales de Enfermedad , Edad Gestacional , Humanos , Hiperoxia/complicaciones , Hiperoxia/patología , Recién Nacido de Bajo Peso , Recién Nacido , Factor I del Crecimiento Similar a la Insulina/metabolismo , Oxígeno/sangre , Pronóstico , Desprendimiento de Retina/etiología , Desprendimiento de Retina/patología , Neovascularización Retiniana/etiología , Neovascularización Retiniana/patología , Vasos Retinianos/patología , Retinopatía de la Prematuridad/patología , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
UNLABELLED: Deep-vein thrombosis and subsequent pulmonary embolism are major complications in total joint arthroplasty of the lower limbs. New oral anticoagulants are increasingly prescribed as thromboprophylaxis due to their simple administration and encouraging phase III marketing studies. PATIENTS, METHODS: In this observational study, we compared the efficacy and safety of rivaroxaban with nadroparin in 1302 unselected patients receiving hip or knee arthroplasty. RESULTS: Venous thrombembolism occurred in 3.3% (2.3%; 4.7%, 95% CI, n = 838) of patients receiving rivaroxaban and in 4.3% (2.7%; 6.7%, 95% CI, n = 464) of patients receiving nadroparin resulting in an absolute risk reduction (ARR) of 1.0% (-1.4%; 3.3%, 95% CI). CONCLUSIONS: With an odds ratio of 0.6 (0.4; 1.0, 95% CI), rivaroxaban was associated with a decreased perioperative drop in haemoglobin exhibiting an improved thromboprophylactic profile when compared to high dose nadroparin. Furthermore, transfusion rates were 8.8% (-2.7%; 19.9%, 95% CI) lower in patients receiving rivaroxaban. However, as previous studies have shown, low preoperative haemoglobin remains the most predictive factor for postoperative transfusions (OR: 2.4 [1.3; 4.4, 95% CI]).
Asunto(s)
Artroplastia de Reemplazo de Cadera/mortalidad , Artroplastia de Reemplazo de Rodilla/mortalidad , Nadroparina/administración & dosificación , Rivaroxabán/administración & dosificación , Tromboembolia Venosa/mortalidad , Tromboembolia Venosa/prevención & control , Artroplastia de Reemplazo de Cadera/estadística & datos numéricos , Artroplastia de Reemplazo de Rodilla/estadística & datos numéricos , Causalidad , Relación Dosis-Respuesta a Droga , Inhibidores del Factor Xa/administración & dosificación , Femenino , Fibrinolíticos/administración & dosificación , Alemania/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/mortalidad , Complicaciones Posoperatorias/prevención & control , Prevalencia , Factores de Riesgo , Tasa de Supervivencia , Resultado del Tratamiento , Tromboembolia Venosa/diagnósticoRESUMEN
Approximately 20-50% of ultraviolet A (UVA) irradiation delivered to the skin surface may reach the human dermal microvascular endothelial cells (HDMEC) that play a pivotal role in cellular inflammatory tissue; however, the pathophysiologic role of HDMEC in UVA-induced skin changes is largely unknown. Based on previous in vivo and in vitro studies revealing UVA-induced expression of endothelial adhesion molecules, we studied isolated HDMEC under various conditions in order to further delineate the impact of UVA on these cells. The expression of cell adhesion molecules was determined by flow cytometry and the resulting changes of stable adhesion of leukocytes to endothelial cells were quantitated for granulocytes, lymphocytes, and monocytes using a newly developed multicellular adhesion assay. Additionally, antibody blocking experiments were performed to delineate the role of individual cell adhesion molecules in UVA-induced leukocyte adherence. High-dose polychromatic UVA (25 J per cm2, maximal emission at 375 nm) induced intercellular adhesion molecule-1 and E-selectin with different kinetics but correlating the adhesion of leukocyte subsets. This effect subsided, however, in the course of 3-6 daily applied UVA doses. Moreover, pro-inflammatory cytokine challenge by tumor necrosis factor-alpha and interleukin-1-alpha resulted in significantly weaker induction of intercellular adhesion molecule-1 and E-selectin in repeatedly UVA-exposed HDMEC. Differential quantitation of peripheral blood derived granulocytes, lymphocytes, and monocytes revealed reduced adhesion particularly of lymphocytes followed by monocytes and granulocytes compared with leukocyte adhesion to nonirradiated but cytokine-stimulated HDMEC. It is concluded that UVA substantially influences endothelial cell adhesion molecules expression and thus directly interferes with leukocyte adhesion to endothelial cells. Divergent UVA-induced effects in this respect can be attributed to the mode of UV exposure as well as to the condition of endothelial cells prior to UVA exposure.