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Host spatial heterogeneity and the spread of vector-borne infection.

We analyze how spatial heterogeneity in host density affects the advance of vector-borne disease. Infection requires vector infestation. The vector spreads only between hosts occupying the same neighborhood, and the number of hosts varies randomly among neighborhoods. Simulation of a spatially detailed model shows that increasing heterogeneity in host abundance reduces pathogen prevalence. Clumping of hosts can limit the advance of the vector, which inhibits the spread of infection indirectly. Clumping can also increase the chance that the pathogen and vector become physically separated during the initial phase of the epidemic process. The latter limitation on the pathogen's spread, in our simulations, is restricted to small interaction neighborhoods. A mean-field model, which does not maintain spatial correlations between sites, approximates simulation results when hosts are arrayed uniformly, but overestimates infection prevalence when hosts are aggregated. A pair approximation, which includes some of the simulation model's spatial correlations, better describes the vector infestation frequencies across host spatial dispersions.

Analysis of Variance↗

Spike glycoprotein-mediated fusion in biliary glycoprotein-independent cell-associated spread of mouse hepatitis virus infection.

The mouse hepatitis virus (MHV) spike glycoprotein mediates attachment of the virus to the MHV receptor, the murine biliary glycoprotein (BGP) carcinoembryonic antigen. Monoclonal antibody CC1 directed against BGP specifically inhibited infection of DBT, Sac-, GT1-7, and OBL21 cells by wild-type MHV-4 and the neuron-adapted variant OBLV60. Binding to this receptor was necessary to establish infection by cell-free MHV; however, the presence of BGP was not required for infection by cell-associated virus. Cell-associated infectious induced syncytium formation on Vero and BHK cells, which lack murine BGP; this activity was not inhibited by monoclonal antibody CC1. Antibody CC1 also did not prevent syncytium formation on DBT cells, which bear BGP. In infectious center assays, the MHV-4 variant OBLV60, which exhibits acid-dependent fusion, spread to cells lacking BGP only when exposed to acidic media. Therefore, spike-mediated fusion was required for BGP-independent spread of MHV infection. Furthermore, BGP-independent, cell-associated spread of MHV-4 was prevented by monoclonal antibodies 5A13.5 and 5B19.2 directed against the spike glycoprotein, but not by other neutralizing and nonneutralizing anti-spike antibodies. Expression of spike glycoprotein by recombinant vaccinia virus resulted in fusion of BGP-negative cells; monoclonal antibodies 5A13.5 and 5B19.2 strongly inhibited spike-mediated fusion in this assay.

Animals↗

Pathway of viral spread in herpes zoster: detection of the protein encoded by open reading frame 63 of varicella-zoster virus in biopsy specimens.

Reactivation of varicella-zoster virus (VZV) in the dorsal root or trigeminal ganglia causes herpes zoster. The pathway of viral spread from the ganglia to the skin and also within the skin is not yet completely understood. Histological studies have revealed that each skin lesion in herpes zoster progresses sequentially through the stages of erythema, vesicles, pustules and finally ulceration. An immunohistochemical study of the early skin lesions of herpes zoster demonstrated a high incidence of hair follicle involvement and the main localization of the virus at the isthmus. This evidence suggests that VZV initially spreads from the ganglia through myelinated nerves, which predominantly end around the isthmus of hair follicles. To further investigate the viral spread within the skin, we analyzed the sequential appearance of the immediate early proteins encoded by ORF 63 of VZV (IE63), using an anti-IE63 antibody raised by immunization of rabbits with a recombinant protein. This antibody could detect IE63 in a western blot analysis of infected cells and also in immunohistochemical analysis of the skin lesions of herpes zoster. IE63 initially appeared in the nuclei of the follicular epithelial cells and basal or parabasal epidermal cells. Later, the nuclei and cytoplasm of cells in the epidermis and hair follicles became positive. IE63 remained in the virus-infected cells even during their degeneration. When we examined the hair follicles in the early erythematous lesions, cells positive for IE63 were predominantly distributed around the isthmus. In addition, some lymphocytes around the blood vessels were also positive for IE63, but these cells were seldom positive for the structural antigen. Thus, these observations suggest that VZV arriving through myelinated nerves infects not only permissive cells, but also non-permissive cells in the involved skin of herpes zoster.

Animals↗

Wide-spread myelinated nerve fibers of the optic disc: do they influence the development of myopia?

PURPOSE: To find correlations between the extent of myelinated nerve fibers with refraction anomalies. METHOD: Searching for myelinated nerve fibers in the slide collection of the University Eye Hospital Freiburg we found 13 patients. We distinguished between eyes with wide-spread myelinated nerve fibers located on and around the optic disc which extended to the midperiphery of the retina (6 patients; Group A) and eyes with circumscribed myelinated nerve fibers, localized merely around the optic disc (7 patients, Group B). In Group A myelinated nerve fibers spared the macula area, but were localized very close to the macula. Color fundus photographs were taken by the Zeiss Fundus camera SK50 (30 degrees and 50 degrees picture size) and by the Olympus Fundus camera GRC-W (same picture size). RESULTS: The myelinated nerve fibers were found to be unilateral in all 13 patients. In all 6 patients of Group A, a strabismus was present. The affected eye had a severe amblyopia and a unilateral myopia (-5.75 to -25.0 D). The nonaffected fellow eye showed a normal visual acuity with no or only a slight refractive error. In the 7 patients of the Group B, no strabismus was present and a normal or a slightly decreased visual acuity of the affected eye was found. No distinct refractive error was present in the affected and non-affected eyes of this group. CONCLUSIONS: Myopia only occurred in eyes with wide-spread myelinated nerve fibers but not in eyes with circumscribed myelinated nerve fibers. We assume that myelinated nerve fibers, if wide-spread, cause myopia.

Adolescent↗

Antisense inhibition of urokinase reduces spread of human ovarian cancer in mice.

Urokinase-type plasminogen activator (uPA) is a protease involved in the process of tissue remodelling and cell migration in vitro. To explore whether uPA is a prerequisite for human ovarian cancer spread in vivo the expression of uPA was suppressed in human ovarian cancer cells by antisense phosphorothioate oligonucleotides (PS-ODN). The suppression of uPA expression was dependent on PS-ODN concentration and only observed in the presence of liposomes. This phenomenon seemed to be due to the fact that PS-ODNs were taken up by the cancer cells only in concert with liposomes as studied by fluorescently-labeled PS-ODNs using flow cytofluorometry and laser scanning microscopy. uPA-deprived cancer cells exhibited a significantly reduced invasive capacity in vitro compared with untreated cancer cells or cells treated with control PS-ODNs (P = 0.003). The intraperitoneal spread of the cancer cells in vivo was significantly diminished when nude mice were treated with uPA antisense PS-ODNs in comparison with control mice (P = 0.009). These results suggest that uPA expression may be required for spread of human ovarian cancer and that its inhibition could provide a therapeutic approach.

Animals↗

Wound healing in the cornea of the chick embryo. V. An observation and quantitative assessment of the cell shapes in the isolated corneal epithelium during spreading in vitro.

Spatio-temporal changes in the shapes of the epithelial cells in culture were followed with the aid of scanning electron microscopy. On a substratum that enables the epithelium to spread extensively, the first remarkable change in shapes of the cells occurred at the margin of epithelium at 12 h of culture. The marginal cells formed leading edges with filo- or lamellipodia, flattened, and lost microvilli on surface. In accordance with those changes, the borderlines among cells became almost indiscrenible. Flattening of the cells was the essential characteristic associated with active epithelial spreading throughout the culture period. Elongation of cells of intermediate zone at right angles to the direction of the locomotion of the marginal cells at 24 h of culture was the second significant change. As the third, the change from the ordinary pentagonal or hexagonal to extraordinary tetragonal or other polygonal shapes, with or without irregular margins, began in cells of the intermediate area at 24 h and propagated to those in inner area. The active deformation of the inner cells with no space in which to move was considered to play some role in the extensive epithelial spreading.

Animals↗

Vimentin filaments in spreading, randomly locomoting, and f-met-leu-phe-treated neutrophils.

Human neutrophils contain intermediate filaments of the vimentin type. A cytoskeletal preparation, produced by high-salt and Triton X-100 extraction of human neutrophils, reveals a major band at 57000 Mr that comigrates with 3T3 cell vimentin on one-dimensional gels. Two-dimensional gel electrophoresis of whole neutrophils illustrates the presence of vimentin but not desmin- or keratin-filament subunits. The presence of vimentin in neutrophils is also shown by its specific staining with avian vimentin antiserum by two-dimensional gel immunoautoradiography. Indirect immunofluorescence studies show that vimentin antiserum labels an area on one side of the nucleus in spreading neutrophils. This bright area appears as a loose knot of vimentin filaments; a few filaments may radiate from the knot. In contrast to spreading neutrophils, those undergoing random locomotion contain a fine network of filaments that are located in the cytoplasm between the nucleus and the trailing end of the cell. Similarly, in chemoattractant-treated neutrophils, vimentin filaments are bundled in the uropod. Transmission electron microscopy of human neutrophil monolayers confirms the intracellular distribution of intermediate filaments as shown by immunofluorescence in spreading and randomly locomoting cells.

Autoradiography↗

Importance of different CD44v6 expression in human gastric intestinal and diffuse type cancers for metastatic lymphogenic spreading.

In 42 human gastric adenocarcinomas of intestinal (n = 25) and diffuse types (n = 17) the expression of CD44v6 splice variants was investigated immunohistochemically and compared with the pattern of lymphogenic tumor spreading. Distinct differences were observed between the two cancer types: 92% of intestinal-type tumors expressed CD44v6 as in the intestinal metaplasia in chronic atrophic gastritis, while v6 expression occurred in only 17% of diffuse-type cancers. The analysis of RNA expression confirmed the immunohistochemical data. Intestinal-type cancers yielded a much more complex pattern of amplification products hybridizing to exon v6 than did normal mucosa, whereas diffuse-type tumors did not express exon v6. Also the pattern of lymphogenic spreading was quite different between the two cancer types: in diffuse-type tumors only a sinus carcinosis without CD44v6 expression was observed in a significantly higher number of lymph nodes than in intestinal-type cancers, which showed in particular infiltrative lymph node metastases always with CD44v6 expression as in the primary tumors. When infiltrative lymph node invasion occurred in v6-negative diffuse-type cancers, v6 neoexpression was also demonstrable in the lymph node metastases. Additionally, the number of infiltrative lymphogenic metastases increased with more extensive v6 expression in primary gastric cancers of both types. These data suggest that the expression of CD44v6 isoform is important for the infiltrative spreading of tumor cells into lymph nodes. Additionally, the phenotypic similarities in v6 expression between intestinal metaplasia and intestinal-type cancers, but not of tumors of diffuse type, may support the Correa hypothesis.

Adenocarcinoma↗

Spreading synaptonemal complexes from Zea mays. I. No synaptic adjustment of inversion loops during pachytene.

Four different inversion heterozygotes of maize were examined for the occurrence of synaptic adjustment. Three substages of pachytene were identified in synaptonemal complex (SC) spreads using side-by-side comparisons of chromosome squashes with two-dimensional spreads of SCs. In SC spreads, inversion loop frequency did not change substantially from early through late pachytene for any of the four inversion heterozygotes examined. In addition, the position and size of the inversion loops remained essentially constant throughout pachytene. These results indicate that synaptic adjustment of inversion loops does not occur during pachytene in Zea mays.

Heterozygote↗

Investigation of the "variable spreading" of X inactivation into a translocated autosome.

A new case of an unbalanced X/autosome translocation, karyotype 46,X,der(X),t(X:14)(q22;q11), is described. The derivative X chromosome was inactivated and showed various degrees of incomplete spreading of late replication into the translocated autosome. This enabled us to test the hypothesis that the extent of this spreading is primarily determined during X inactivation in the early embryo so that the various DNA replication patterns of the derivative X occur in a clonal fashion. However a dilution plating experiment gave no evidence that such a clonality exists. In the inactivated autosome, late-replicating bands obviously turned to earlier replication during cell aging in vitro. It is suggested that the degree of spreading of X inactivation into an autosome is not primarily induced but results from ineffective maintenance of the inactivation on the autosome, presumably due to an irreversible loss of methyl cytosine.

Chromosome Banding↗

Spread of herpes simplex virus to the cerebrospinal fluid and the meninges in experimental mouse encephalitis.

The development of the inflammatory response within the brain, meninges and cerebrospinal fluid (CSF) compartment has been studied for the first time simultaneously in experimental herpes simplex virus (HSV) encephalitis after inoculation via the cornea. Two major viral pathways were found from the eye to the brain: one through the trigeminal nerve to the brain stem and one through the nasolacrimal duct to the olfactory system. Viral antigen was found to be present in the CNS before there were clinical signs or cellular infiltration of brain tissue. Subsequently, the virus spread to all parts of the trigeminal brain stem complex. This phenomenon was accompanied by severe inflammation of the meninges covering the trigeminal root near its entry into the brain stem. The meninges near the entry of the olfactory fila also contained antigen. However, HSV-1 did not spread along meningeal rami of the trigeminal nerve and, consequently, is--at least in this experimental model--not a route to reach the inferior frontal and temporal lobes. The development of CSF changes followed the histopathological development of meningitis and encephalitis closely. HSV-DNA could be detected in the CSF from day 4 post inoculation (p.i.) and HSV-1-specific immunofluorescence in CSF cells was convincingly present on day 5 p.i.; on the same days (4 and 5 p.i.) inflammatory cells were found in apposition to infected cells in the brain. We postulate that HSV is carried to the CSF by infected leukocytes rather than a direct spread to the CSF by simple extension of the encephalitic process to the meningeal surface.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Mechanism of liver-specific metastatic tumor spread in a murine tumor model.

Malignant tumors frequently show an organ-specific metastatic spread, the causes of which are still largely unknown. Using an experimental tumor model, a methylcholanthrene-induced pleomorphic myofibrosarcoma ER 15-P of the C57Bl6J mouse, we wanted to find out whether this phenomenon is due to an adaptation or to a selection of tumor cells. After i.v. injection of tumor cells from the primary ER 15-P into the tail vein of male mice, metastases were regularly found in the lungs, mediastinal lymph nodes, and brain, as well as in the liver and kidneys, and occasionally in the adrenals. The following experimental procedures were used to isolate a tumor cell line with a possible liver preference: (1) Tumor cells from the primary ER 15-P were injected into a mesenteric vein of male mice. Tumor cells from the resulting liver colonies were again injected into the portal system of one group of mice. In a second group, part of the same cell suspension was injected into the tail vein. This procedure was performed four times. (2) Tumor cells from the primary ER 15-P were applied into the tail vein of male mice. Tumor cells from the resulting liver metastases were reinjected directly into the tail vein. This experiment was repeated three times. (3) Tumor cells from the primary ER 15-P were injected into the tail vein of male mice. Tumor cells from liver metastases were then injected, first, into the portal system of one group of male mice, and thereafter into the tail vein of another group of animals. This experiment was repeated twice. The following results were obtained: (1) By a repeated adaptation of tumor cells from the primary ER 15-P to liver tissue, no tumor cell line could be isolated that would show a preferential metastatic spread to this organ after tail-vein injection. (2) Repeated i.v. passages of tumor cells from liver metastases into the tail vein led to the selection of a tumor cell line with a tendency to liver metastasis. (3) Tumor cells selected from liver metastases induced via tail-vein injection showed, after a prolonged stay in the liver and a successive i.v. passage into the tail vein, a marked specificity for this organ. These results indicate that the liver-specific spread of tumor cells in our model is based on the selection of a tumor cell line from the primary ER 15-P influenced by the hepatic microenvironment.

Animals↗

The spreading of focal brain edema induced by ultraviolet irradiation.

Focal brain edema limited to one cerebral hemisphere was produced by ultraviolet irradiation of the exposed cortex. Tissue water content was determined by the gravimetric method which allows microsampling. Therefore, the spread of edema around the small necrotic area could be mapped more precisely than by determination of dry weight which calls for larger samples. As early as 30 min following irradiation, hyperemia and swelling of the brain are observed under the operating microscope. This correlates with venous stasis, hyperemia, and broadened perivascular spaces around venules and large capillaries accompanied by a marked rise in the specific weight of the tissue. After 4 h an edema front can be observed spreading from the perinecrotic zone in which there is a marked rise in endothelial cell vesicular activity. Edema reaches maximum levels in the deep white matter at 48 h post irradiation with normalisation of the tissue water content after 96 h. The velocity at which the edema front spreads from the cortex to the periventricular area lies in the range of 0.25 mm/hr. Edema reabsorption coincides with signs of retrograde micropinocytosis in endothelial cells.

Animals↗

Brewster angle microscopy. A new method of visualizing the spreading of Meibomian lipids.

The spreading behaviour of the Meibomian lipids is important for the integrity of the whole tear film. This paper presents the application of Brewster Angle Microscopy (BAM) for the observation of the spreading process in vitro. Meibomian gland secretions were studied in a Langmuir trough. The secretion was characterized by an extremely rapid continuous spreading, suggesting that enough material would be available to recover the superficial lipid layer of the tears between the blinks of the eye. This new technique provides important information on how the normal tear film works and how tear substitutes might act.

Humans↗

Herpes simplex virus infection of isolated autonomic neurons in culture: viral replication and spread in a neuronal network.

Cultures of isolated neurons, derived from the superior cervical ganglion (SCG) of the newborn rat and maintained in the absence of nonneuronal cells, were infected with herpes simplex virus (HSV) type 1. By phase-contrast microscopy, including time-lapse cinematography, cytopathologic changes appeared first in neuronal cell bodies and only approximately 24 hours later were axonal abnormalities detectable. Despite low yields of viral progeny, infection spread readily within the two-dimensional network of neurons and their processes. Immunoperoxidase staining for viral antigens confirmed the replication and spread of virus and revealed that antigen extended along axons during infection. Antiviral antibody added to the overlay medium slowed but did not prevent the spread of infection, indicating that virus passed from neuron to neuron over axonal pathways. Despite alteration of neuronal macromolecular synthesis early in infection, axonal transport is apparently preserved long enough to allow propagation of virus over interconnecting neural pathways.

Animals↗

Trans fatty acid contents in spreads and cold cuts usually consumed by children.

A high intake of trans fatty acids in children may be disadvantageous because of untoward effects on lipoprotein metabolism and a possible impairment of arachidonic acid synthesis. We measured the trans fatty acid content of different brands of spreads and cold cuts typically consumed by German children because these foods may contribute a considerable portion of total trans fatty acid intake. The highest trans fatty acid contents were found in regular margarines (4.5, 0.0-10.6; median %-wt/wt of fatty acids, minimal-maximal), chocolate spreads (5.5, 0.7-11.1), butter (4.7, 3.7-5.2) and cheese (3.6, 1.8-4.0), while lower values were present in diet margarines (0.2, 0.0-0.4), vegetarian spreads (0.2, 0.1-0.4), peanut butter (0.0, 0.0-0.3) and sausages (1.7, 0.6-6.4). Calculations of typical dietary plans for young children show that food selection and variations in trans fatty acid contents may lead to marked differences in daily trans intake of > 100% (3.1 g/d vs. 1.5 g/d). We propose that trans fatty acid content should be declared on labels of fatty food products to enable the consumer to choose, and further attempts should be made to lower trans fatty acid formation during technical hydrogenation.

Animals↗

Imaging the direct bidirectional spread of disease between the abdomen and the female pelvis via the subperitoneal space.

This report expands the concept of the subperitoneal space (SS) as the potential conduit for direct spread of disease in the abdomen to include the female pelvis. The normal anatomy of the SS in the lower abdomen, the female pelvis, and its uninterrupted continuation between the abdomen and pelvis are demonstrated by several imaging modalities. Surgically proven cases of bidirectional spread of disease between the abdomen and female pelvis are reported. The unifying concept of the interrelationship formed by the SS provides an understanding of the basic concepts of the pathways of direct spread of disease and the pathogenesis of the clinical presentation of disease distant from its site of origin.

Abdomen↗

Secondary involvement of the transverse colon by tumors of the pelvis: spread of malignancies along the greater omentum.

Based on selected case studies the pathways of spread of malignancies arising from the pelvis are discussed. Secondary involvement of the transverse colon with characteristic lesions at the inferior border may be seen in these cases, caused by metastatic spread via the greater omentum. Ultrasonography and computed tomography may prove this diagnosis by showing peritoneal metastatic spread and tumorous infiltration of the greater omentum.

Barium Sulfate↗