RESUMEN
Venous malformations are low-flow vascular lesions consisting of disorganized thin-walled vascular channels. These can occur sporadically but also as an autosomal dominant condition termed venous malformations, cutaneous and mucosal (VMCM; OMIM 600195). In two large unrelated kindreds mapping to chromosome 9, the identical R849W missense mutation was identified in the first kinase domain of Tie2, an endothelial cell-specific receptor tyrosine kinase. We report here the identification of four new kindreds with inherited venous malformations. Unlike the initial two families described, these four families demonstrate allelic and locus heterogeneity. In one of these families, the R849W mutation co-segregates with the disease phenotype. Three other families with venous malformations lack this mutation. One of these families is linked to markers near TIE2 on chromosome 9. In this family, we identified a novel mutation within the first kinase domain of Tie2 resulting in a Y897S change. Results from COS-1 cell transfections using expression constructs containing either the R849W or the Y897S mutation suggest that the receptors containing either mutation show ligand-independent hyperphosphorylation. These results suggest a gain-of-function mechanism for development of venous malformations in these families. Of the two remaining families, one excludes linkage to the TIE2 locus, establishing the existence of at least one additional locus for dominantly inherited venous malformations.
Asunto(s)
Variación Genética , Enfermedades Vasculares/genética , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Animales , Secuencia de Bases , Células COS , Femenino , Humanos , Ligandos , Masculino , Datos de Secuencia Molecular , Mutación , Linaje , Fosforilación , Alineación de Secuencia , Transfección , Enfermedades Vasculares/patologíaRESUMEN
DNA pooling is an efficient method to rapidly perform genome-wide linkage scans in autosomal recessive diseases in inbred populations where affected individuals are likely to be homozygous for alleles near the disease gene locus. We wanted to examine whether this approach would detect linkage in autosomal dominant (AD) disorders where affected individuals may share one allele identical by descent at loci tightly linked to the disease. Two large outbred pedigrees in which the AD diseases familial venous malformation (FVM) and hereditary hemorrhagic telangiectasia (HHT1), linked to 9p and 9q, respectively, were investigated. Separate pools of DNA from affected (n = 21 for FVM and 17 for HHT1) and unaffected family members (n = 9 FVM and HHT1), and 25 unrelated population controls were established. Polymorphic markers spanning chromosome 9 at approximately 13.5-cM intervals were amplified using standard PCR. Allele quantitation was performed with a fluorimager. Visual inspection of allele intensities and frequency distributions suggested a shift in frequency of the most common allele in the affecteds lane when compared to control lanes for markers within 30 cM of the FVM and HHT1 loci. These subjective assessments were confirmed statistically by testing for the difference between two proportions (one-sided; P < or = 0.05). When using population controls, the true-positive rates for FVM and HHT1 were 5/5 and 2/5 markers, respectively. False-positive rates for FVM and HHT1 were 3/9 and 2/9, respectively. In both AD diseases investigated, quantitative DNA pooling detected shifts in allele frequency, thus identifying areas of known linkage in most cases. The utility of this technique depends on the size of the pedigree, frequency of the disease-associated allele in the population, and the choice of appropriate controls. Although the false-positive rate appears to be high, this approach still serves to reduce the amount of overall genotyping by about 60%. DNA pooling merits further investigation as a potential strategy in increasing the efficiency of genomic linkage scans.
Asunto(s)
Malformaciones Arteriovenosas/genética , ADN/análisis , Genes Dominantes , Ligamiento Genético , Telangiectasia Hemorrágica Hereditaria/genética , Alelos , Cromosomas Humanos Par 9 , Frecuencia de los Genes , Marcadores Genéticos , Pruebas Genéticas/métodos , HumanosRESUMEN
Differentiation cultures of embryonic stem (ES) cells can be a useful in vitro system for understanding cardiac myocyte development. However, cell morphometry, sarcomere development, and functional cell-cell junction formation have not been examined in detail to determine whether ES cell-derived cardiac myocytes exhibit structural and functional characteristics similar to cardiac myocytes within the developing heart. Therefore, we examined cellular dimensions, sarcomere formation, and cell-cell contacts in differentiating cardiac myocytes derived from mouse D3-ES cell cultures. Cells exhibited rod-shaped morphology and had single centrally located nuclei, typical of maturing cardiac myocytes. The cellular dimensions of 59 individual cardiac myocytes within contracting foci of ES cell cultures were analyzed (length = 42.2 +/- 2.1 microns, area = 197 +/- 19 microns2, and diameter = 5.5 +/- 0.3 microns) and found to be similar to myocytes in vivo. Transmission electron micrographs of ES cell-derived cardiac myocytes indicated myofibrillar architecture ranged from sparse and disorganized to densely packed, parallel arrays of myofibrils organized into mature sarcomeres. This pattern of myofibrillar assembly in maturing sarcomeres was similar to that observed during in vivo myocyte differentiation. Another hallmark of cardiac development is the formation of intercalated discs, which functionally couple adjacent cardiac myocytes. Electron micrographs indicated nascent intercalated discs were forming in foci of ES cell-derived cardiac myocytes. In addition, indirect immunostaining with anti-connexin 43 antibody (Ab), a monoclonal Ab to the gap junction component of the intercalated disc, indicated that gap junctions were present in contracting ES cell foci. Furthermore, microinjection of single cardiac myocytes with Lucifer yellow (2.5 microM) resulted in the spread of fluorescence to adjacent cells within a contracting focus, an indication of functional cell-cell coupling across these gap junctions. Together, these results indicate ES cell-derived cardiac myocytes exhibit cell morphology, sarcomere formation, and cell-cell junctions similar to those observed in cardiac myocytes developing in vivo.
Asunto(s)
Uniones Intercelulares/ultraestructura , Miocardio/ultraestructura , Animales , Diferenciación Celular , Tamaño de la Célula , Células Cultivadas , Desmosomas/ultraestructura , Técnica del Anticuerpo Fluorescente Indirecta , Colorantes Fluorescentes , Uniones Comunicantes/ultraestructura , Ratones , Microscopía Confocal , Contracción Miocárdica , Miocardio/citología , Sarcómeros/ultraestructura , Células MadreRESUMEN
Venous malformations (VMs), the most common errors of vascular morphogenesis in humans, are composed of dilated, serpiginous channels. The walls of the channels have a variable thickness of smooth muscle; some mural regions lack smooth muscle altogether. A missense mutation resulting in an arginine-to-tryptophan substitution at position 849 in the kinase domain of the receptor tyrosine kinase TIE2 segregates with dominantly inherited VM in two unrelated families. Using proteins expressed in insect cells, we demonstrate that the mutation results in increased activity of TIE2. We conclude that an activating mutation in TIE2 causes inherited VMs in the two families and that the TIE2 signaling pathway is critical for endothelial cell-smooth muscle cell communication in venous morphogenesis.
Asunto(s)
Endotelio Vascular/fisiología , Músculo Liso Vascular/fisiología , Neovascularización Patológica/genética , Proteínas Tirosina Quinasas/fisiología , Proteínas/fisiología , Venas/anomalías , Secuencia de Aminoácidos , Mapeo Cromosómico , Cromosomas Humanos Par 9 , Activación Enzimática , Femenino , Haplotipos , Humanos , Ligandos , Masculino , Datos de Secuencia Molecular , Linaje , Fosforilación , Mutación Puntual , Polimorfismo Genético , Receptor TIE-2 , Proteínas Recombinantes , Alineación de Secuencia , Transducción de SeñalRESUMEN
Venous malformations are a common form of vascular anomaly that cause pain and disfigurement and can be life threatening if they involve critical organs. They occur sporadically or in a familial form, where multiple lesions are usually present. We have identified a large kindred showing autosomal dominant inheritance of venous malformations. Using this family we confirm linkage of a familial form of venous malformations to chromosome 9p. We suggest that blue rubber bleb naevus syndrome can be considered a particular manifestation of this form of familial venous malformations. The candidate region for this gene encompasses the interferon gene cluster and the MTS1 (p16) tumour suppressor gene.
Asunto(s)
Mapeo Cromosómico , Cromosomas Humanos Par 9/genética , Venas/anomalías , Salud de la Familia , Femenino , Genes Dominantes , Ligamiento Genético , Humanos , Masculino , LinajeRESUMEN
Six families in which a few members, in three generations, were affected with medial telangiectatic nevus (salmon patch, stork bite, angel's kiss) on the forehead, glabella, upper eyelids, upper lip, nose, and nuchal and occipital areas are presented. This is a mild variant of lateral telangiectatic nevus (nevus flammeus, port-wine stain) that disappears in about 50 percent of patients during the first years of life. In one family, lateral telangiectatic nevus (nevus flammeus, port-wine stain) and superficial (strawberry) hemangioma coexisted with medial telangiectatic nevus. This paper discusses the familial incidence of medial telangiectatic nevus and a new modality of treatment. Moreover, the paper presents a classification of vascular malformations and proposes a new terminology.
Asunto(s)
Hamartoma/genética , Hemangioma/genética , Neoplasias Cutáneas/genética , Adulto , Niño , Preescolar , Femenino , Hamartoma/enzimología , Hamartoma/patología , Neoplasias de Cabeza y Cuello/congénito , Neoplasias de Cabeza y Cuello/genética , Hemangioma/congénito , Hemangioma/patología , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Linaje , Neoplasias Cutáneas/congénito , Neoplasias Cutáneas/patologíaRESUMEN
Three adult patients (one man and two women) with acquired lateral telangiectatic nevus (acquired port-wine stain or acquired nevus flammeus) on the face are presented. One patient had no history of preceding trauma. However, in two others, chronic sun exposure probably caused actinic damage of the skin with telangiectasia. A review of the literature on acquired lateral telangiectatic nevus and its causative factors is presented.
Asunto(s)
Enfermedades de la Piel/patología , Adulto , Cara , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Two families with multiple lateral telangiectatic nevi (LTN) (port-wine stains or nevi flammei) in various areas of the body in two and three generations are presented. In the second family, some members in addition to LTN also had superficial (strawberry) hemangiomas and hemangioma-like venous malformations. The pedigrees of these families indicate autosomal dominant inheritance of multiple LTN.
Asunto(s)
Hemangioma/genética , Neoplasias Primarias Múltiples/genética , Neoplasias Cutáneas/genética , Adulto , Niño , Preescolar , Femenino , Hemangioma/congénito , Humanos , Masculino , Neoplasias Primarias Múltiples/congénito , Linaje , Neoplasias Cutáneas/congénitoRESUMEN
We developed a patient eye shield consisting of a sandwich of polymethylmethacrylate and tinfoil to provide corneal and retinal protection from inadvertent injury during argon, neodymium:YAG, or dye laser treatment. The shield was tested with argon, dye, neodymium:YAG and CO2 lasers. This new eye shield is safe, comfortable, and easy to clean and use.
Asunto(s)
Dispositivos de Protección de los Ojos , Párpados/cirugía , Terapia por Láser/instrumentación , Equipos de Seguridad , Diseño de Equipo , Humanos , Rayos Láser , Ensayo de Materiales , Metilmetacrilatos , EstañoRESUMEN
In recent years, adipocytes obtained by suction-assisted lipectomy have been used for implantation by injection methods. This study is designed to assess the appearance of suctioned and excised adipose tissue and its survival after being injected or implanted into different tissues (0.5 cc into the rectus muscle and 0.5 cc into the dorsal ear skin) of New Zealand White rabbits. The results showed that significant numbers of adipocytes were ruptured after suction procedures. The intact cells represented approximately 10 percent of the fat cell population. Fat cells in aspirated and excised samples remained intact and did not differ histologically. After being injected into tissue, adipocytes appeared to survive better for a short term in a more vascularized bed (rectus muscle) than in a low vascular area (ear dermis). Long-term studies at 6- to 9-month intervals revealed transplanted adipose tissue, taken by suction or excision, being replaced with fibrosis, although cystic spaces and only a small number of surviving adipocytes were still present. Insulin did not show any protective effects on survival of the adipocytes during their transplantation.
Asunto(s)
Tejido Adiposo/trasplante , Tejido Adiposo/citología , Animales , Supervivencia de Injerto , Masculino , Conejos , Cirugía Plástica/métodosRESUMEN
Absence of the right pectoralis major muscle and hypoplasia of the ipsilateral breast was observed in 3 females and hypoplasia or agenesis of the right pectoralis major muscle in 2 males of the same family. One member of this family, a 17-year-old girl, underwent a right latissimus dorsi muscle flap, placement of silicone-gel breast implant, and a right infraclavicular natural Y prosthesis. Although none of our 5 patients from this family had congenital upper limb abnormalities, we believe that they still qualify as having Poland's syndrome. This would distinguish them as being the fourteenth known family reported in the world literature with this diagnosis. A brief review of the history as well as hypotheses of etiological mechanisms are presented.
Asunto(s)
Síndrome de Poland/genética , Sindactilia/genética , Adolescente , Femenino , Humanos , Masculino , Linaje , Síndrome de Poland/cirugía , Cirugía PlásticaRESUMEN
A modified hematoxylin and eosin staining method for glutaraldehyde fixed, osmium tetroxide postfixed, and epoxy resin (Medcast Resin) embedded tissue is described. Two microns thick sections of human and animal tissues are treated with 4% H2O2 for 4 minutes, washed, dryed, and then flooded with Gill's III hematoxylin in a moist chamber at 37 degrees C for 90 minutes. Subsequent steps are: washing; bluing in ammonia water for 1 minutes; washing again and staining in 1% eosin Y alcoholic solution for 5 minutes; rinsing in 100% ethanol; drying and mounting with Permont. This procedure is quick, easy and successful in demonstrating both color scale and quality similar to hematoxylin and eosin stains obtained in standard paraffin sections.
Asunto(s)
Benzopiranos , Eosina Amarillenta-(YS) , Resinas Epoxi , Hematoxilina , Técnicas Histológicas , Animales , Humanos , Coloración y Etiquetado/métodosRESUMEN
Quantitative study of the capillary density of normal dermis of 113 biopsy specimens taken from 20 body sites from 6 cadavers was carried out. Histologic quantification of dermal capillaries using the alkaline phosphatase method to delineate vascular endothelium and automated image analysis demonstrates statistically significantly greater capillary density in the head-face/neck region both in the papillary and reticular dermis than in the lower parts of the body. The smallest numbers of the dermal capillary density were noted in the calf and shin areas. These data support the hypothesis that random-pattern skin flaps can be safely raised longer in the face and neck than in other parts of the body.
Asunto(s)
Piel/irrigación sanguínea , Anciano , Anciano de 80 o más Años , Capilares/anatomía & histología , Extremidades , Femenino , Cabeza , Humanos , Masculino , Persona de Mediana Edad , Cuello , Valores de Referencia , Colgajos QuirúrgicosRESUMEN
Two patients with tuberous sclerosis whose skin lesions included facial angiofibromas (adenoma sebaceum), fibromatous pigmented plaque, and periungual fibromas were treated with the argon laser. Their lesions responded favorably and did not recur during our follow-up period of four to five years.
Asunto(s)
Histiocitoma Fibroso Benigno/cirugía , Terapia por Láser , Neoplasias Cutáneas/cirugía , Esclerosis Tuberosa/cirugía , Adolescente , Adulto , Neoplasias Faciales/cirugía , Femenino , HumanosRESUMEN
Histologic quantitation of the thickness of human tissues that were expanded using silicone expanders showed that the epidermis underwent significant thickening after 5 weeks to 5 months of expansion. The dermis and subcutaneous tissue, on the other hand, were significantly thinner after expansion. Capsules were formed in all 19 patients. The capsule was significantly thickest after 2 to 2.5 months of expansion. Expanded tissues 2 years after cessation of expansion had the same thickness as control tissues and had no remnant fibrous capsule.
Asunto(s)
Tejido Conectivo/anatomía & histología , Prótesis e Implantes , Piel/anatomía & histología , Cirugía Plástica/instrumentación , Adolescente , Adulto , Factores de Edad , Tejido Conectivo/patología , Epidermis/anatomía & histología , Epidermis/patología , Femenino , Fibrosis , Humanos , Masculino , Persona de Mediana Edad , Siliconas , Piel/patología , Factores de TiempoRESUMEN
This study describes the presence of crystalline inclusions in the endothelial cells of foreskins. They were found in 9 normal full-term newborn infants, without maternal medication or complication during pregnancy and delivery. These cytoplasmic crystalloids occurred in 10% of endothelial cells of small blood vessels. The diameter of the inclusions ranged from 0.3 to 1.5 micron and they appeared as round, oval, hexagonal or irregular polygonal in shape. These inclusions were surrounded by a triple membrane and their contents demonstrated granular, homogeneous and crystalloid-like material with a regular periodicity of dense and less dense layers measuring about 20-25 nm. Similar crystalloids in the endothelial cells were observed in the normal upper lip skin of a 6-week-old girl, although they were present in much smaller numbers than in foreskin. No endothelial inclusions were found in normal skin taken from 11 body areas in 29 patients aged 2.5 to 56 years. The nature and function of these cytoplasmic crystalloids are unknown.
Asunto(s)
Endotelio Vascular/ultraestructura , Cuerpos de Inclusión/ultraestructura , Piel/ultraestructura , Adolescente , Adulto , Niño , Preescolar , Cristalización , Endotelio Vascular/patología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Piel/irrigación sanguínea , Piel/patologíaRESUMEN
An unusual case of angiolymphoid hyperplasia with eosinophilia (ALHE) simulating port-wine stain in a 50-year-old woman is reported. The lesions of ALHE are typically papules or subcutaneous masses that range from light pink to red-brown in color. In addition to the usual histologic findings of ALHE, the biopsy in our patient showed some fibrin-like material and fibrous long-spacing collagen on ultrastructural examination. This unusual lesion necessitates biopsy because the differential diagnosis includes port-wine stain, sarcoidosis, lupus erythematosus, and non-Hodgkin lymphoma (mycosis fungoides). Many different forms of treatment have been attempted for ALHE including radiotherapy, cytotoxic chemotherapy, corticosteroids, and antibiotics. The lesions in our patient responded to argon laser therapy and surgical excision, though there has been recurrence on the border of the treated area. Because laser energy is noncumulative in the tissues and effective in removing the lesions, we recommend it as the treatment of choice for these lesions.
Asunto(s)
Hiperplasia Angiolinfoide con Eosinofilia/cirugía , Neoplasias de Cabeza y Cuello/cirugía , Terapia por Láser , Hiperplasia Angiolinfoide con Eosinofilia/patología , Femenino , Neoplasias de Cabeza y Cuello/patología , Humanos , Persona de Mediana EdadRESUMEN
This article describes 2 patients with angiokeratoma circumscriptum for whom the argon laser proved to be a highly successful means of treatment. Both patients had no recurrences of the lesions. Also included is an updated and comprehensive review of the various types of angiokeratoma.
Asunto(s)
Angioqueratoma/cirugía , Enfermedades del Pie/cirugía , Terapia por Láser , Neoplasias Cutáneas/cirugía , Adulto , Angioqueratoma/clasificación , Angioqueratoma/patología , Preescolar , Femenino , Humanos , MusloRESUMEN
Heterotopic brain tissue in the upper lip of a newborn child is presented and discussed. This rare developmental anomaly is usually present at birth and may simulate hemangioma. Before any surgical procedure can be performed, thorough radiographic and neurosurgical examination is essential to rule out eventual communication of the tumor with intracranial space.
Asunto(s)
Encéfalo , Coristoma/patología , Neoplasias de los Labios/patología , Encéfalo/patología , Coristoma/congénito , Humanos , Lactante , Recién Nacido , Neoplasias de los Labios/congénito , MasculinoRESUMEN
In this article the authors summarize statistical data from 19 patients obtained during quantitative analysis of the thickness of expanded skin and soft tissues utilizing silicone expander procedures. Histopathologic and ultrastructural changes that take place in individual levels of expanded tissues are also illustrated.