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A 31-year-old woman developed necrobiotic xanthogranuloma (NXG), a thickened choroid, and syncytial giant cell hepatitis, a previously unreported association. NXG and syncytial giant cell hepatitis may have a common autoimmune pathogenesis.
During early seed development, nuclear divisions in the endosperm are not followed by cell division, leading to the development of a syncytium. The simple organization of the Arabidopsis endosperm provides a model in which to study the regulation of the cell cycle in relation to development. To monitor nuclear divisions, we constructed a HISTONE 2B::YELLOW FLUORESCENT PROTEIN gene fusion (H2B::YFP). To validate its use as a vital marker for chromatin in plants, H2B::YFP was expressed constitutively in Arabidopsis. This enabled the observation of mitoses in living root meristems. H2B::YFP was expressed specifically in Arabidopsis syncytial endosperm by using GAL4 transactivation. Monitoring mitotic activity in living syncytial endosperm showed that the syncytium was organized into three domains in which nuclei divide simultaneously with a specific time course. Each mitotic domain has a distinct spatiotemporal pattern of mitotic CYCLIN B1;1 accumulation. The polar spatial organization of the three mitotic domains suggests interactions between developmental mechanisms and the regulation of the cell cycle.
INTRODUCTION: The mechanisms by which a defibrillation shock directly stimulates regions of cardiac tissue distal to the stimulus electrodes ("far-field" stimulation) are still not well understood. Existing hypotheses have proposed that intercellular discontinuities and/or fiber curvatures induce the requisite membrane polarizations. This article hypothesizes a third potential mechanism: one based on the existence and influences of syncytial (anatomic) heterogeneities inherent throughout the bulk myocardium itself. METHODS AND RESULTS: We simulated the effects of such heterogeneities in a model of a two-dimensional region of passive cardiac tissue subjected to uniform 1 V/cm longitudinal or transverse field stimuli. Heterogeneities were manifested via random spatial variations of intracellular volume fractions (fi) over multiple length scales, with mean fi of 80% and standard deviation of fi (sigma[fi]) ranging from 0% to 10%. During field stimulation, many interspersed and variously shaped and sized islands of hyperpolarization and depolarization developed across the tissue, with their locations and extents correlated to the spatial gradients of the underlying heterogeneities. Increases in sigma(fi) correspondingly increased the shock-induced magnitudes of resulting membrane polarizations. The ratio of maximal polarizations for equivalent longitudinal and transverse shocks approximated 2:1 across all sigma(fi) tested. At sigma(fi) = 5%, these maximal induced polarizations were 17.4 +/- 2.4 mV and 8.18 +/- 1.5 mV, respectively. Assuming an excitation threshold of 25 mV, these data suggest corresponding diastolic thresholds of 1.47 +/- 0.20 V/cm and 3.14 +/- 0.50 V/cm, respectively. CONCLUSION: This study predicts that syncytial heterogeneities inherent within cardiac tissue could represent a significant-and heretofore unappreciated-mechanism underlying field-induced polarizations throughout the bulk myocardium.
Adult syncytial giant cell hepatitis (GCH) is an uncommon and often fulminant form of hepatitis that may be caused by infection with a novel paramyxo-like virus. We present the case of a 69-yr-old man who presented with acute, community-acquired hepatitis and chronic lymphocytic leukemia. A liver biopsy showed the typical findings of panlobular syncytial giant cell hepatitis. Electron microscopic examination demonstrated abundant nucleocapsid-like protein material in the cytoplasm and nuclei of affected hepatocytes. These structures were similar to, but distinct from, those of known paramyxoviridae, suggesting infection with a novel, related virus. In situ hybridization studies with a probe directed against the measles fusion protein gene gave a positive signal with a hepatocyte distribution. No signal was obtained with the measles nucleocapsid protein probe, suggesting that the disease agent was genetically distinct from, but related to, the measles virus. Subsequent liver biopsies were characterized by the gradual disappearance of the giant cell changes and by the concomitant development of cirrhosis. This is a case of adult GCH that resolved spontaneously and led to cirrhosis, thus implicating GCH as a potential cause of "cryptogenic" liver disease. Our findings provide further support for the existence of a distinct, as yet unidentified viral species as a cause of this disease.
We have developed a complementation assay, using transiently transfected COS cells, to facilitate a molecular analysis of the herpes simplex virus type 1 glycoprotein gH. When infected by a gH-null syncytial virus, COS cells expressing wild-type gH generate infectious progeny virions and form a syncytium with neighboring cells. By deletion and point mutagenesis, we have found particular residues in the gH cytoplasmic tail to be essential for generation of a syncytium but apparently dispensable for production of infectious virions. This study emphasizes the different requirements for cell-cell and cell-envelope fusion and demonstrates that changes in the non-syn locus UL22-gH can reverse the syncytial phenotype.
Most spontaneously occurring mutations that cause extensive herpes simplex virus type 1 (HSV-1)-induced cell fusion are single amino acid changes within glycoprotein K (gK). Despite the strong genetic association of gK with virus-induced cell fusion, its direct involvement in cellular membrane fusion has been controversial, largely due to previously unsuccessful efforts to detect gK expression on virion and cellular surfaces. Recently, we showed that gK is expressed on HSV-1 virions and functioned in virus entry (T. P. Foster, G. V. Rybachuk, and K. G. Kousoulas, J. Virol. 75:12431-12438, 2001). To determine whether gK is expressed on cellular surfaces, as well as its membrane topology, we generated the recombinant viruses gKV5DI, gKV5DII, gKV5DIII, and gKV5DIVcontaining insertions of the V5 antigenic epitope within each of four domains of gK predicted to localize either in the cytoplasmic side or in the extracytoplasmic side of cellular membranes. Immunohistochemical and confocal microscopy analyses of infected cells showed that both wild-type and syncytial forms of gK were expressed on cell surfaces. Analysis of the topology of the V5-tagged gK revealed that gK domains I and IV were located extracellularly, whereas domains II and III were localized intracellularly. Transiently expressed gK failed to localize in cellular plasma membranes. In contrast, infection of gK-transfected cells with the gK-null virus DeltagK enabled expression of gK on cell surfaces, as well as gK-mediated membrane fusion. Transient-coexpression experiments revealed that the UL20 protein enabled cell surface expression of gK, but not gK-mediated cell-to-cell fusion, indicating that additional viral proteins are required for expression of the gK syncytial phenotype.
One hundred endometrial biopsies of various histological patterns, and material from 10 tubal pregnancies together with their associated uterine decidua, were examined for the presence of human placental lactogen using affinity-purified first and second antibodies and an indirect immunoperoxidase technique. Positive cells in endometrial curettings were seen only in association with an intrauterine pregnancy and morphologically resembled syncytiotrophoblast. Decidua associated with tubal pregnancy, pseudodecidua in progestogen-treated patients, and proliferative, secretory, and basal endometria were all negative. An immunoperoxidase stain for human placental lactogen is a useful marker for intrauterine pregnancy and supports the placental origin of the syncytial giant cells in so-called 'syncytial endometritis'. The technique is of potential value in those endometrial biopsies where pregnancy is suspected but no villi are seen.
Formation of the Drosophila embryo's dorsal-ventral pattern requires the maternal product of the Toll gene. DNA sequence and genetic analyses together suggested that the Toll gene product is a transmembrane protein which communicates information from an extracytoplasmic compartment to the cytoplasm. Using antibodies as probes, we show that the Toll protein is a 135 x 10(3) Mr glycoprotein which is tightly associated with embryonic membranes. During the syncytial stage when dorsal-ventral polarity is established, the maternal Toll protein is associated with the plasma membrane around the entire embryo. During later embryonic stages, the Toll protein is expressed zygotically on many cell surfaces, possibly to promote cell adhesion. The plasma membrane localization of the Toll protein in the syncytial embryo suggests that transmembrane signaling from the extracellular perivitelline space to the cytoplasm is required for establishment of the embryonic dorsal-ventral pattern.
Cytoplasmic organization, nuclear migration, and nuclear division in the early syncytial Drosophila embryo are all modulated by the cytoskeleton. In an attempt to identify genes involved in cytoskeletal functions, we have examined a collection of maternal-effect lethal mutations induced by single P-element transposition for those that cause defects in nuclear movement, organization, or morphology during the syncytial embryonic divisions. We describe three mutations, grapes, scrambled, and nuclear-fallout, which define three previously uncharacterized genes. Females homozygous for these mutations produce embryos that exhibit extensive mitotic division errors only after the nuclei migrate to the surface. Analysis of the microfilament and microtubule organization in embryos derived from these newly identified mutations reveal disruptions in the cortical cytoskeleton. Each of the three mutations disrupts the actin-based pseudocleavage furrows and the cellularization furrows in a distinct fashion. In addition to identifying new genes involved in cytoskeletal organization, these mutations provide insights into cytoskeletal function during early Drosophila embryogenesis.
The syncytial epithelium of parasitic flatworms offers the opportunity to examine epithelial transport physiology in the absence of paracellular pathways. The asymmetric enzymatic and permeability properties of the apical and basal membranes confirm the transepithelial transport function of the syncytial epithelium. Although the absence of a paracellular pathway has led to the suggestion that the syncytium is a 'tight' epithelium, which would be consistent with its low osmotic and diffusive water permeability, the ion transport mechanisms in the apical membrane are more consistent with those predominating in 'leaky' epithelia. Contrary to that expected of an animal covered with a 'tight' epithelium, the parasitic flatworms are not good ion regulators. The apical membrane contains a Cl-:Na+ co-transport occurs by an active H+ extrusion mechanism, a large part of H+ secretion is coupled to Na+ influx as in 'leaky' will have to await electrical potential profile determinations which are made difficult by the electrical coupling of the syncytium to the underlying nerve-muscle syncytium.
We report the case history of a 31-year old woman with a rare morphologic form of nodular sclerosing Hodgkin disease (NSHD) termed "syncytial variant." Its histologic features mimic metastatic carcinoma, thymoma, melanoma, non-Hodgkin lymphoma and germ-cell tumor. Antigens expressed on Reed-Sternberg cells, the hallmark of Hodgkin disease, and other neoplastic cells were screened to determine the correct diagnosis. This patient demonstrates the importance of using specific immunohistochemical techniques to clarify the diagnosis of NSHD of the "syncytial variant" subtype.
We have investigated the centrosome cycle in Drosophila syncytial embryos at the ultrastructural level by using a transmission electron microscope equipped with an electron energy filtering device (Omega filter). This new technique allows the study of uncontrasted thick sections with a high resolution. We have been able to characterize two classes of filamentous structures in the centrosomal apparatus that were not detectable on ultrathin sections. These new filamentous structures are: 1) a very orderly lattice that connects the two centrioles during mitosis; and 2) a fibrogranular connection between the centrosome and the nuclear envelope. The intercentriolar linkage could be involved in the precise timing of separation of the centrioles during late anaphase. The centrosome-nuclear envelope connection probably prevents the loss of centrosomes in this syncytial environment, and ensures the proper migration of the centrosomes along the surface of the nucleus. This connection may also couple the nuclei to the cytoskeleton, thus allowing their migration and their anchorage to the cortex at the blastoderm stage. This thick section analysis has also allowed us to precisely reconstitute the centrosome cycle. From their separation at telophase and throughout most of interphase, centrosomes are composed of a single centriole. We conclude that in the early Drosophila embryo there is an unusual delay between the separation of the parent centrioles and their duplication. This leaves a surprisingly short time to assemble a daughter centriole.
Conditionally replicating (oncolytic) viruses, which selectively replicate in tumor cells but not in normal cells, show great promise as antitumor agents for cancer therapy. The principal antitumor activity of these viruses derives from their replication within tumor cells, which results in cell destruction and the production of progeny virions that can spread to adjacent tumor cells. However, one potential limitation of this approach is that viral gene deletions conferring tumor selectivity also result frequently in reduced potency of the virus in tumors. Therefore, strategies designed to enhance the potency of current oncolytic viruses will likely increase their chance of clinical success. Here we report the construction of an oncolytic herpes simplex virus (HSV) of which the infection also causes strong cell membrane fusion (syncytial formation). In vitro characterization on a variety of human tumor cells of different tissue origins showed that the plaques from this virus (Fu-10) are phenotypically unique and are significantly larger than those from the parental G207 virus, a well-characterized oncolytic HSV lacking fusogenic function. Furthermore, the syncytial formation caused by this virus depended on HSV replication, indicating that cell membrane fusion will only occur in dividing cells (such as tumor cells) where the virus can undergo a full infection cycle but not in normal cells where the viral replication is restricted. Systemic administration of Fu-10 into mice with established lung metastatic breast cancer resulted in a dramatic therapeutic effect. These studies demonstrate that incorporation of fusogenic function into an oncolytic virus can significantly increase the potency of viral oncolysis; this may lead to an enhanced clinical performance, especially in late-stage cancer patients.
Part X of this review is devoted to the remaining pathologico-anatomic patterns which are associated with regressive alterations. Increased syncytial proliferation is the most important aspect within that complex, since it may be a consequence of intervillous and intravillous hypoxia and may thus provide a clue to effects of that kind. Placental calcification may be subdivided by two major groups. The first is relating to "dystrophic" calcification following the same rules in the placenta as it does in other places, in other words, it is calcification of necrotic tissue portions or acidotic areas of decreased circulation. Calcification may just as well occur to particular structures of the placenta, such as the epithelial basal membrane, syncytial proliferations or in walls of vessels. Placental cysts usually are localized at the placental base (in septa), their development being owed to hypoxic events during ontogenesis. They actually are pseudocysts. Placental icterus (along with severe maternal icterus) is macroscopically identifiable with unambiguity. The biliary pigment, histologically, is localized in HOFBAUER cells. Additional reference is made to melanin deposits (in concomitance with congenital giant naevus) and placental alterations in conjunction with rare metabolic disorders.
Cocultivation of equal numbers of cells from a fetal lamb kidney line infected with bovine leukemia virus and African green monkey (Vero) cells results in the rapid production of syncytia. The effect was blocked or inhibited by serum containing antibodies to bovine leukemia virus. A serological test based on syncytial inhibition was compared to the agar gel immunodiffusion test and the modified direct complement fixation test for the detection of bovine leukemia virus antibodies in sera from leukosis-free cattle, cases of adult enzootic bovine lymphosarcoma and cattle from herds in contact with enzootic lymphosarcoma. The results showed the syncytial inhibition test to react positively with sera from all cases of adult enzootic lymphosarcoma, but to be much less sensitive than the other tests in detecting bovine leukemia virus antibodies in sera of exposed animals.
The villous syncytium of the placenta of the macaque was found to contain channel-like formations bounded by syncytial membrane. They were present in placental specimens obtained from rhesus monkeys at periods of gestation varying from 90 to 164 days and were identifiable only by electron microscopy. These syncytial channels communicated with the intervillous space but were quite distinct from junctional complexes described in the syncytium of human placental villi. They appeared to be extensions of the intervillous space whereby areas of the syncytium would come in contact with maternal plasma flowing at a greatly reduced rate. Features of these channels, of their bounding membrane and of the adjacent cytoplasm, could point to a phenomenon of regional specialisation in the syncytiotrophoblast.
Glycoproteins of the herpes simplex virus type 1 (HSV-1) non-syncytial strain Kupka showed two times higher affinity for the Helix pomatia (HP) lectin than glycoproteins of the syncytial strain HSZP. As revealed by the results of immunoprecipitation test and by the comparison of the synthesis of virus glycoproteins, glycoprotein C (gC) was synthesized in sufficient amounts in the HSZP strain-infected cells. The difference in the binding to HP lectin was found to be caused by decreased affinity of gC of the strain HSZP for HP lectin. The decreased affinity for HP lectin was brought about by lower proportion of O-linked oligosaccharides in the gC molecule. The glycoproteins of either HSV-1 strain under study synthesized in BHK cells displayed higher affinity for HP lectin than those synthesized in VERO cells.
The authors studied by means of sterological methods the volume density of syncytial sprouts in different cotyledonary regions of the human term placenta. The syncytial sprouts account for 4.92% of the placenta volume. Meanwhile, there were significant differences according to the site from which the sample was obtained. The lowest value (2.72%) corresponds to the central-parabasal zone of the cotyledon, close to the entry of the maternal blood into the intervillous space, whereas the highest values correspond to the "venous" regions. The results of the present study, as well as those reported by others, suggest that the lateral-subchorial zone would be the growing region of the cotyledon.