Expression of the c-erbB-2-encoded oncoprotein and progesterone receptor in human meningiomas

The present study investigated the expression of c-erbB-2 in 59 meningiomas, including different histological subtypes and anaplastic variants, by immunocytochemistry and molecular biological techniques. Immunohistochemistry using the monoclonal antibody FWP-51 directed against c-erbB-2-encoded oncoprotein gp185 demonstrated variable degrees of immunoreactivity in all meningiomas. The intensity of immunostaining correlated with the degree of expression as assessed by Western analysis in 28 meningiomas using polyclonal antiserum 21N. There was no correlation between the degree of expression and histological variants. Immunoreactivity of all menigiomas was distinctly less intense, however, than that of the human breast cancer cell line SK-BR-3, and slightly lower than that of brain metastases of breast and ovarian carcinomas that served as positive controls for both methods. By Southern analysis all meningiomas showed a single copy of the c-erbB-2 gene. Non-neoplastic arachnoid cap cells also exhibited c-erbB-2 expression and the degree of immunoreactivity was comparable with the majority of meningiomas. These data argue against an overexpression of c-erbB-2 in meningiomas, but rather indicate a cell-type-specific constitutive expression of the c-erbB-2 gene product in meningiomas and their putative progenitor cells. Since a subgroup of meningiomas is known to express progesterone receptors (PR), gp185 immunoreactivity was compared to the hormone receptor status using monoclonal antibody KD68. Fifty-six percent meningiomas showed PR immunoreactivity, but there was no statistically significant correlation with the degree of gp185 expression.This study was supported by a grant of the Tumorzentrum Heidelberg/Mannheim (M.K., No. 10028060)     

Oblique effects,vertical effects and meridional amblyopia in monkeys

Orientation anisotropies were investigated for monkeys with normal visual acuity and for monkeys with experimentally induced amblyopia. It was found that the majority of control monkeys showed a normal oblique effect if any existing refractive errors were carefully corrected, but a few of the control monkeys had a meridional amblyopia, i.e., an orientation anisotropy in which the grating orientation for the greatest and lowest contrast sensitivities were correlated with the principal meridians of an astigmatic refractive error even when the refractive error was corrected. For monkeys with strabismic amblyopia caused by a surgically induced divergent strabismus, the orientation anisotropies showed a vertical effect in which contrast sensitivity was lower for vertically oriented gratings than for horizontally oriented gratings. However, monkeys with the same degree of amblyopia resulting from experimental procedures that did not involve a misalignment of the visual axes showed orientation anisotropies that corresponded to the usual oblique effect.     

Behavioral studies of stimulus deprivation amblyopia in monkeys

Contrast sensitivity and increment-threshold functions were studied for three rhesus monkeys with stimulus deprivation amblyopia. The monkeys' right eyelids were sutured closed before the age of 1 month for periods of two weeks, 19 months and 23 months. Contrast sensitivity measurements for all three monkeys showed greatly reduced visual function in the deprived eye with a high spatial frequency cut-off 6 octaves lower in the deprived than the nondeprived eyes. The increment-threshold data collected for the two long-term lid-sutured monkeys showed both photopic and scotopic abnormalities in the deprived eyes. For example, with complete dark adaptation although the spectral sensitivity data for both the deprived and nondeprived eyes were well fit by the scotopic luminosity function, the sensitivity for the deprived eye was approximately 4 log units lower than the nondeprived eye. In addition, the spectral sensitivity data for the deprived eyes showed scotopic luminosity functions for achromatic adapting field luminances of 188, 750 and 3000 td whereas the nondeprived eye showed normal photopic function for all light adapted conditions. Even when the spectral sensitivity measurements were made in the presence of intense blue backgrounds, the data obtained for the deprived eyes were best described as showing scotopic function over the short wavelengths and photopic function only at the longer wavelengths. The increment-threshold functions for achromatic stimuli showed normal rod-cone interactions in the nondeprived eyes, but the functions were monotonic for the deprived eyes over a 9 log unit range of background luminances. Therefore, the results of these experiments show that stimulus deprivation causes profound defects for visual resolution, rod saturation and the rate of change of sensitivity with light adaptation.     

Suprathreshold spatial frequency detection and binocular interaction in strabismic and anisometropic amblyopia.

We have investigated suprathreshold contrast sensitivity and binocular interactions in strabismic and anisometropic amblyopes using a reaction time paradigm. For every spatial frequency, reaction time increased as the grating contrast decreased. At all spatial frequencies and contrast values the reaction times using the amblyopic eye were prolonged compared to the nonamblyopic eye, but most markedly at high spatial frequencies. In the middle range of spatial frequencies, the contrast vs. reaction time function for the nonamblyopic eyes was biphasic, suggesting that two separate mechanisms detect gratings at high and low contrast levels. These functions in deep amblyopia were monotonic, and in shallow amblyopia the break in the functions was present but shifted to lower contrast levels. Binocular interaction experiments showed that binocular summation was absent at all contrast levels, but binocular occlusion was evident at high contrast levels for amblyopic observers.     

The effects of interocular correlation and contrast on stereoscopic depth magnitude estimation.

PURPOSE: Decreasing the interocular correlation in random dot stereograms elevates disparity detection thresholds. Whether decorrelation also affects perceived depth from suprathreshold disparity magnitudes is unknown. The present study investigated the effects of interocular correlation and contrast on the magnitude of perceived depth in suprathreshold random dot stereograms. METHODS: Stereoscopic depth magnitude estimation as a function of percent interocular correlation of dynamic random dot stimuli was measured for five human subjects with clinically normal binocular vision. Each trial's stimulus was randomly assigned one of two magnitudes of either crossed or uncrossed relative disparity. Subjects verbally reported the direction and magnitude of perceived relative depth for each trial using a modulus-free scale. Normalized depth magnitude estimations as a function of the percent interocular correlation demonstrated the relationship between perceived depth, interocular correlation and contrast within subjects. Inter-subject variability was examined with comparisons of data across subjects. RESULTS: The depth magnitude perceived for a given magnitude of disparity declined as the percent of correlation of elements between the eyes decreased for both crossed and uncrossed directions. The effect generally was greater for uncrossed disparities and lower contrast. Some subjects demonstrated asymmetries in perceived depth for crossed vs. uncrossed disparities of the same magnitude. CONCLUSIONS: Magnitude estimation of suprathreshold stimuli provided a method of studying performance characteristics of stereoscopic depth perception across the range of functional disparities. Differences found in depth magnitude estimation as a function of the sign of disparity suggest that the neural mechanisms underlying depth perception from uncrossed disparity are more sensitive to image decorrelation, particularly at low contrast, than the mechanisms underlying depth estimation from crossed disparity. These results could occur from differences in near and far disparity-sensitive neurons, from the geometrical relationship between disparity and physical distance in normal viewing, or from the response measure independent of perception.     

Charles F. Prentice Award Lecture 2006: a neuron doctrine for glaucoma.

The glaucomas are a group of potentially blinding optic neuropathies that are characterized by progressive pathological losses of the retinal ganglion cells (RGCs) and their axons that form the optic nerve. The causes are unknown and, therefore, the diagnosis and assessment of progression of disease depends on ophthalmic testing to identify and quantify clinical characteristics of glaucomatous neuropathy, such as the pattern of visual field defects and/or thinning of the retinal nerve fiber layer. To relate these clinical measurements to the basic pathology of glaucoma, a neuron doctrine for glaucoma has been proposed to correlate data from standard tests (standard automated perimetry and optical coherence tomography) to the loss of RGCs. The doctrine was derived through initial laboratory studies of experimental glaucoma in macaque monkeys and, then, modified and refined though patient-based clinical investigations. The final formulation of the doctrine produced concordance between subjective and objective measurements when the results were translated to their common parameter of RGCs, for both normal vision and defective vision from glaucoma. Thus, it was concluded that for individual patients, alterations in structure-function relationships usually should be in agreement for the degree and location of visual field defects caused by glaucoma.     

Stereopsis is perturbed by vergence error

Fixation disparity or vergence noise produce instantaneous vergence errors. These errors are analogous to the imposition of a pedestal disparity, which is known to elevate stereothresholds. In this study, stereothresholds were measured as a function of induced vergence errors in subjects with normal binocular vision. Stereo half-images were viewed in the dark through a custom mirror haploscope. Vergence constant error and vergence variability were induced by introducing horizontal disconjugate position offsets in a pair of moveable mirrors within the haploscope, resulting in forced vergence demands of 6(Delta) base-in to 12(Delta) base-out. In addition, vergence variability was simulated by producing oscillatory disconjugate retinal image motion via motion of the moveable mirrors. The motion of the mirrors was either sinusoidal (frequency=2-6 Hz) or random, with peak-to-peak amplitudes of 0 degrees -0.5 degrees per eye. Stereopsis worsened systematically with induced or simulated VV that exceeded approximately 1.5' disparity. The results were similar regardless of whether the vergence error was induced by forced vergence or was simulated by periodic or random disconjugate retinal image motion. Stereothresholds were invariant with the frequency of disconjugate oscillation, within the range of frequencies and amplitudes tested. Hence, the simulated vergence velocity is not the essential factor that limits stereopsis within Panum's fusional area. The results indicate that the stereothreshold is elevated if the vergence error exceeds a critical value.     

The effects of reverse monocular deprivation in monkeys II. Electrophysiological and anatomical studies

Summary Monkeys had one eye closed at about 30 days of age for 14, 30, 60, or 90 days, then opened, and the fellow eye closed for another 120 days. The animals then had at least 10 months of binocular visual experience before extensive behavioral training and testing were carried out. In terminal experiments concluded more than 18 months later, microelectrode investigations of the striate cortex demonstrated that there was almost a complete absence of binocular neurons in all animals. The initially deprived eyes (IDEs) dominated the majority of cortical neurons, even when soma size measurements of lateral geniculate neurons indicated that the LGN cells driven by the IDE had not regained their normal size. The monkeys which had significant interocular differences in spatial vision also exhibited abnormalities in the distribution of the metabolic enzyme, cytochrome oxidase (CO), within the striate cortex. These results demonstrate that many of the severe alterations in cortical physiology and eye dominance produced by early monocular form deprivation can be reversed, with recovery of normal cortical function, via the reverse-deprivation procedure.Supported by National Eye Institute grants R01 EY01120, R01 EY03611, R01 EY01139, and EY02520     

Monoclonal antibodies directed to the erbB-2 receptor inhibit in vivo tumour cell growth.

Four monoclonal antibodies (MAbs) specific for the extracellular domain of the human erbB-2/HER2 protein (FRP5, FSP16, FWP51 and FSP77) have been isolated (Harwerth et al., J. Biol. Chem., 267, 15160-15167, 1992). In this paper we describe the effects of erbB-2 specific MAb administration on the tumorigenic growth of human erbB-2 transformed NIH3T3 cells implanted into athymic nude mice. Two antibodies, FWP51 and FSP77, inhibited the onset of tumour growth, while the administration of FRP5 and FSP16 did not affect tumour growth. In addition, administration of MAbs FWP51 and FSP77 led to a retardation in the growth of established tumours. Treatment was not curative in that tumours regrew within two weeks of the final treatment. The administration of a combination of MAbs FWP51 and FSP77 which react with two distinct regions on the erbB-2 molecule was more effective than treatment with either MAb alone. The two growth-inhibitory antibodies were also effective in the treatment of tumours established from SKOV3 cells, a human ovarian tumour cell line with high levels of the erbB-2 protein. The effect of the MAbs on the anchorage-independent growth of erbB-2 transformed cells and on erbB-2 receptor turnover was also measured.