Examination of HIV-1 protease secondary structure specificity using conformationally constrained inhibitors.
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Amino Acid Sequence↗
Biomedical subjects
D Fitzpatrick
Publications and source records attributed to D Fitzpatrick.
Neurophysiological effects of left vagal stimulation in man.
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Adult↗
Myocyte mitotic division in the aging mammalian rat heart.
To determine whether myocyte mitotic division occurs in the adult mammalian heart and whether this cellular process is affected by aging, we measured the percentage of myocyte nuclei showing metaphase chromosomes in myocytes isolated from the left and right ventricles of rats at 8-12, 19-24, and 28-32 months after birth. Metaphase chromosomes were found at all ages in both ventricles. However, from 8-12 to 28-32 months, the fraction of nuclei exhibiting metaphase chromosomes increased 6.3-fold and 2.3-fold in the left and right ventricles, respectively. Thus, myocyte cellular hyperplasia is present in the adult and aging myocardium as a compensatory mechanism to regenerate tissue mass and recover function, which are lost with the progression of life and senescence.
Aging↗
The aging population. A critical issue in medicine for the 21st century.
One critical issue facing medical science concerns the aging population. The number of individuals 65 years and older has increased during the past decade and likely will double by the year 2030, when the elderly will represent nearly 20% of the total population. This dramatic increase has numerous ramifications; health care is of utmost importance. Inherent in meeting the medical needs of these individuals is a fundamental understanding of the effects of aging on the functional integrity of numerous organ systems. In recognition of this problem, the Department of Pharmacology and Therapeutics at the University of South Florida College of Medicine has initiated a major effort focused on age-related research. The objectives are to elucidate fundamental biochemical, physiological, and pharmacological alterations that occur as a consequence of normal aging and to investigate the role of these perturbations on the manifestations of disease. Information gained from such studies will provide a rational approach in developing therapeutic strategies for the treatment of diseases affecting older citizens. This article presents a brief overview of four areas of research currently being pursued. These include aging and brain function, age-related alterations in drug metabolism, aging and smooth muscle function, and the effects of aging on the immune system.
Aging↗
Terminal arbors of individual, physiologically identified geniculocortical axons in the tree shrew's striate cortex.
We studied the terminal patterns of single, physiologically identified geniculocortical axons in the striate cortex of the tree shrew by using intracellular recording and labeling methods. Axons were classified by their response to the onset (ON-center) or offset (OFF-center) of a light stimulus presented to the ipsilateral or contralateral eye. Then, we attempted to penetrate each axon for labeling with horseradish peroxidase. We recovered 23 axons and studied 16 of these in detail. Light microscopic reconstructions of these axons revealed several distinct terminal patterns within cortical layer IV. ON-center axons had terminal arbors that ended mainly in the upper part of layer IV (IVa), while OFF-center axons ended in the lower part of layer IV (IVb). Within layers IVa and IVb, axons driven by the ipsilateral eye and those driven by the contralateral eye had overlapping distributions. However, their terminal arbors differed in size, in shape, and in the number of boutons. Compared with contralateral eye arbors, ipsilateral eye axons were on average three times larger in lateral extent (925 microns vs. 325 microns), spread over four times the surface area (0.13 mm2 vs. 0.03 mm2), and supported one and one-half times as many terminal boutons (1,647 vs. 1,086). The ipsilateral eye axons had more boutons at the edges of layer IV (i.e., the upper part of layer IVa and the lower part of layer IVb), while those from the contralateral eye axons were more evenly distributed. These results show that each functional class of geniculocortical fiber has a different laminar and areal arrangement of boutons and we consider the significance of these differences for visual cortical function.
Animals↗
Distribution of delta-aminolevulinic acid synthetase and delta-aminolevulinic acid dehydratase in liver and kidney of rainbow trout (Salmo gairdnerii).
1. Activities of delta-aminolevulinic acid synthetase (ALA-S) and delta-aminolevulinic acid dehydratase (ALA-D) in trout liver and kidney were compared with those in the mouse. 2. ALA-S activity (per unit tissue fresh weight) exceeded ALA-D activity in trout liver and kidney. 3. In trout kidney, ALA-S activity slightly exceeded, and ALA-D activity far exceeded, their activities in trout liver. 4. In trout, heme synthesis differs from that in mammals in that appreciable synthesis occurs in the kidney, and in that ALA-S activity is not rate limiting.
5-Aminolevulinate Synthetase↗
Innervation patterns of single physiologically identified geniculocortical axons in the striate cortex of the tree shrew.
We examined the termination patterns of single geniculocortical axons in the striate cortex of the tree shrew by using intracellular recording and horseradish peroxidase staining methods. Axons were classified by whether they responded to light onset (ON center) or light offset (OFF center) and whether they were driven by the ipsi- or contralateral eye. Afferents with ON-center responses end in the upper part of layer IV (IVa) whereas afferents with OFF-center responses end in the lower part of layer IV (IVb). Within each tier, axons driven by the ipsilateral and contralateral eye overlap. These results suggest that binocular convergence occurs within layer IV without mixing the information from the ON- and OFF-center pathways and we consider the significance of this arrangement for visual cortical function.
Afferent Pathways↗
Cholinergic and monoaminergic innervation of the cat's thalamus: comparison of the lateral geniculate nucleus with other principal sensory nuclei.
The cholinergic and monoaminergic innervation of the lateral geniculate nucleus (GL) and other thalamic nuclei in the cat was examined by using immunocytochemical and tract-tracing techniques. Cholinergic fibers, identified with an antibody to choline acetyltransferase (ChAT), are present in all layers of the GL. They are fine in caliber and exhibit numerous swellings along their lengths. The A layers, the magnocellular C layer, and the medial interlaminar nucleus are rich in cholinergic fibers that give rise to prominent clusters of boutons, while the parvicellular C layers contain fewer fibers that are more uniformly distributed. The interlaminar zones are largely devoid of ChAT-immunoreactive fibers. Double-label experiments show that cholinergic projections to the GL originate from two sources, the pedunculopontine reticular formation (PPT) and the parabigeminal nucleus (Pbg). The PPT contributes cholinergic fibers to all layers, while Pbg projections are limited to the parvicellular C layers. The lateral geniculate nucleus has a much greater density of cholinergic fibers than the other principal sensory nuclei: the density of fibers in the A layers is more than three times greater than that in the ventral posterior nucleus (VP) or the ventral division of the medial geniculate nucleus (GMv). In contrast, serotonin (5-HT)-immunoreactive fibers are distributed with equal density across the principal thalamic nuclei, while tyrosine hydroxylase (TH)-immunoreactive fibers (presumed to contain norepinephrine) are noticeably less dense in the GL than in the others. Monoaminergic fibers also differ from cholinergic fibers in their laminar distribution within the GL: both TH- and 5HT-immunoreactive fibers are distributed evenly across the layers and interlaminar zones and are slightly more abundant in the parvicellular C layers than in the other layers. Other thalamic nuclei rich in cholinergic fibers include the pulvinar nucleus, the ventral lateral geniculate nucleus, the intermediate nucleus of the lateral group, the lateral medial and suprageniculate nuclei (Graybiel and Berson: Neuroscience 5:1175-1238, '80), and the paracentral and central-lateral components of the intralaminar nuclei. This pattern matches the distribution of projections from the PPT and is similar, but not identical, to the pattern of acetylcholinesterase staining. The fact that most of the nuclei rich in cholinergic fibers have been implicated in visual sensory or visual motor functions suggests that cholinergic projections from the reticular formation play an especially important role in visually guided behavior.
Animals↗
Organization of cholinergic synapses in the cat's dorsal lateral geniculate and perigeniculate nuclei.
In the preceding article, we showed that cholinergic fibers originating from the brainstem reticular formation provide a dense innervation of the lateral geniculate nucleus. In this report we describe the ultrastructure of these fibers and their relations with other elements in the neuropil of the lateral geniculate nucleus. Cholinergic fibers were labeled with an antibody to choline acetyltransferase (ChAT), the synthesizing enzyme for acetylcholine (ACh). In the A-laminae of the lateral geniculate nucleus, ChAT + profiles are small and contain tightly packed, mostly round vesicles. Some end in encapsulated synaptic zones where they form asymmetrical synaptic contacts with processes of both projection cells and interneurons. Others form synapses upon the shafts of dendrites. Of the four classical types of vesicle-containing profiles identified by Guillery (Z. Zellforsch. Mikrosk. 96:1-38, '69; Vision Res. [Suppl.] 3:211-227, '71), ChAT + profiles most closely resemble RSD profiles (Round vesicles, Small profile, Dark mitochondria). However, as a population, ChAT + profiles can be distinguished from the unlabeled population of RSD profiles because they are larger in size, contain more mitochondria, and make synapses with smaller postsynaptic membrane specializations. Each of these differences is statistically significant and together they indicate that ChAT + profiles are a distinct morphological type of synaptic profile. ChAT + profiles in the perigeniculate nucleus resemble those found in the lateral geniculate nucleus; they also make synapses with obvious postsynaptic thickenings.
Animals↗
Cholinergic innervation of the superior colliculus in the cat.
The superficial and intermediate gray layers of the superior colliculus are heavily innervated by fibers that utilize the neurotransmitter acetylcholine. The distribution, ultrastructure, and sources of the cholinergic innervation of these layers have been examined in the cat by using a combination of immuno-cytochemical and axonal transport methods. Putative cholinergic fibers and cells were localized by means of a monoclonal antibody to choline acetyltransferase (ChAT). ChAT immunoreactive fibers are distributed throughout the depth of the superior colliculus, with particularly dense zones of innervation in the upper part of the superficial grey layer and in the intermediate grey layer. Within the superficial grey layer, the fibers form a continuous, dense band, whereas within the intermediate grey layer the fibers are arranged in clusters or patches. Although the patches are present throughout the rostrocaudal extent of the superior colliculus, they are most prominent in middle to caudal sections. The structure of the ChAT immunoreactive terminals was examined electron microscopically. The appearance of the terminals is similar in the superficial and intermediate grey layers. They contain closely packed, mostly round vesicles, and form contacts with medium-sized dendrites that exhibit small, but prominent postsynaptic densities; a few of the terminals contact vesicle-containing profiles. To identify the sources of the cholinergic input to the superior colliculus, injections of wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) were made in the superior colliculus and the sections were processed to demonstrate both the retrograde transport of WGA-HRP and ChAT immunoreactivity. Neurons containing both labels were found in the parabigeminal nucleus, and in the lateral dorsal and pedunculopontine tegmental nuclei of the pontomesencephalic reticular formation. Almost every cell in these nuclei that contained retrograde label was also immunoreactive for ChAT. The similarities between the laminar distributions of the ChAT terminals and the terminations of the pathway from the parabigeminal nucleus (Graybiel: Brain Res. 145:365-374, '78) support the view that the latter nucleus is a source of the cholinergic fibers in the superficial grey layer. The possibility that the pedunculopontine tegmental nucleus is a source of cholinergic fibers in the deep layers was tested by examining the distribution of labeled fibers following injections of WGA-HRP into this region of the tegmentum. Patches of labeled terminals were found in the intermediate grey layer that resemble in distribution the patches of ChAT immunoreactive fibers in this layer.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Morphology of retinogeniculate axons in the macaque.
The size, pattern of terminal arborizations, and laminar specificity of individual retinogeniculate axons were studied in the macaque following injections of HRP into the optic tract. Axons that terminated in the magnocellular layers had significantly larger fiber diameters and wider terminal fields than those that terminated in the parvocellular layers. Terminal fields of magnocellular fibers spanned most of the width of their target layer, whereas those of parvocellular fibers were restricted to approximately one-half the width of their target layers; almost all terminal fields were oriented along lines of projection. All of the optic tract fibers that we examined terminated in only one layer of the lateral geniculate nucleus (GL), including a population of fine caliber fibers that project to the intercalated layers, and none had collateral projections outside the GL. The results suggest that each layer--magnocellular, parvocellular, and intercalated--receives projections from a morphologically distinct population of optic tract fibers.
Animals↗
Arthroscopic surgery of the wrist.
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Arthroscopes↗
New view of the organization of the pulvinar nucleus in Tupaia as revealed by tectopulvinar and pulvinar-cortical projections.
The projections of the superficial layers of the superior colliculus to the pulvinar nucleus in Tupaia were reexamined by injecting WGA-HRP into the tectum. The main result was finding two different patterns of terminations in the pulvinar nucleus: a zone remote from the lateral geniculate nucleus, which occupies the dorsomedial and caudal poles of the pulvinar nucleus, was almost entirely filled with terminals in every case irrespective of the location of the injection site; and a second division of the pulvinar nucleus, adjacent to the lateral geniculate nucleus, contained irregular patches--much more densely populated--and the distribution of patches varied from case to case. We call the first projection "diffuse" and the patchy projection "specific." Next we injected several divisions of the extrastriate visual cortex to find the cortical target of each pathway. The diffuse path terminates in the ventral temporal area (Tv). The specific path terminates in the dorsal temporal area (Td) and area 18. We speculated about the significance of the two pathways: the specific path may be responsible for the preservation of vision after removal of the striate cortex; the diffuse path may have an important place in the evolution of the visual areas of the temporal and occipital lobe. We argued that the target of the diffuse path is in a position to relate limbic and visual impulses and relay the product of such integration to the other visual areas, striate as well as extrastriate cortex.
Animals↗
Cholinergic projections from the midbrain reticular formation and the parabigeminal nucleus to the lateral geniculate nucleus in the tree shrew.
The distribution and sources of putative cholinergic fibers within the lateral geniculate nucleus (GL) of the tree shrew have been examined by using the immunocytochemical localization of choline acetyltransferase (ChAT). ChAT-immunoreactive fibers are found throughout the thalamus but are particularly abundant in the GL as compared to other principal sensory thalamic nuclei (medial geniculate nucleus, ventral posterior nucleus). Individual ChAT-immunoreactive fibers are extremely fine in caliber and display numerous small swellings along their lengths. Within the GL, ChAT-immunoreactive fibers are more numerous in the layers than in the interlaminar zones and, in most cases, the greatest density is found in layers 4 and 5. Two sources for the ChAT-immunoreactive fibers in the GL have been identified--the parabigeminal nucleus (Pbg) and the pedunculopontine tegmental nucleus (PPT)--and the contribution that each makes to the distribution of ChAT-immunoreactive fibers in GL was determined by combining immunocytochemical, axonal transport, and lesion methods. The projection from the Pbg is strictly contralateral, travels via the optic tract, and terminates in layers 1, 3, 5, and 6 as well as the interlaminar zones on either side of layer 5. The projection from PPT is bilateral (ipsilateral dominant) and terminates throughout the GL as well as in other thalamic nuclei. Lesions of the Pbg eliminate the ChAT-immunoreactive fibers normally found in the optic tract but have no obvious effect on the density of ChAT-immunoreactive fibers in the contralateral GL. In contrast, lesions of PPT produce a conspicuous decrease in the number of ChAT-immunoreactive fibers in the GL and in other thalamic nuclei on the side of the lesion but have no obvious effect on the number of ChAT-immunoreactive fibers in the optic tract. These results suggest that there are two sources of cholinergic projections to the GL in the tree shrew which are likely to play different roles in modulating the transmission of visual activity to the cortex. The Pbg is recognized as a part of the visual system by virtue of its reciprocal connections with the superficial layers of the superior colliculus, while the PPT is a part of the midbrain reticular formation and is thought to play a non-modality-specific role in modulating the activity of neurons throughout the thalamus and in other regions of the brainstem.
Animals↗
Multiple pulmonary emboli in a patient with afibrinogenaemia.
The case history of a patient with afibrinogenaemia, who developed multiple pulmonary emboli as a consequence of treatment, is described.
Adult↗
Distribution of GABAergic neurons and axon terminals in the macaque striate cortex.
Antisera to glutamic acid decarboxylase (GAD) and gamma-aminobutyric acid (GABA) have been used to characterize the morphology and distribution of presumed GABAergic neurons and axon terminals within the macaque striate cortex. Despite some differences in the relative sensitivity of these antisera for detecting cell bodies and terminals, the overall patterns of labeling appear quite similar. GABAergic axon terminals are particularly prominent in zones known to receive the bulk of the projections from the lateral geniculate nucleus; laminae 4C, 4A, and the cytochrome-rich patches of lamina 3. In lamina 4A, GABAergic terminals are distributed in a honeycomb pattern which appears to match closely the spatial pattern of geniculate terminations in this region. Quantitative analysis of axon terminals that contain flat vesicles and form symmetric synaptic contacts (FS terminals) in lamina 4C beta and in lamina 5 suggest that the prominence of GAD and GABA axon terminal labeling in the geniculate recipient zones is due, at least in part, to the presence of larger GABAergic axon terminals in these regions. GABAergic cell bodies and their initial dendritic segments display morphological features characteristic of nonpyramidal neurons and are found in all layers of striate cortex. The density of GAD and GABA immunoreactive neurons is greatest in laminae 2-3A, 4A, and 4C beta. The distribution of GABAergic neurons within lamina 3 does not appear to be correlated with the patchy distribution of cytochrome oxidase in this region; i.e., there is no significant difference in the density of GAD and GABA immunoreactive neurons in cytochrome-rich and cytochrome-poor regions of lamina 3. Counts of labeled and unlabeled neurons indicate that GABA immunoreactive neurons make up at least 15% of the neurons in striate cortex. Layer 1 is distinct from the other cortical layers by virtue of its high percentage (77-81%) of GABAergic neurons. Among the other layers, the proportion of GABAergic neurons varies from roughly 20% in laminae 2-3A to 12% in laminae 5 and 6. Finally, there are conspicuous laminar differences in the size and dendritic arrangement of GAD and GABA immunoreactive neurons. Lamina 4C alpha and lamina 6 are distinguished from the other layers by the presence of populations of large GABAergic neurons, some of which have horizontally spreading dendritic processes. GABAergic neurons within the superficial layers are significantly smaller and the majority appear to have vertically oriented dendritic processes.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Laminar asymmetry in the distribution of choline acetyltransferase-immunoreactive neurons in the retina of the tree shrew (Tupaia belangeri).
Cholinergic neurons in the retina of the tree shrew were identified immunocytochemically using a monoclonal antibody directed against choline acetyltransferase (ChAT). The chief result is that roughly 4 times as many ChAT-immunoreactive neurons are found in the inner nuclear layer (INL) as in the ganglion cell layer (GCL). In the INL, two classes of cholinergic neuron can be distinguished on the basis of soma size, one large and one small. The large neurons correspond closely in size and number to the displaced cholinergic neurons in the GCL, suggesting that these are the matching populations of cholinergic amacrine cells reported in other species. The small ChAT-immunoreactive neurons, on the other hand, which make up 60% of the total number of ChAT-positive neurons in the retina, appear to have no counterpart in the GCL. Whether these small neurons are a separate class of amacrine cell or some other cell type (e.g. bipolar, interplexiform, etc.) remains to be determined.
Animals↗
Laminar organization of geniculocortical projections in Galago senegalensis and Aotus trivirgatus.
The projections of the lateral geniculate nucleus to striate cortex were traced by anterograde and retrograde transport of WGA-HRP in two primates, Galago and Aotus. The goal was to determine the laminar organization of the terminals of individual layers of the lateral geniculate nucleus. The results show that in both species the magnocellular layers project to cortical layer IV alpha, the parvicellular layers project to IV beta, and the intercalated geniculate layers (which term includes layers 4 and 5 in Galago) project to layers III and I. The distribution of terminals in layer III is periodic, which is to say, there are regularly spaced regions of terminals separated by regions devoid of terminals. When the two species are compared to Saimiri, it is clear that the basic organization of the three pathways relaying in the lateral geniculate nucleus is common to all three primates. At the same time, there are some significant species differences. The total pattern of projections in Galago is compressed in comparison to that in the monkey, and this compression seems to be related to the poorer differentiation of cortical layers in the prosimian. For example, layer IIIC is distinct only in the two monkeys and at the same time it is spared from geniculate terminations. Both Galago and Aotus differ from Saimiri in that they lack a projection from the parvicellular geniculate layers to the layer IIIB. These species comparisons are relevant to the questions of the functional significance of the three pathways and the evolution of the primate striate cortex.
Animals↗