RESUMEN
We have studied the lymphatic phenotypes of 2 mutations, known to cause abnormalities of lymphatics in humans, in mice. The Cx47 R260C mutation (variably penetrant in humans heterozygous for it and causing limb lymphedema) had an adult mouse phenotype of hyperplasia and increased lymph nodes only in homozygous condition but we did not find any anatomical phenotype in day 16.5 homozygous embryos. Mice harboring the Sos1 mutation E846K (causing Noonan's in man which occasionally shows lymphatic dysplasia) had no adult heterozygous phenotype in lymphatic vessel appearance and drainage (homozygotes are early embryonic lethals) while day 16.5 heterozygous embryos also had no detectable anatomical phenotype.
Asunto(s)
Enfermedades Linfáticas , Vasos Linfáticos , Proteína SOS1 , Animales , Humanos , Ratones , Heterocigoto , Homocigoto , Vasos Linfáticos/anomalías , Vasos Linfáticos/embriología , Mutación , Fenotipo , Linfedema/embriología , Linfedema/genética , Enfermedades Linfáticas/embriología , Enfermedades Linfáticas/genética , Proteína SOS1/genética , Conexinas/genéticaRESUMEN
New findings reopen the controversy about centrifugal vs. centripetal origin of the lymphatic system and support that the latter may be the predominant source of lymphatic endothelial cells from mesenchymal lymphangioblasts.
RESUMEN
Connexin proteins form gap junctions controlling exchange of ions and small molecules between cells and play an important role in movement of lymph within lymphatic vessels. Connexin47 (CX47) is highly expressed in lymphatic endothelial cells and CX47 missense mutations, i.e., R260C, cosegregate with primary lymphedema in humans. However, studies utilizing CX47 knockout mice have failed to demonstrate any lymphatic anomalies. To unravel the lymphatic consequences of expressing a mutant CX47 protein, we used CRISPR technology to create a mouse carrying a Cx47 missense mutation (Cx47R259C) equivalent to the human CX47R260C missense mutation associated with human primary lymphedema. Intradermal Evans Blue dye injection identified a 2-fold increase in regional lymph nodes in homozygous Cx47R259C mice compared to wildtype, particularly in the jugular region (4.8 ± 0.4 and 2.0 ± 0.0, respectively, p<0.01). Associated lymphatic channels were increased in Cx47R259C mice and mesenteric lymph reflux occurred in homozygous Cx47R259C mice but not in wildtype. Contractility of superficial cervical lymphatics, assessed by pressure myography, was reduced in homozygous Cx47R259C mice compared to wildtype. In conclusion, our data are the first to demonstrate a role for the Cx47 protein in lymphatic anatomy and function. This phenotype is similar to that found with other valve deficient mouse mutants, e.g., in Foxc2. Of significance, this study is the first to use CRISPR technology to develop a pre-clinical model of primary lymphedema and demonstrates the importance of distinguishing between lack of and presence of mutant protein when developing clinically relevant animal models for translation of pre-clinical findings.
Asunto(s)
Vasos Linfáticos , Linfedema , Animales , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Conexinas/genética , Células Endoteliales/metabolismo , Células Endoteliales/patología , Humanos , Vasos Linfáticos/patología , Linfedema/patología , Ratones , Ratones Noqueados , Fenotipo , Mutación PuntualRESUMEN
To determine the historical use and utility of various lymphatic imaging modalities in Noonan syndrome (NS) patients, we performed a comprehensive literature review by collecting the published medical imaging of NS lymphatic dysplasias. We correlated imaging findings with clinical phenotypes and treatment. Our analysis of lymphatic imaging modalities provides an algorithmic approach to imaging and patient care across the spectrum of NS developmental defects. A total of 54 NS cases have been published since 1975. Using the observations reported in 15 reviewed publications, an association was made between disruptions in central lymphatic flow and poor clinical presentations/outcomes in NS patients.
Asunto(s)
Vasos Linfáticos , Síndrome de Noonan , Diagnóstico por Imagen , Humanos , Vasos Linfáticos/diagnóstico por imagen , Síndrome de Noonan/diagnóstico por imagen , Síndrome de Noonan/genética , FenotipoRESUMEN
We have created a human chromosomal map of the location of known and candidate genes involved in primary lymphedema (PLE). This should facilitate further discovery and provide a basis for understanding microdeletions which cause lymphedema.
Asunto(s)
Linfangiogénesis , Linfedema , Cromosomas Humanos , Humanos , Linfangiogénesis/genética , Linfedema/genéticaRESUMEN
[Editorial] Lymphatic vessels and lymph are a missing link in SARS-CoV-2/COVID-19 pathophysiology and therapeutic strategies. Based on well-established principles of lymphatic function and dysfunction and a neglected literature, this article highlights promising directions for future research and clinical exploration.
Asunto(s)
COVID-19/fisiopatología , Linfa/fisiología , Vasos Linfáticos/fisiología , SARS-CoV-2 , Drenaje , HumanosRESUMEN
Detailed imaging of the lymphatic system often requires direct injection of contrast into lymph nodes which can be technically challenging, time consuming, and produce painful stimuli. We sought to describe the use of non-contrast MR lymphography (NCMRL) for normal controls and patients with a variety of rare disorders associated with lymphatic pathologies. Two control subjects and five affected patients (decompensated Fontan circulation, central conducting lymphatic abnormality, familial lymphedema and two with Gorham-Stout disease) were studied. NCMRL images were segmented in a semiautomated fashion and the major lymphatic channels and thoracic duct (TD) highlighted for identification. Adequate imaging was available for both controls and 4/5 affected patients; the youngest patient could not be imaged given patient motion. For the two controls, the TD was seen in the expected anatomic location. For the decompensated Fontan patient, there were numerous tortuous lymphatic channels, predominantly in the upper chest and neck. For the familial lymphedema patient, a TD was not identified; instead, peripheral lymphatic collaterals near the lateral chest walls. For the first Gorham- Stout patient, the TD was enlarged with large intrathoracic lymph collections. For the second Gorham-Stout patient, there were bilateral TD with lymph collections in vertebral bodies. Using NCMRL, we were able to image normal and abnormal lymphatic systems. An important learning point is the potential need for sedation for younger patients due to long image acquisition times and fine resolution of the structures of interest.
Asunto(s)
Anomalías Linfáticas/diagnóstico por imagen , Linfografía/métodos , Imagen por Resonancia Magnética/métodos , Estudios de Casos y Controles , Humanos , Vasos Linfáticos/anomalías , Vasos Linfáticos/diagnóstico por imagen , Osteólisis Esencial/diagnóstico , Enfermedades Raras , Conducto Torácico/anomalíasRESUMEN
[Editorial] Thoracic duct decompression (TDD) is an idea first proposed and applied as a novel therapeutic strategy by lymphologists in the 1960's. TDD is recently being reexamined and, in selected patients with portal hypertension from hepatic cirrhosis or with central venous hypertension from isolated right-sided heart failure, undertaken using advanced surgical and image-guided interventional radiologic approaches.
Asunto(s)
Hipertensión Portal , Conducto Torácico , Descompresión , Humanos , Cirrosis Hepática , Stents , Conducto Torácico/diagnóstico por imagen , Conducto Torácico/cirugíaRESUMEN
[Editorial] Evolution of the 2020 international society of lymphology consensus document parallels advances in lymphology: An historical perspective.
Asunto(s)
Linfedema/historia , Linfedema/terapia , Guías de Práctica Clínica como Asunto/normas , Consenso , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Cooperación Internacional , Linfedema/diagnósticoRESUMEN
Congenital chylothorax is an uncommon condition but represents the main cause of congenital pleural effusion during the neonatal period. It usually appears before birth, both as an isolated disorder or in association with hydrops fetalis, negatively affecting the subsequent neonatal outcome. Prenatal treatment is usually considered to ensure a satisfactory lung development in case of moderate to severe pleural effusion or in the presence of hydrops, although consensus on treatment timing and modalities has not been reached to date. Both medical and surgical therapeutic strategies are available to treat this condition and novel treatment options have been recently attempted with acceptable results in both prenatal and post-natal setting. The heterogeneous clinical presentation of congenital chylothorax together with its rarity, its numerous etiologies and the absence of a highly effective treatment renders the diagnostic and therapeutic approach difficult to standardize. In addition, adequate visualization of the lymphatic system is complex, especially in small neonates, although new promising techniques have been developed lately and may contribute to improved management of this serious but infrequent condition. This review focuses on the current evidence base for the diagnosis and treatment options for congenital chylothorax, suggesting a rational diagnostic and therapeutic approach both in the prenatal and in the neonatal period.
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Quilotórax/congénito , Algoritmos , Quilotórax/diagnóstico , Quilotórax/etiología , Quilotórax/terapia , Toma de Decisiones Clínicas , Terapia Combinada , Diagnóstico por Imagen , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Medicina Basada en la Evidencia , Femenino , Humanos , Recién Nacido , Fenotipo , Embarazo , Diagnóstico Prenatal/métodos , Pronóstico , Evaluación de Síntomas , Resultado del TratamientoRESUMEN
The aim of this study is to assess whether early cervical lymphatic obstruction is associated with a sonographically detectable dilatation of the ventricular system in the 1st trimester of pregnancy. In particular, the objective is to assess whether fetuses with non-immune hydrops fetalis (NIHF), cystic hygroma, or enlarged nuchal translucency (NT) have a greater atrial width/biparietal diameter (AW/BPD) ratio than normal at time of the combined first trimester screening scan. This retrospective study included 96 first trimester fetuses (33 normal and 63 with various degree of cervical lymphatic engorgement). Inclusion criteria were CRL in the 45-84 mm range and availability of one or more three-dimensional volume datasets of the fetal head, acquired from the BPD plane. Each three-dimensional volume dataset was opened and multiplanar correlation employed to align the three orthogonal planes. The ratio between the atrial width and the BPD (AW/BPD ratio) was used to evaluate the possible presence of increased amount of cerebrospinal fluid. Abnormal cases were placed into 4 categories: 1) enlarged non-septated NT 2.5-3.9 mm, no hydrops; 2) grossly enlarged non-septated NT / edema >3.9 mm; 3) cystic hygroma and/ or NIHF; 4) major anomalies with NT <2.5 mm. Presence of dilatation of the laterocervical jugular lymphatic sacs, karyotype and presence of congenital anomalies were also recorded. The One-way ANOVA test was used to compare means. Intra- and inter-observer variability were also assessed. The AW/BPD ratio was found to be significantly higher in fetuses with grossly enlarged NT/nuchal edema and NIHF/septated cystic hygroma than in normal (p <0.05 and p <0.01, respectively). Also, the AW/BPD ratio was significantly higher in NIHF/septated cystic hygroma than in enlarged NT 2.5-3.9 mm (p <0.05). In case of enlarged NT (2.5-3.9 mm), the AW/BPD ratio is significantly higher in presence of JLS (p <0.01). At the end of the first trimester, presence of cervical lymphatic engorgement, in terms of grossly enlarged NT, nuchal edema, septated cystic hygroma, and NIHF, is statistically associated with a moderate dilatation of the ventricular system. Of note, among fetuses with moderately enlarged NT, those with evidence of dilatation of the JLS show a statistically significant increase in the AW/BPD ratio.
Asunto(s)
Ventrículos Cerebrales/patología , Susceptibilidad a Enfermedades , Hidropesía Fetal/etiología , Hidropesía Fetal/patología , Vasos Linfáticos/patología , Cariotipo Anormal , Ventrículos Cerebrales/diagnóstico por imagen , Aberraciones Cromosómicas , Diagnóstico Diferencial , Dilatación Patológica , Femenino , Predisposición Genética a la Enfermedad , Humanos , Hidropesía Fetal/diagnóstico por imagen , Linfangioma Quístico/diagnóstico por imagen , Linfangioma Quístico/patología , Vasos Linfáticos/diagnóstico por imagen , Embarazo , Tomografía Computarizada por Rayos XRESUMEN
Context: Historically, administration and dosing of antivenom (AV) have been guided primarily by physician judgment because of incomplete understanding of the envenomation process. As demonstrated previously, lymphatic absorption plays a major role in the availability and pharmacokinetics (PK) of coral snake venom injected subcutaneously, which suggests that absorption from subcutaneous tissue is the limiting step for venom bioavailability, supporting the notion that the bite site is an ongoing venom depot. This feature may underlie the recurrence phenomena reported in viperid envenomation that appear to result from a mismatch between venom and AV PK. The role of lymphatic absorption in neutralization of venom by AV administered intravenously remains unclear. Methods: The effect of AV on systemic bioavailability and neutralization of Micrurus fulvius venom was assessed using a central lymph-cannulated sheep model. Venom was administered by subcutaneous injection in eight sheep, four with and four without thoracic duct cannulation and drainage. Two hours after venom injection, AV was administered intravenously. Venom and AV concentrations in serum and lymph were determined by ELISA assay from samples collected over a 6-h period and in tissues harvested post-mortem. Results: After AV injection, venom levels in serum fell immediately to undetectable with a subsequent increase in concentration attributable to non-toxic venom proteins. In lymph, AV became detectable 6 min after treatment; venom levels dropped concurrently but remained detectable 4 h later. Post-mortem samples from the venom injection site confirmed the presence of venom near the point of injection. Neither venom nor AV was detected at significant concentrations in major organs or contralateral skin. Conclusions: Intravenous AV immediately neutralizes venom in the bloodstream and can extravasate to neutralize venom absorbed by lymph but this neutralization seems to be slow and incomplete. Residual venom in the inoculation site demonstrates that this site functions as a depot where it is not neutralized by AV, which allows the venom to remain active with slow delivery to the bloodstream for ongoing systemic distribution.
Asunto(s)
Antivenenos/uso terapéutico , Serpientes de Coral , Venenos Elapídicos/sangre , Linfa/metabolismo , Mordeduras de Serpientes/tratamiento farmacológico , Absorción Fisiológica , Animales , Antivenenos/sangre , Modelos Animales de Enfermedad , Femenino , Inyecciones Intravenosas , Inyecciones Subcutáneas , Masculino , Especificidad de Órganos , Ovinos , Piel/metabolismo , Mordeduras de Serpientes/sangreRESUMEN
The number of patients surviving repair of complex congenital heart disease (CCHD) has increased due to improved surgical techniques, post operative management and outpatient care. Likewise, this growing patient population has demonstrated an increasing number and complexity of complications involving the lymphatic system. To evaluate the peripheral and central lymphatic system, whole-body lymphangioscintigraphy (LAS) is considered as the initial imaging evaluation of choice. To date, very few publications exist on the value of lymphatic imaging techniques in infants and small children with lymphatic complications following surgery for congenital heart disease. A retrospective review of medical records from 2008 to 2018 was performed for pediatric patients referred for lymphatic complications after CCHD surgery at an academic medical center. LAS and SPECT/CT was performed using intradermal bipedal injections of Tc 99m labeled filtered sulfur colloid, and in some patients also bilateral hand injections, followed by dynamic imaging and whole- body planar imaging typically up to 180 minutes post injection. Clinical decision making and outcomes were recorded. LAS and SPECT/CT were performed without complication in pediatric patients with prior surgery for CCHD. LAS successfully localized various lymphatic abnormalities such as lymphatic obstruction, reflux, and leaks, which were further delineated by SPECT/CT. LAS findings directed further evaluation with more definitive studies, management and prognosis. Five of the ten patients had follow up outcome data - 2 years and up to 10 years. LAS and SPECT/CT are safe and effective techniques for the initial evaluation of lymphatic abnormalities in pediatric patients with CCHD. LAS, particularly with further 3D localization by SPECT/CT, provides functional imaging of peripheral and central lymphatic flow and thus provides guidance for medical therapy, non operative interventional management, and surgical therapy for these diverse, debilitating, and often life threatening disorders.
Asunto(s)
Cardiopatías Congénitas/complicaciones , Enfermedades Linfáticas/diagnóstico , Enfermedades Linfáticas/etiología , Linfocintigrafia , Complicaciones Posoperatorias/diagnóstico , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón Único , Imagen de Cuerpo Entero , Niño , Preescolar , Femenino , Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/cirugía , Humanos , Lactante , Linfocintigrafia/métodos , Masculino , Estudios Retrospectivos , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón Único/métodos , Imagen de Cuerpo Entero/métodosRESUMEN
We performed whole exome sequencing in a family with FOXC2 mutation where the phenotype in one generation was strikingly more severe. Although there were 3 mutations shared by 2 fatal fetal hydrops cases and not the mildly affected mother, none of them were likely to be the cause of the marked phenotypic change.
Asunto(s)
Factores de Transcripción Forkhead/genética , Genes Modificadores , Hidropesía Fetal/genética , Linfedema/genética , Mutación , Factores de Edad , Edad de Inicio , Perfilación de la Expresión Génica , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Hidropesía Fetal/diagnóstico , Lactante , Recién Nacido , Linfedema/diagnóstico , Linaje , Fenotipo , Polimorfismo de Nucleótido Simple , Secuenciación del ExomaRESUMEN
A peculiar brain lymphatic drainage system has been recently fully recognized in animals and humans. It comprises different draining pathways, including the lymphatic system, the perivascular drainage pathway, and the cerebrospinal fluid (CSF) drainage routes. Although scant data are available about its function during the neonatal period, it may play a role in neonatal brain diseases. In this review, we focus on the actual knowledge of brain lymphatic drainage system, and we hypothesize potential implications of its impairment and dysfunction in major neonatal neurological diseases.
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Encéfalo/fisiopatología , Feto/fisiopatología , Enfermedades del Recién Nacido/fisiopatología , Sistema Linfático/fisiopatología , Enfermedades del Sistema Nervioso/fisiopatología , Drenaje , Líquido Extracelular , Humanos , Recién NacidoRESUMEN
In Memoriam: With deep sadness the world of Lymphology learned of the death of Prof. Prof. h.c. Dr. med. Michael Földi, a ground breaking pioneer of modern Lymphology. Words alone will never fully describe or capture the breadth and depth of Michael's contribution to our lymphatic knowledge and the legacy he has left for us all.
Asunto(s)
Sistema Linfático/patología , Linfedema/historia , Historia del Siglo XX , Historia del Siglo XXI , HumanosRESUMEN
Percutaneous intravenous central catheter (PICC) complications are not common and generalized edema and anasarca in neonates as a complication of PICC malposition is even rarer. Documentation of the pathomechanisms of lymphedema in cases of severe anasarca in neonates is not often done. Here we document thoracic duct obstruction as the cause of lymphedema in a neonate with severe nonpitting generalized edema. Most PICC procedures should ideally be guided by point-of-care bedside ultrasound (US), and this precaution may prevent malposition of PICC lines although it will not detect subsequent migration or extravasation.
RESUMEN
Lymphangioleimyomatosis and Gorham- Stout disease, rare disorders which share features of proliferating lymphatic vessels, predominantly in the lung in the former and bone in the latter, commonly manifest as progressive lung disease often associated with life-threatening complications of chylous reflux from central lymphatic obstruction/ leakage. This Lymphspiration-Editorial proposes that, rather than a secondary complication, lymphatic obstruction/ dysfunction is a much earlier or even the primary event in the pathogenesis of both disorders and that lymphostasis drives the cellular proliferative response in both lung and bone and even distant sites.
RESUMEN
In Fontan circulations created for univentricular hearts, systemic venous return is diverted to the lungs before returning to the heart. The Total Cavopulmonary Connection (TCPC) is often the preferred surgical procedure whereby a 4-way anastomosis is created with inflow from the superior vena cava (SVC) and inferior vena cava (IVC) and outflow to the right and left branches of the pulmonary artery. In this arrangement, the systemic venous pressure must be elevated sufficiently to perfuse the lungs passively without the normal boost of the right ventricle. Hence, unlike surgical corrections for other congenital heart conditions, the systemic venous pressures in a Fontan circuit must be elevated to make the circulation work. It is proposed here that the incidence of PLE/LLE is directly related to elevated venous and lymphatic pressures, which cause leakage of proteins/lymph into the gastrointestinal tract (GIT) and expulsion from the body. It is commonly held that elevated venous pressures are relatively better tolerated in the upper body, but much less so in the heptatosplanchnic circulation and the lower body. It is also well established that elevated venous pressure increases lymph formation, most of which is produced in the hepatosplanchnic region (liver and intestine). It is further argued here that the increase in lymph filling pressure arising from the higher lymph flow, in association with the backpressure exerted by elevated venous pressure at the main drainage point into the venous system, results in a substantial increase in pressure in the thoracic duct. This pressure is transmitted back to the intestinal lymphatics, causing dilatation with lacteal rupture and protein or bulk lymph leakage into the intestine. We propose in this paper a new approach, based on experimental evidence, to prevent and/or alleviate this condition by draining or redirecting the thoracic duct (or, alternatively, a more localized intestinal lymphatic vessel) into one of the pulmonary veins or the left atrium, which are typically at near-normal pressure in a Fontan circulation. This "lymphatic-venous right-to-left" shunt maneuver would significantly reduce the venous backpressure on the lymphatics as well as improve lymph circulation, resulting in a decrease in the intestinal lymphatic pressure and thereby prevent or alleviate protein/lymph loss, i.e. lymph balance would be restored. Moreover, the greatly facilitated lymphatic flow would encourage further capillary filtration to relieve excessive venous pressure in the hepatosplanchnic region and protect the liver and kidneys. This paper is intended as a discussion document for elicitation of comments on the soundness and viability of this proposal as well as on technical challenges and steps to explore and advance it.