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Biomedical subjects

W Singer

Publications and source records attributed to W Singer.

At least 73 records · Page 4Linked to original sources

A novel type of pituitary adenoma: morphological features and clinical correlations.

Twenty patients with a novel, frequently aggressive type of pituitary adenoma, termed silent subtype 3 adenoma on the basis of fine structural criteria, are reported. The surgically removed tumors were studied by morphological techniques, and the findings were correlated with clinical and biochemical data. All tumors were macroadenomas, often with parasellar extension. The histologically diffuse tumors frequently exhibited focal immunopositivity for one or more adenohypophysial hormones, although the majority of adenoma cells were negative. The tumors had characteristic electron microscopic features, assuring specific diagnosis and delineating this tumor type as a distinct ultrastructural entity. The tumors were removed from 9 women and 11 men (median ages, 27 and 41 yr, respectively). In all women, mild to moderate hyperprolactinemia and its sequelae were present from the early phase of the disease, leading to the erroneous diagnosis of prolactinoma. Bromocriptine therapy (3 patients) reduced serum PRL levels to normal, but failed to halt tumor growth. In men, most adenomas were nonfunctioning; 4 men had mild to moderate hyperprolactinemia. Three men had elevated serum GH levels and acromegaly, suggestive of multidirectional differentiation. Although the putative cell type giving rise to silent subtype 3 adenomas is not known, the tumor should be recognized to avoid erroneous diagnosis and inappropriate treatment.

Adenoma

Suprasellar craniopharyngioma associated with hyperprolactinemia, pituitary lactotroph hyperplasia, and microprolactinoma. Case report.

A case with the coexistence of a microprolactinoma and suprasellar craniopharyngioma lactotroph hyperplasia is presented. Loss of inhibitory hypothalamic dopaminergic input may have played a role in hyperprolactinemia and the proliferation of pituitary lactotrophs. This is believed to be the first published case of suprasellar craniopharyngioma with this association.

Brain Neoplasms

Structure-function correlations of human pituitary gonadotroph adenomas in vitro.

Two pituitary gonadotroph adenomas were studied in vitro to characterize structure-function correlations. Both tumors were from men, aged 63 and 69 years, who had elevated blood levels of follicle-stimulating hormone (FSH) and normal blood luteinizing hormone (LH) and testosterone values. The surgically resected adenomas contained diffuse immunohistochemical positivity for beta-FSH, beta-LH, and alpha-subunit of glycoprotein hormones; by electron microscopy they were composed of well-differentiated gonadotrophs. In vitro, both tumors released FSH, LH, and alpha-subunit. Morphometric studies were performed on surgically resected and cultured adenoma cells. Compared with the surgical specimens, the cultured cells had decreased cytoplasmic volume densities of endoplasmic reticulum and Golgi apparatus and slightly increased cytoplasmic volume densities of secretory granules. Incubation with gonadotropin-releasing hormone (GnRH) for 2 and 24 hours increased FSH, LH, and alpha-subunit release by both tumors; morphometry after 2 consecutive days of exposure confirmed significant increases in cytoplasmic volume densities of endoplasmic reticulum and Golgi regions and marked decreases in that of secretory granules. There was no significant change in cell size, nuclear/cytoplasmic ratio, or secretory granule diameter. The two tumors differed in their response to gonadal steroids. Estradiol, testosterone, and progesterone stimulated release of FSH, LH, and alpha-subunit by one tumor and the morphologic changes paralleled the biochemical response; addition of testosterone suppressed the secretory and morphologic response to GnRH. The other tumor showed no significant response to estradiol or testosterone and addition of these steroids did not alter the response to GnRH. The results are consistent with the interpretation that GnRH stimulates not only release but also synthesis of gonadotropins by gonadotroph adenomas of men. The data also indicate variable sensitivity of these tumors to gonadal steroids with paradoxical stimulation alone and inhibition of response to GnRH. The structural changes correlate with the hormone release response in vitro.

Adenoma

Blockade of "NMDA" receptors disrupts experience-dependent plasticity of kitten striate cortex.

Intracortical infusion of the "N-methyl-D-aspartate" (NMDA) receptor blocker D,L-2-amino-5-phosphonovaleric acid (APV) renders kitten striate cortex resistant to the effects of monocular deprivation. In addition, 1 week of continuous APV treatment (50 nanomoles per hour) produces a striking loss of orientation selectivity in area 17. These data support the hypothesis that crucial variables for the expression of activity-dependent synaptic modifications are a critical level of postsynaptic activation and calcium entry through ion channels linked to NMDA receptors.

2-Amino-5-phosphonovalerate

Immunohistochemical localization of calcium-binding proteins, parvalbumin and calbindin-D 28k, in the adult and developing visual cortex of cats: a light and electron microscopic study.

In the cat primary visual cortex, we investigated with immunohistochemical techniques the developmental changes in the cellular and subcellular localization of the Ca2+-binding proteins parvalbumin (PV) and calbindin-D 28K (CBP), in order to determine whether there is a correlation between the expression of Ca2+-dependent processes and the time course of the critical period for use-dependent plasticity. On the 54th day of gestation and at 1 week postnatally, both calcium-binding proteins were present only in a subpopulation of neurons in layers V and VI. During subsequent maturation, the number of PV(+) and CBP(+) neurons increased significantly and labeled cells were detected in more superficial layers. Moreover, the homogeneous labeling of some CBP(+) neurons in layers IV to VI decreased and changed to a punctate pattern. In adult cats PV(+) neurons were evenly distributed throughout layers II to VI, whereas CBP(+) neurons were concentrated in layers II/III. Only a few immunoreactive cells had morphological features characteristic of pyramidal cells; the large majority were nonpyramidal. Electron microscopy confirmed the presence of PV- and CBP-reaction product within the perikarya, axons, and dendrites of labeled cells. It was associated preferentially with microtubules, postsynaptic densities, and intracellular membranes. Immunoreactive neurons received immunonegative asymmetric synapses on their dendritic shafts and made symmetric synaptic contacts with labeled and unlabeled somata and with unlabeled dendritic shafts. The large number and widespread distribution of immunoreactive neurons implies that PV and CBP play an important role in the regulation of calcium-dependent processes in the visual cortex. Furthermore, the developmental redistribution of PV and CBP points to changes in the organization of Ca2+-dependent processes during maturation.

Aging

The brainstem projection to the lateral geniculate nucleus in the cat: identification of cholinergic and monoaminergic elements.

The pontomesencephalic projection to the dorsal lateral geniculate nucleus (dLGN) of the cat was analyzed by combining retrograde transport of rhodamine-labeled latex spheres and immunohistochemistry. After injections of latex beads into the dLGN, sections of the brainstem were treated immunohistochemically for choline acetyltransferase (ChAT), serotonin (Ser), tyrosine hydroxylase (TH), and dopamine-beta-hydroxylase (DBH). Essentially, six regions in the brainstem contained retrogradely labeled cells: the superior colliculus, the parabigeminal nucleus, the dorsal raphe nuclei, the parabrachial area of the central tegmental field, the marginal nucleus of the brachium conjunctivum, and the nucleus coeruleus. Furthermore, isolated retrogradely labeled cells were present in the central nucleus of the raphe, in the cuneiform nucleus, and in the periaqueductal gray. Most serotoninergic double-labeled cells were found in the medial and lateral divisions of the dorsal raphe nuclei, but a few were also present in the central nucleus of the raphe. In the sections immunostained for ChAT, double-labeled cells were located in the central tegmental field, in the marginal nucleus of the brachium conjunctivum, and in the nucleus coeruleus. In the sections treated for TH and DBH, double-labeled cells showed a similar distribution, and like the ChAT(+) cells, they were located mainly in the central tegmental field, in the marginal nucleus of the brachium conjunctivum, and in the nucleus coeruleus. In these regions the cholinergic and noradrenergic cells that projected to the lateral geniculate nucleus were intermingled, the former predominating rostrally and the latter caudally. The majority of retrogradely labeled cells were located in the region of the central tegmental field in the vicinity of the brachium conjunctivum, and most of these cells were also ChAT-immunoreactive. We, therefore, conclude that the cholinergic projection is the most important of the central core projections ascending to the dLGN.

Animals

The serotoninergic fibers in the dorsal lateral geniculate nucleus of the cat: distribution and synaptic connections demonstrated with immunocytochemistry.

The distribution, morphology, and synaptic contacts of serotoninergic fibers were studied with immunocytochemical methods in the lateral geniculate complex of the cat. The serotonin-immunoreactive fibers are diffusely distributed throughout the main laminae of the dorsal lateral geniculate nucleus (dLGN) and the perigeniculate nucleus (PGN) and reach a particular density in the ventral lateral geniculate nucleus (vLGN). The labeled fibers are in most cases very thin and sometimes varicose. There is no obvious order in their distribution pattern except that they sometimes partially encircle the unlabeled cell bodies of the dLGN. The synaptic connections of the serotoninergic fibers were investigated mainly in the A laminae of the dLGN. Few synaptic complexes were found, most of them with asymmetric morphology. The postsynaptic elements were small dendritic profiles. Perisomatic serotoninergic fibers were seen, but no convincing synaptic contacts were found between labeled fibers and cell somata. In the dLGN, serotoninergic profiles were almost exclusively confined to the extraglomerular neuropile. In the PGN serotoninergic fibers also contacted dendritic profiles and formed asymmetrical synapses, but as in the geniculate, synaptic specializations were very rare.

Animals

Quantitative analysis of the choline acetyltransferase-immunoreactive axonal network in the cat primary visual cortex: I. Adult cats.

The laminar distribution of cholinergic axons was analyzed quantitatively in the visual cortex of adult cats by using immunocytochemistry with a monoclonal antibody against choline acetyltransferase (ChAT). ChAT(+) fibers and varicosities were counted at different locations within area 17 and the distribution patterns in various animals were compared. Choline acetyltransferase-immunoreactivity was localized in fine, varicose fibers, which were present in all layers of the visual cortex. The density of labeled fibers was highest in layer I, which contained 14% of all fibers and 19.5% of all varicosities, and decreased toward deeper layers. The number of varicosities decreased more markedly toward deeper layers than the frequency of fibers. These distribution patterns were very consistent, showing only slight intra- and interindividual variability.

Animals

Quantitative analysis of the choline acetyltransferase-immunoreactive axonal network in the cat primary visual cortex: II. Pre- and postnatal development.

The pre- and postnatal development of cholinergic projections was investigated in the cat striate cortex by applying immunohistochemical methods based on a monoclonal antibody against choline acetyltransferase (ChAT). The earliest age investigated was gestational day 54. At this stage a sparse network of ChAT(+) fibers was distributed throughout the striate cortex. Subsequent postnatal maturation of ChAT(+) fibers was characterized by an increase in fiber density that started in layer VI and gradually progressed toward more superficial layers. By 4 weeks of age the density of ChAT(+) fibers and varicosities had reached adult levels in layers V and VI but was still subnormal in layers I-IV. The mature pattern of cholinergic innervation was established by 13 weeks of age. There was no evidence for developmental gradients in the anteroposterior and mediolateral directions within area 17. These results indicate that the cholinergic projection to striate cortex develops continuously in an inside-out sequence as is characteristic for most cortical maturation processes. There was no indication that striate cortex receives an especially dense cholinergic input during the critical period.

Animals

A search for choline acetyltransferase-like immunoreactivity in neurons of cat striate cortex.

The goal of this study was to determine whether cat striate cortex contains neurons with choline acetyltransferase-like immunoreactivity. Two different monoclonal antibodies were applied with various fixation protocols. As controls served selected regions of the cat brain and the rat neocortex where cholinergic neurons had been demonstrated previously with independent methods. All experimental protocols labelled the presumptive cholinergic neurons in the central regions but revealed only a few weakly stained neurons in cat striate cortex. These had a non-pyramidal morphology and were scattered throughout all layers.

Animals

Topographic organization of the orientation column system in large flat-mounts of the cat visual cortex: a 2-deoxyglucose study.

We developed a flat-mount technique in order to visualize, without additional reconstruction, the system of orientation columns in the cat visual cortex by using 2-deoxyglucose-autoradiography. Experimental animals were injected with 2-deoxyglucose and then stimulated for 45-60 minutes either with vertical or horizontal or oblique gratings alone or with vertical and horizontal gratings presented in alternation. In both areas 17 and 18 stimulation with either vertical or horizontal or oblique stripes produced similar and highly ordered patterns of parallel bands of increased 2-deoxyglucose uptake that were perpendicular to the boundaries of the areas. In area 17 they occasionally extended without interruption from the 17/18 border on the top of the lateral gyrus to the monocular segment in the splenial sulcus. Superposition of serial sections revealed that these bands were present in all cortical layers and in precise register along lines orthogonal to the lamination. The center-to-center spacing of the bands was 1.0-1.1 mm in area 17 and 1.2-1.4 mm in area 18. Stimulation with alternating vertical and horizontal contours led to a pattern the general organization of which resembled that induced by a single orientation but the spacing of which was reduced by a factor of 0.5. This strongly supports the concept that orientation is mapped in a system of parallel bands and argues against a recently formulated hypothesis that iso-orientation bands extend like spokes from centers that lack orientation selectivity (Braitenberg and Braitenberg, Biol. Cybern. 33:179-186, '79). Another characteristic feature, revealed by the flat-mount technique, was a periodic variation of 2-deoxyglucose uptake along the bands that gave them a beaded appearance. The mean center-to-center distance between adjacent beads on the same band was in the range of 0.9-1.2 mm and remained unchanged when horizontal and vertical gratings were presented in alternation. We propose that these beads reflect another columnar system whose features have yet to be determined.

Animals

Neuronal dynamics in the visual corticothalamic pathway revealed through binocular rivalry.

Single unit activity was recorded from principal cells in the A-laminae of the cat dorsal lateral geniculate nucleus (dLGN). A steady state pattern of afferent activation was induced by presenting a continuously drifting square wave grating of constant spatial frequency to the eye (the dominant eye) that provided the excitatory input to the recorded cell. Intermittently, a second grating stimulus was presented to the other, nondominant, eye. In most neurones nondominant eye stimulation led to inhibition of relay cell responses. The latency of this suppressive effect was unusually long (up to 1 s) and its intensity and duration depended critically on the similarity between the gratings that were presented to the two eyes. Typically suppression was strongest when the gratings differed in orientation, direction of movement and contrast and when the nondominant eye stimulus was moving rather than stationary. Ablation of visual cortex abolished these long latency and feature-dependent interferences. We conclude that the visual cortex and the corticothalamic projections are involved in the mediation of these interocular interactions. We interpret our results as support for the hypothesis that corticothalamic feedback modifies thalamic transmission as a function of the congruency between ongoing cortical activation patterns and afferent retinal signals.

Animals

A current source density analysis of field potentials evoked in slices of visual cortex.

The method of one-dimensional current source density (CSD) analysis was applied to field potentials recorded from 350 microns thick slices of the primary visual cortex of rats and cats. Field potentials were elicited by stimulation of the white matter and recorded along trajectories perpendicular to the cortical layers at spatial intervals of 25 to 50 microns. The resulting CSD distributions resembled closely those recorded from the cat visual cortex "in vivo". The responses with the shortest latency were distinct sinks in layers IV and VI probably reflecting monosynaptic EPSP's from specific thalamic afferents. From layer IV activity was relayed along three major routes: 1. to the supragranular layers via strong local connections to layer III and from there via both short and long range connections to layer II, 2. to targets within layer IV, and 3. to layer V. The source distributions suggest that the projections to layers III and II terminate on the proximal and distal segments, respectively, of apical dendrites of layer III pyramidal cells while the projection to layer V contacts the apical dendrites of layer VI pyramidal cells. These results indicate that all the excitatory pathways that are detectable with the CSD technique in the "in vivo" preparation remain intact in 350 micron thick cortical slices. However, in the slice paired pulse stimulation did not lead to a depression of the response to the second stimulus while this is the case "in vivo". This might be due to reduced inhibition in the slice which has been reported by several authors.

Age Factors

The pattern of ocular dominance columns in flat-mounts of the cat visual cortex.

Ocular dominance (OD) columns in the cat visual cortex were visualized with autoradiography after intravitreal injection of (3H)proline. Extending previous studies, a flat-mount technique was applied that enabled the analysis of the distribution of label throughout extensive regions of the visual cortex without requiring reconstruction from serial sections. OD-columns were confined to layer IV and consisted of isolated patches and short bands. The latter were parallel to each other and regularly spaced, the main trajectory being orthogonal to the 17/18 border. This pattern of the geniculo-cortical terminals was similar in the hemispheres ipsi- and contralateral to the injected eye. The mean periodicities of the OD-bands were virtually identical in the two hemispheres of the same animal: 850 microns and 830 microns in cat D1 and 770 microns and 800 microns in cat D2. However, the ipsilateral OD-columns appeared smaller, more heavily labeled and more sharply delineated than the contralateral columns.

Animals

A self-organizing neural network sharing features of the mammalian visual system.

This paper describes a neural network model whose structure is designed to closely fit neuroanatomical and -physiological data, and not to be most suitable for rigorous mathematical analysis. It is shown by computer simulation that a process of self-organization that departs from a fixed retinotopic order at peripheral layers and includes Hebbian modifications of synaptic connectivity at higher processing levels leads to a system that is capable of mimicking various functions of visual systems: In the initial state the overall structure of the network is preset, individual connections at higher levels are randomly selected and their strength is initialized with random numbers. For this model the outcome of the self-organization process is determined by the stimulation during the developmental phase. Depending on the type of stimuli used the model can either develop towards a feature-selective "preprocessor" stage in a complex vision system or towards a subsystem for associative recall of abstract patterns. This flexibility supports the hypothesis that the principles embodied are rather universal and can account for the development of various nervous system structures.

Animals

Deoxyglucose mapping in the cat visual cortex following carotid artery injection and cortical flat-mounting.

Two techniques are described for improving the efficiency of the deoxyglucose metabolic mapping procedure for studies on the cat visual cortex. The first technique involves the bilateral cannulation of the lingual arteries and the symmetrical injection of 2-deoxy-D-[U-14C]glucose in amounts significantly smaller than required with systemic intravenous administration. The second technique is carried out at the end of the stimulation period and involves unfolding the grey matter of the occipital region of the unfixed cortex by blunt dissection (defibrillation) and cutting of the white matter to make a cortical flat-mount: this permits the preparation of large sections parallel to the cortical laminae and thus the interpretation of deoxyglucose uptake patterns in any one lamina over a large area of the visual cortex. The experiments are relatively cheap and the time required to flat-mount the cortices does not seem to produce any significant decrease in spatial resolution of the autoradiograms. In appropriate experiments (published elsewhere) the techniques allow a comparative analysis of the deoxyglucose patterns between hemispheres receiving different visual stimulation.

Animals

Evidence for a threshold in experience-dependent long-term changes of kitten visual cortex.

In order to determine the role of unstructured and of spontaneous activity in the developmental plasticity of the visual cortex, we blocked in 7 kittens the retinal activity of one eye completely by intraocular injections of tetrodotoxin (TTX) while the other eye was left open. Littermates of these kittens were monocularly deprived by lid suture and served as controls. In 3 additional kittens one eye was inactivated with TTX and the other closed by lid suture to assess whether mere asymmetries in the activation levels of the two eyes were sufficient to induce ocular dominance changes. Despite some variability between the matched pairs, the ocular dominance shift towards the normal eye did not differ significantly in the kittens with monocular lid suture and monocular TTX injection (P greater than 0.3/chi 2). In the TTX-treated kittens there was a trend for neurones to be less sharply tuned for orientation but it was not significant (P greater than 0.08/chi 2). In the kittens which had one eye injected with TTX and the other sutured closed no shift of ocular dominance was apparent. Separate analysis of both hemispheres revealed only a small bias towards the respective contralateral eye. We conclude that the process mediating activity-dependent long-term changes of ocular dominance has a threshold. Afferent activity that fails to excite the postsynaptic neuron above this threshold plays neither a significant role in the stabilization nor in the disruption of functional connections.

Animals