Biomedical subjects

P M Hofman

Publications and source records attributed to P M Hofman.

5 recordsLinked to original sources

PubMed2000

Ultrastructure of the polymorphonuclear leucocytes in human immunodeficiency virus infection.

The ultrastructure of polymorphonuclear leucocytes (PMNL) was studied in 16 patients infected with the human immunodeficiency virus (HIV). PMNL were isolated from HIV-infected patients with CD4+ lymphocytes counts > 200/mm3 (without signs of active infection) (n = 12) (group 1), or < 200/mm3 (n = 4) (group 2), and from 16 healthy volunteers (group 3). Immunoelectron microscopy staining using an anti-beta 2 integrin antibody (anti-CD18) was performed on PMNL from three individuals of group 2 and of three individuals of group 3, before and after incubation with N-formyl-methionyl-leucylphenylalanine (f-MLP). The radical oxygen intermediates (ROI) production of PMNL was investigated by luminol-mediated chemiluminescence. A number of ultrastructural abnormalities in PMNL were found in a higher proportion in HIV-infected patients. These were: (a) an increase in the size of the Golgi apparatus and in the number of mitochondria, and in the quantity of endoplasmic reticulum; (b) some dysplastic features including large cytoplamic vacuoles, whorl of myelin, and nuclear pockets; (c) an increase prevalence of multivesicular bodies compared with control PMNL; (d) some cylindrical confronting cisternae and tubuloreticular structures. After anti-CD18 staining, gold particles were seen on the plasma membrane and more rarely inside the cytoplasm of PMNL from each group but no decrease in this staining was noted in HIV PMNL. Incubation with f-MLP similarly increased the immunostaining of the PMNL in each group. In vitro ROI production was significantly depressed for HIV PMNL compared with control PMNL. Some ultrastructural abnormalities observed in this study could support the possibility that one of the mechanisms underlying the qualitative functional defects of PMNL from HIV-infected patients may be related to some cytopathic effect.

Acquired Immunodeficiency Syndrome↗

PubMed1998

Relearning sound localization with new ears.

Because the inner ear is not organized spatially, sound localization relies on the neural processing of implicit acoustic cues. To determine a sound's position, the brain must learn and calibrate these cues, using accurate spatial feedback from other sensorimotor systems. Experimental evidence for such a system has been demonstrated in barn owls, but not in humans. Here, we demonstrate the existence of ongoing spatial calibration in the adult human auditory system. The spectral elevation cues of human subjects were disrupted by modifying their outer ears (pinnae) with molds. Although localization of sound elevation was dramatically degraded immediately after the modification, accurate performance was steadily reacquired. Interestingly, learning the new spectral cues did not interfere with the neural representation of the original cues, as subjects could localize sounds with both normal and modified pinnae.

Adaptation, Physiological↗

PubMed1998

Spectro-temporal factors in two-dimensional human sound localization.

This paper describes the effect of spectro-temporal factors on human sound localization performance in two dimensions (2D). Subjects responded with saccadic eye movements to acoustic stimuli presented in the frontal hemisphere. Both the horizontal (azimuth) and vertical (elevation) stimulus location were varied randomly. Three types of stimuli were used, having different spectro-temporal patterns, but identically shaped broadband averaged power spectra: noise bursts, frequency-modulated tones, and trains of short noise bursts. In all subjects, the elevation components of the saccadic responses varied systematically with the different temporal parameters, whereas the azimuth response components remained equally accurate for all stimulus conditions. The data show that the auditory system does not calculate a final elevation estimate from a long-term (order 100 ms) integration of sensory input. Instead, the results suggest that the auditory system may apply a "multiple-look" strategy in which the final estimate is calculated from consecutive short-term (order few ms) estimates. These findings are incorporated in a conceptual model that accounts for the data and proposes a scheme for the temporal processing of spectral sensory information into a dynamic estimate of sound elevation.

Adult↗

PubMed1997

Unmasking of intestinal epithelial lateral membrane beta1 integrin consequent to transepithelial neutrophil migration in vitro facilitates inv-mediated invasion by Yersinia pseudotuberculosis.

Idiopathic intestinal disease states characterized by active inflammation associated with transepithelial migration of neutrophils may, paradoxically, be associated with an increased risk of infection by enteric pathogens. Although the specific ligands with which various intestinal pathogens associate remain largely unknown, it is thought that many reside on the basolateral membrane. For example, beta1 integrin, a basolateral membrane protein, mediates the specific interaction between epithelial cells and the inv gene product (invasin) on the surface of Yersinia pseudotuberculosis. Our observations indicate that neutrophil migration across model T84 cell intestinal epithelia produced transient separation of epithelial cells at sites of neutrophil migration, resulting in microdiscontinuities that remained unsealed for several hours. We hypothesized that such sites of microdiscontinuities would yield a potential route for luminal pathogens to gain access to basolateral ligands and, thus, provide a window of risk for enteric infection. The surface biotinylation and fluorescence localization studies reported here revealed that, as in natural intestinal epithelia, beta1 integrin was strictly polarized to the basolateral membrane in confluent T84 monolayers. However, the transient microdiscontinuities resulting from neutrophil migration permitted access to beta1 integrin from the apical reservoir. Coincident with such basolateral exposure of beta1 integrin, monolayers became susceptible to invasion by Y. pseudotuberculosis. Fluorescence localization indicated that Y. pseudotuberculosis selectively associated with monolayers at sites where small discontinuities resulting from neutrophil transmigration were found. An increased risk for Y. pseudotuberculosis infection was specifically related to exposure of beta1 integrin (normally concealed by tight junctions) to the apical compartment, as Y. pseudotuberculosis cells lacking the inv gene were unable to invade following neutrophil transepithelial migration. Following closure of the microdiscontinuities associated with neutrophil migration, a small pool of beta1 integrin remained apically localized, presumably due to incomplete repolarization. However, this small apical pool of beta1 integrin was insufficient to support a detectable increased risk of Yersinia infection. Together, these observations indicate that by transiently perturbing monolayer continuity, neutrophil transepithelial migration is associated with a window of risk in which luminal pathogens can access basolateral ligands such as beta1 integrin.

Adhesins, Bacterial↗

PubMed1995

Surface attachment of Salmonella typhimurium to intestinal epithelia imprints the subepithelial matrix with gradients chemotactic for neutrophils.

During intestinal disease induced by Salmonella typhimurium transepithelial migration of neutrophils (PMN) rapidly follows attachment of the bacteria to the epithelial apical membrane. Among the events stimulated by these interactions is the release of chemotaxins that guide PMN through the subepithelial matrix and subsequently through the epithelium itself (McCormick, B.A., S.P. Colgan, C. Delp-Archer, S.I. Miller, and J.L. Madara. 1993. J. Cell Biol. 123:895-907). Given the substantial volume flow that normally characterizes matrix compartments underlying transporting epithelia, it is unclear how such transmatrix signaling is sustained. Here we show that when underlying matrices are isolated from biophysically confluent polarized monolayers of the human intestinal epithelial cell line T84, they fail to support substantial transmatrix migration of PMN unless an exogenous chemotactic gradient is imposed. In contrast, such matrices isolated from confluent monolayers apically colonized with S. typhimurium support spontaneous transmatrix migration of PMN. Such chemotactic imprinting of underlying matrices is resistant to volume wash and is paralleled by secretion of the known matrix-binding chemokine IL-8. Chemotactic imprinting of the matrix underlying S. typhimurium-colonized monolayers is dependent on epithelial protein synthesis, is directional implying the existence of a gradient, and is neutralized by antibodies either to IL-8 or to the IL-8 receptor on PMN. An avirulent S. typhimurium strain, PhoPc, which attaches to epithelial cells as efficiently as wild-type S. typhimurium, fails to induce basolateral secretion of IL-8 and likewise fails to imprint matrices. Together, these observations show that the epithelial surface can respond to the presence of a luminal pathogen and subsequently imprint the subepithelial matrix with retained IL-8 gradients sufficient to resist washout effects of the volume flow that normally traverses this compartment. Such data further support the notion that the primary role for basolateral secretion of IL-8 by the intestinal and likely other epithelia is recruitment of PMN through the matrix to the subepithelial space, rather than directing the final movement of PMN across the epithelium.

Bacterial Proteins↗