Biomedical subjects
Publications and source records attributed to J T Littleton.
This article describes a case of obstructed supernumerary tracheal bronchus with partial atelectasis and pneumonia of the right upper lobe, diagnosed using trispiral tomograms. An obstructing broncholith, a supernumerary tracheal bronchus, and granulation tissue mass extruding from the bronchus were confirmed by resection of the pulmonary segment.
Since the demonstration that Ca2+ influx into the presynaptic terminal is essential for neurotransmitter release, there has been much speculation about the Ca2+ receptor responsible for initiating exocytosis. Numerous experiments have shown that the protein, or protein complex, binds multiple Ca2+ ions, resides near the site of Ca2+ influx, and has a relatively low affinity for Ca2+. Synaptotagmin is an integral membrane protein of synaptic vesicles that contains two copies of a domain known to be involved in Ca(2+)-dependent membrane interactions. Synaptotagmin has been shown to bind Ca2+ in vitro with a relatively low affinity. In addition, synaptotagmin has been shown to bind indirectly to Ca2+ channels, positioning the protein close to the site of Ca2+ influx. Recently, a negative regulatory role for synaptotagmin has been proposed, in which it functions as a clamp to prevent fusion of synaptic vesicles with the presynaptic membrane. Release of the clamp would allow exocytosis. Here we present genetic and electrophysiological evidence that synaptotagmin forms a multimeric complex that can function as a clamp in vivo. However, upon nerve stimulation and Ca2+ influx, all synaptotagmin mutations dramatically decrease the ability of Ca2+ to promote release, suggesting that synaptotagmin probably plays a key role in activation of synaptic vesicle fusion. This activity cannot simply be attributed to the removal of a barrier to secretion, as we can electrophysiologically separate the increase in rate of spontaneous vesicle fusion from the decrease in evoked response. We also find that some syt mutations, including those that lack the second Ca(2+)-binding domain, decrease the fourth-order dependence of release on Ca2+ by approximately half, consistent with the hypothesis that a synaptotagmin complex functions as a Ca2+ receptor for initiating exocytosis.
Synaptotagmin is an integral synaptic vesicle protein proposed to be involved in Ca(2+)-dependent exocytosis during synaptic transmission. Null mutations in synaptotagmin have been made in Drosophila, and the protein's in vivo function has been assayed at the neuromuscular synapse. In the absence of synaptotagmin, synaptic transmission is dramatically impaired but is not abolished. In null mutants, evoked vesicle release is decreased by a factor of 10. Moreover, the fidelity of excitation-secretion coupling is impaired so that a given stimulus generates a more variable amount of secretion. However, this residual evoked release shows Ca(2+)-dependence similar to normal release, suggesting either that synaptotagmin is not the Ca2+ sensor or that a second, independent Ca2+ sensor exists. While evoked transmission is suppressed, the rate of spontaneous vesicle fusion is increased by a factor of 5. We conclude that synaptotagmin is not an absolutely essential component of the Ca(2+)-dependent secretion pathway in synaptic transmission but is necessary for normal levels of transmission. Our data support a model in which synaptotagmin functions as a negative regulator of spontaneous vesicle fusion and acts to increase the efficiency of excitation-secretion coupling during synaptic transmission.
The mammalian homolog of the yeast Sec1p, n-Sec1/Munc-18 has been demonstrated to bind the presynaptic membrane protein syntaxin, a putative synaptic vesicle docking protein. To determine the role of n-Sec1/Munc-18 in neurotransmitter release in vivo, we have overexpressed the Drosophila homolog, rop, in third instar larvae and measured the electrophysiological consequences at the neuromuscular junction. A 3- to 5-fold induction of the rop protein causes a dramatic decrease in neurotransmitter release, suggesting rop may restrict the ability of vesicles to dock or of docked vesicles to fuse. Consistent with this hypothesis, rop overexpression also reduces the number of spontaneous vesicle fusions by more than 50%, and repetitive stimulation results in significant decreases in evoked responses similar to those observed in rab3a mutant mice. However, rop overexpression does not alter significantly the Ca2+ dependence of neurotransmitter release. We propose that the Drosophila n-Sec1/Munc-18 homolog plays a negative role in neurotransmitter release in vivo, in addition to its previously identified positive function, possibly by modulation of docking of synaptic vesicles or activation of a pre-fusion complex at the active zone.
In an attempt to identify mutations in the Drosophila synaptotagmin gene we have isolated many new rearrangements, point mutations and P element insertions in the 22F1-2; 23B1-2 cytological interval on chromosome arm 2L. This interval encompasses 13 cytological bands and is shown to contain 13 essential complementation groups, including decapentaplegic, synaptotagmin and Curly. Through chemical and P element mutagenesis we have isolated seven new deletions, which combined with previously isolated rearrangements, have allowed us to order most genes in the interval. A genomic walk covering approximately 100 kb within this interval spans at least five essential genes as identified by chromosomal aberrations. Preliminary phenotypic characterizations of the mutant phenotype and lethal phase is presented for many mutations. Three loci within this interval are shown to be required for proper neural development. Given that the average number of alleles per complementation group is greater than seven, it is very likely that all essential genes within this cytological interval have been identified.
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Synaptotagmin (syt), a synaptic vesicle-specific protein known to bind Ca2+ in the presence of phospholipids, has been proposed to mediate Ca(2+)-dependent neurotransmitter release. We have addressed the role of syt in neurotransmitter release in vivo by generating mutations in synaptotagmin (syt) in the fruitfly and assaying the subsequent effects on neurotransmission. Most embryos that lack syt fail to hatch and exhibit very reduced, uncoordinated muscle contractions. Larvae with partial lack-of-function mutations show almost no evoked excitatory junctional potentials (EJPs) in 0.4 mM Ca2+ and a 15-fold reduction in EJP amplitude in 1.0 mM Ca2+ when compared with heterozygous controls. In contrast, we observe an increase in the frequency of spontaneous miniature EJPs in the mutants. These results provide in vivo evidence that syt plays a key role in Ca2+ activation of neurotransmitter release and indicate the existence of separate pathways for evoked and spontaneous neurotransmitter release.
Synaptotagmin is a synaptic vesicle-specific integral membrane protein that has been suggested to play a key role in synaptic vesicle docking and fusion. By monitoring Synaptotagmin's cellular and subcellular distribution during development, it is possible to study synaptic vesicle localization and transport, and synapse formation. We have initiated the study of Synaptotagmin's expression during Drosophila neurogenesis in order to follow synaptic vesicle movement prior to and during synapse formation, as well as to localize synaptic sites in Drosophila. In situ hybridizations to whole-mount embryos show that synaptotagmin (syt) message is present in the cell bodies of all peripheral nervous system neurons and many, if not all, central nervous system neurons during neurite outgrowth and synapse formation, and in mature neurons. Immunocytochemical staining with antisera specific to Synaptotagmin indicates that the protein is present at all stages of the Drosophila life cycle following germ band retraction. In embryos, Synaptotagmin is only transiently localized to the cell body of neurons and is transported rapidly along axons during axonogenesis. After synapse formation, Synaptotagmin accumulates in a punctate pattern at all identifiable synaptic contact sites, suggesting a general role for Synaptotagmin in synapse function. In embryos and larvae, the most intense staining is found along two broad longitudinal tracts on the dorsal side of the ventral nerve cord and the brain, and at neuromuscular junctions in the periphery. In the adult head, Synaptotagmin localizes the discrete regions of the neurophil where synapses are predicted to occur. These data indicate that synaptic vesicles are present in axons before synapse formation, and become restricted to synaptic contact sites after synapses are formed. Since a similar expression pattern of Synaptotagmin has been reported in mammals, we propose that the function of Synaptotagmin and the mechanisms governing localization of the synaptic vesicle before and after synapse formation are conserved in invertebrate and vertebrate species. The ability to mark synapses in Drosophila should facilitate the study of synapse formation and function, providing a new tool to dissect the molecular mechanisms underlying these processes.
Radiographic studies to discriminate benign from malignant pulmonary masses have previously focused on the morphologic and, more recently, the computed tomographic (CT) attenuation characteristics of the lung mass. Experience with the use of an intravenously administered iodinated contrast medium in examining the enhancement properties of lung masses was reviewed. Distinctive differences in the vascularity, pathophysiologic features, and pharmacodynamics of malignant versus benign pulmonary masses were identified. Forty-five patients with peripheral pulmonary masses were examined. Enhancement was evaluated by means of optical density values measured on trispiral tomograms of the lung masses before and after bolus injection of contrast medium. Results suggest that contrast enhancement of pulmonary masses can be measured on sectional images and that this may become a feasible diagnostic method in the detection of lung cancer. CT offers a simplified technique that is now being explored by the authors.
A rare case of a combination of an accessory cardiac bronchus and a right tracheal bronchus found incidentally is presented, together with a discussion of the anatomy, embryology, and possible clinical ramifications of these anomalies. The incidence of these anomalies occurring in 2,000 tomographic studies of the chest at University of South Alabama Medical Center is cited.
The definition of the left hemidiaphragm is frequently lost when patients are evaluated with portable radiographic equipment. Experimental evidence, based on results of radiography and subsequent sagittal sectioning of a frozen, unembalmed human thorax, corroborated the authors' hypothesis that this finding is related to loss of tangential imaging of the apex of the hemidiaphragm due to cephalic angulation of the central beam accompanied by projection of extrapleural fat onto the base of the left lung. In eight of ten patients in whom portable radiography was performed in 10 degrees-15 degrees of lordosis, varying degrees of loss of definition of the left hemidiaphragm were seen, in the absence of disease. This potential pitfall can be avoided by ensuring that the central beam is tangent to the hemidiaphragm. To do otherwise can create the false impression of disease in the left lower lobe, pleural space, or both.
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Ninety-one sets of polytomograms were analyzed for diagnosis and treatment of 123 patients with cervical spine injuries. Pluridirectional polytomographis is valuable in evaluation of acute cervical spine injuries when the findings on plain roentgenograms do not correlate well with the clinical symptoms and signs. The polytomographic study had a dramatic impact on the diagnosis and a lesser but nevertheless significant impact on the treatment of cervical spine injuries. Polytomograms were especially valuable for the diagnosis and treatment of atlantoaxial injuries.
The recent introduction of high resolution computed tomography (CT) capable of resolving delicate bony structures such as the temporal bone marks another significant advance in diagnostic imaging. This study was designed to compare the integrity of these new CT images, standard CT images, and conventional complex motion tomographic images against contact radiographs of sliced anatomic specimens. Temporal bones of three frozen cadaver heads were studied with complex motion tomograms at 1 mm intervals and contiguous CT scans at 1.5 mm intervals in axial, coronal, and sagittal projections. The heads were physically sectioned at 2 mm intervals in planes corresponding to the radiographic planes using a precise indexing and sawing system. The tomographic images were compared for information content to contact radiographs of the anatomic specimen sections. Conventional tomographic images and expanded number range target reconstruction CT images proved to be highly accurate. Standard CT reconstruction images were not. The probable clinical effectiveness of each method is discussed.
The basic imaging capabilities of 15 degrees linear, 30 degrees linear, hypocycloidal, and trispiral tomographic movements were compared using a fresh frozen human cadaver. Large numbers of tomograms, 100 with each tomographic movement, were compared as a motion study developed by copying the four tomographic series on movie film. In addition, the integrity of the tomograms was compared with radiographs of representative 2 mm coronal sections sawed from the fresh frozen thorax specimen. The study demonstrated the theoretical conclusion that a linear tomogram is not a sectional image and does not truthfully represent the planar anatomy of the intended layer. The pluridirectional tomograms, on the other hand, do accurately depict the anatomic section. The more general use of pluridirectional tomographic techniques in the chest is encouraged and should be used as the basis for comparing conventional tomographic imaging capabilities to other new modalities, particularly computed tomography.
The problem of radiation-induced cataract development in the lenses of patients and users exposed to diagnostic-quality radiation is reviewed. A cataractogenic dose appears to be about 200 rads from a single exposure and up to 750 rads in protracted doses. Routine use of new protective glasses developed by the authors is recommended for patients. For users, any of the commercially available high lead-content glasses will reduce doses to safe levels. About 70% reduction of dose is afforded by the new photochromic sunglasses.