Perceptual correlates of massive cortical reorganization.
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Cerebral Cortex↗
Biomedical subjects
M Stewart
Publications and source records attributed to M Stewart.
Structure of tropomyosin at 9 angstroms resolution.
We have used molecular replacement followed by a highly parameterized refinement to determine the structure of tropomyosin crystals to a resolution to 9 A. The shape, coiled-coil structure and interactions of the molecules in the crystals have been determined. These crystals have C2 symmetry with a = 259.7 A, b = 55.3 A, c = 135.6 A and beta = 97.2 degrees. Because of the unusual distribution of intensity in X-ray diffraction patterns from these crystals, it was possible to solve the rotation problem by inspection of qualitative aspects of the diffraction data and to define unequivocally the general alignment of the molecules along the (332) and (3-32) directions of the unit cell. The translation function was then solved by a direct search procedure, while electron microscopy of a related crystal form indicated the probable location of molecular ends in the asymmetric unit, as well as the anti-parallel arrangement. The structural model we have obtained is much clearer than that obtained previously with crystals of extraordinarily high solvent content and shows the two alpha-helices of the coiled coil over most of the length of the molecules and establishes the coiled-coil pitch at 140(+/- 10) A. Moreover, the precise value of the coiled-coil pitch varies along the molecule, probably in response to local variations in the amino acid sequence, which we have determined by sequencing the appropriate cDNA. The crystals are constructed from layers of tropomyosin filaments. There are two molecules in the crystallographic asymmetric unit and the molecules within a layer are bent into an approximately sinusoidal profile. Molecules in consecutive layers in the crystal lie at an angle relative to one another as found in crystalline arrays of actin and myosin rod. There are three classes of interactions between tropomyosin molecules in the spermine-induced crystals and these give some insights into the molecular interactions between coiled-coil molecules that may have implications for assemblies such as muscle thick filaments and intermediate filaments. In interactions within a layer, the geometry of coiled-coil contacts is retained, whereas in contacts between molecules in adjacent layers the coiled-coil geometry varies and these interactions instead appear to be dominated by the repeating pattern of charged zones along the molecule.
Amino Acid Sequence↗
Effects of atropine on hippocampal theta cells and complex-spike cells.
The medial septal nuclei are essential for the naturally occurring hippocampal theta rhythm. Evidence that the rhythmic activity of the septum is carried via cholinergic afferents to the hippocampus has been: (a) the existence of a cholinergic septo-hippocampal projection, and (b) the sensitivity of one type of theta rhythm to antimuscarinic agents or cholinergic depletion. The muscarinic action of acetylcholine on pyramidal cells, however, is too slow to carry even a 4 Hz signal. Recent in vitro studies have confirmed a fast excitatory response by some hippocampal interneurons to muscarinic agonists. In urethane anesthetized rats, iontophoretic application of atropine to 17 hippocampal theta cells (presumed interneurons) during the theta rhythm, reduced their firing rates to an average of 24% of control rates. The effect of iontophoretic atropine application to 4 CA1 complex-spike cells (presumed pyramidal cells) was a selective elimination of their bursting activity with no significant effect on overall firing rate. The data suggest that: (1) interneuronal firing, during the hippocampal theta rhythm, is dominated by an excitatory cholinergic input and not by excitatory collaterals of pyramidal cells; and (2) somatic burst firing by CA1 pyramidal cells requires the presence of acetylcholine.
Acetylcholine↗
Molecular interactions in myosin assembly. Role of the 28-residue charge repeat in the rod.
We have used internal deletions of multiples of seven residues to change the phase of the 28-residue charge repeat in a light meromyosin cDNA construct expressed in Escherichia coli. The solubility behaviour of these mutants was similar to that of the wild-type material, but the molecular packing in the aggregates formed at low ionic strength was different. Whereas wild-type material formed paracrystals in which molecules were in close contact over most of their length, molecules in the paracrystals formed by the mutants were in close contact for only a short distance, which was just short enough to exclude the deletion from the overlap. These data indicate that, although the 28-residue charge periodicity is important in myosin molecular interactions, it is probably not the major driving force for myosin assembly and instead influences the detailed axial stagger of the interacting molecules.
Base Sequence↗
Firing relations of medial entorhinal neurons to the hippocampal theta rhythm in urethane anesthetized and walking rats.
The firing of neurons from layers II and III of medial entorhinal cortex (MEC) was examined in relation to the hippocampal theta rhythm in urethane anesthetized and walking rats. 1) MEC neurons showed a significant phase relation to the hippocampal theta rhythm in both walking and urethane anesthetized rats, suggesting that this region contributes to the generation of both atropine-resistant and atropine-sensitive theta rhythm components. 2) The proportion of phase-locked cells was three times greater in walking rats (22/23 cells) as compared to anesthetized rats (8/23 cells), indicating that MEC cells made a greater contribution during walking theta rhythm. This difference was also manifest in the greater mean vector length for the group of phase-locked MEC cells during walking: 0.39 +/- 0.13 versus 0.21 +/- 0.08. Firing rate differences between walking and urethane conditions were not significant. 3) In walking rats, MEC cells fired on the positive peak of the dentate theta rhythm (group mean phase = 5 degrees; 0 degrees = positive peak at the hippocampal fissure). This is close to the reported phases for dentate granule and hippocampal pyramidal cells. The distribution of MEC cell phases in urethane anesthetized rats was broader (group mean phase = 90 degrees), consistent with the phase data reported for hippocampal projection cells. These findings suggest that medial entorhinal neurons are the principal determinant of theta-related firing of hippocampal neurons and that their robust rhythmicity in walking as compared to urethane anesthesia accounts for EEG differences across the two conditions.
Anesthesia↗
The objective evaluation of alternative treatment plans. III: The quantitative analysis of dose volume histograms.
The computer program OSCAR evaluates dose-volume histograms in a consistent way for use in 3-dimensional treatment planning. Based on a dose prescription specified by a radiation oncologist, the technique provides a quantitative and easily understood visual analysis of a proposed dose distribution. Rapid, reliable, and consistent choices can be made between alternative treatment plans, and if necessary the results of OSCAR calculations can be used to guide the design of a plan that will be closer to the required prescription. The method is well suited to use in the definition of treatment protocols. The use of OSCAR is demonstrated by applying it to the evaluation of alternative volumetric treatment plans for ca lung. The results demonstrate the importance of using corrections for inhomogeneous tissue density in the calculation of 3-dimensional dose distributions.
Computer Graphics↗
Phase II study of tauromustine in malignant glioma.
46 eligible patients with either anaplastic astrocytoma (AA) or glioblastoma (GBM) and clinical and computed-tomography-confirmed relapse following primary surgery and radiotherapy received oral tauromustine 130 mg/m2 every 5 weeks. A prospective design allowed for concurrent assessment of both clinical and radiological responses and drug toxicity. 41% of patients improved clinically whilst 46% improved radiologically with 3 complete, 7 partial and 7 minimal responses (WHO criteria). Toxicity included grade III or IV gastrointestinal side-effects (15%), grade III or IV leukopenia (24%) and grade III and IV thrombocytopenia (44%). In 9 clinically responding patients, haematological toxicity led to discontinuation of treatment. All patients were followed-up until death and second-line chemotherapy was not used. Median post-treatment survival was 26 weeks for patients with GBM and 57 weeks for patients with AA. Overall 2-year survival rate was 69% for AA and 23% for GBM. Tauromustine given at the time of relapse has demonstrable antitumour activity in patients not previously treated with chemotherapy.
Adult↗
Nuclear pore structure and function.
Nuclear pores are huge macromolecular assemblies, approximately 120 nm in diameter, that perforate the nuclear membrane and mediate nucleocytoplasmic transport. Nuclear pores are constructed from a cylindrical spoke-plug complex sandwiched between nucleoplasmic and cytoplasmic rings. The spoke-plug complex has pronounced 8-fold rotational symmetry, which is also present in the rings. Nucleocytoplasmic transport is an energy-requiring process that takes place through the centre of the pores and can accommodate particles up to about 25 nm diameter. Translocation is preceded by a separate binding step which does not require energy. Several nuclear pore proteins have been isolated and characterized. Many of these proteins contain O-linked N-acetyl glucosamine residues and may have similar modular domain structures.
Animals↗
Helicobacter pyrlori in Malawi, central Africa.
A total of 160 adult Malawians with epigastric pain for longer than 2 weeks was investigated by endoscopy and serologically for evidence of infection with Helicobacter pylori. The organism was demonstrated histologically and/or by culture in 141 (88%) patients. With histological means and/or culture as the 'gold standard', the histological technique was 100% sensitive while culture was only 81% sensitive. All isolates tested were sensitive to amoxycillin and tetracycline; 74% were resistant to metronidazole. Endoscopic findings were normal in 104 (65%) patients (86.5% H. pylori positive). Evidence of duodenal ulcer was found in 41 (25%) patients (95% H. pylori positive). Histologically, gastritis was common, severe gastritis being associated with increased colonisation by H. pylori. Two kinds of urease test were found to be 100% specific for the presence of H. pylori. The sensitivity of the serological test (Helico-G test) was 98% but its specificity was only 27%. These results provide important background information for planned therapeutic studies in patients with upper gastro-intestinal disease in Malawi.
Adolescent↗
Pathway of incorporation of microinjected lamin A into the nuclear envelope.
When microinjected into the cytoplasm of 3T3 cells, biotinylated human lamin A rapidly enters the nucleus and gradually becomes incorporated into the nuclear lamina region as determined by immunofluorescence. The incorporation of the microinjected material takes several hours and progresses through a series of morphologically identifiable stages. Within minutes after microinjection, lamin A is found in spots distributed throughout the nucleus, except in nucleolar regions. Over a time course of up to 6 h, these spots appear to decrease in size and number as the biotinylated lamin A becomes associated with the endogenous nuclear lamina. Eventually, the typical nuclear rim staining pattern normally revealed by immunofluorescence with nuclear lamin antibodies is seen with antibiotin. This latter rim staining property is passed on to daughter cells following mitosis. These results indicate that the microinjected biotinylated nuclear lamin A retains those properties required for its integration into the lamina, as well as those necessary for the disassembly and subsequent reassembly of the nuclear lamina during cell division. The initial rapid accumulation into foci and the subsequent slower incorporation into the nuclear lamina appear to be analogous to the stages of incorporation following the microinjection of cytoskeletal intermediate filament proteins such as vimentin and keratin (Vikstrom, K., G. G. Borisy, and R. D. Goldman. 1989. Proc. Natl. Acad. Sci. USA. 86:549-553; Miller, R. K., K. Vikstrom, and R. D. Goldman. 1991. J. Cell Biol. 113:843-855). Foci are also observed in some uninjected cells using nuclear lamin antibodies, indicating that these features are a genuine component of nuclear substructure. Evidence is presented that shows the appearance of these nuclear structures is cell cycle dependent.
3T3 Cells↗
Perceptual correlates of massive cortical reorganization.
Following long-term deafferentation of one upper limb in adult primates, the cortical areas corresponding to that limb become responsive to stimuli applied to the face. To explore this phenomenon, we studied some patients after upper limb amputation. In patient VQ, stimuli applied to the lower face or 7 cm above the stump evoked precisely localized referred sensations in individual digits which were often modality specific. Similarly, in another patient, WK several complete somatotopic representations of the phantom limb were found, on the face, chest and axilla, indicating the emergence of such maps in regions remote from the stump. These effects may be a direct perceptual correlate of the physiological observations of Merzenick et al (1984), Wall (1977) and Pons et al (1991).
Adolescent↗
The paediatrician and children of divorce.
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Adolescent↗
Familial hollow visceral myopathy with varying urological manifestations.
A family with hereditary hollow visceral myopathy is described, with characteristic variation in expression between affected members. Very severe and widespread involvement of the gastrointestinal and urinary tracts in 1 patient contrasted with isolated urinary tract involvement in 2 others, and it is suggested that hollow visceral myopathy should be considered in the differential diagnosis of primary detrusor failure. The management of urinary tract involvement is discussed and a conservative approach is recommended.
Adult↗
Different firing patterns generated in dendrites and somata of CA1 pyramidal neurones in guinea-pig hippocampus.
1. Intracellular recordings, taken from CA1 pyramidal cells in guinea-pig hippocampal slices, were used to examine the origins of repetitive and burst firing in these cells. Single action potentials were elicited by depolarizing current injection at somatic recording sites. In contrast, current injection during intradendritic recordings initiated burst firing in the dendrites. Burst firing could be elicited in the soma by direct depolarization of distal apical dendrites (> 150 microns from the cell body layer) with large extracellular polarizing electrodes. 2. Intracellular recordings were taken simultaneously from the apical dendrites and pyramidal cell somata with the intention of impaling the same neurone with both electrodes. Paired dendrite-soma recordings confirmed that rhythmic single action potentials were generated at the cell soma, whereas bursts of action potentials were initiated in the distal apical dendrites (> 150 microns from the cell body layer). Fast spikes in the dendrite often triggered fast spikes in the soma, but not all fast spikes in the dendritic burst were 'relayed' to the soma. 3. In paired recordings, when a dendritic action potential failed to elicit a full somatic action potential, a 'd-spike' was commonly recorded in the soma. Somatic d-spikes were uniform all-or-none responses that could be shown, in some cases, to trigger the full somatic action potentials. 4. Attenuated spikes could be recorded in the dendrites, triggered by action potentials initiated at the cell soma. Dendritic responses to somatic stimulation sometimes varied in amplitude, but always showed a direct correspondence with somatic action potentials. 5. Dendritic recordings taken closer to the pyramidal cell bodies (< 150 microns from the cell body layer) showed a 'transitional' region where single action potentials rather than burst discharges could be evoked. After-potentials of these single spikes differed from those associated with somatic spikes in that proximal dendritic spikes had depolarizing after-potentials. The observed shift from after-hyperpolarization to depolarizing after-potentials in intradendritic recordings taken progressively further from the cell body corresponds to the change from repetitive to burst firing. 6. The results indicate that activity of the CA1 pyramidal cell soma, presumably a reflection of its output, can be either burst or repetitive firing. Somatic 'bursts,' unlike the burst discharges seen in the apical dendrites or the burst discharges reported in CA3 cells, are not initiated locally. Rather, they appear to be simply a rapid spike-for-spike response by the soma to the fast spikes that form part of the apical dendritic burst.(ABSTRACT TRUNCATED AT 400 WORDS)
Action Potentials↗
Structural comparison of urease and a GroEL analog from Helicobacter pylori.
Electron microscopy of purified protein preparations indicated that Helicobacter pylori urease consisted of circular particles that are 13 nm in diameter, some of which showed indications of threefold rotational symmetry. A GroEL analog of H. pylori (Hp60K) appeared as a disc-shaped molecule with a diameter similar to that of urease but possessed sevenfold rotational symmetry. In a side-view projection, Hp60K appeared as two or four discs stacked side by side.
Amino Acid Sequence↗
Pathogenesis of feline leukemia virus T17: contrasting fates of helper, v-myc, and v-tcr proviruses in secondary tumors.
A naturally occurring feline thymic lymphosarcoma (T17) provided the unique observation of a T-cell antigen receptor beta-chain gene (v-tcr) transduced by a retrovirus. The primary tumor contained three classes of feline leukemia virus (FeLV) provirus, which have now been characterized in more detail as (i) v-tcr-containing recombinant proviruses, (ii) v-myc-containing recombinant proviruses, and (iii) apparently full-length helper FeLV proviruses. The two transductions appear to have been independent events, with distinct recombinational junctions and no sequence overlap in the host-derived inserts. The T17 tumor cell line releases large numbers of FeLV particles of low infectivity; all three genomes are encapsidated, but passage of FeLV-T17 on feline fibroblast and lymphoma cells led to selective loss of the recombinant viruses. The oncogenic potential of the T17 virus complex was, therefore, tested by infection of neonatal cats with virus harvested directly from the primary T17 tumor cell line. A single inoculation of FeLV-T17 caused persistent low-grade infection culminating in thymic lymphosarcoma and acute thymic atrophy, which was accelerated by coinfection with the weakly pathogenic FeLV subgroup A (FeLV-A)/Glasgow-1 helper. Molecularly cloned FeLV-tcr virus (T-31) rescued for replication by a weakly pathogenic FeLV-A/Glasgow-1 helper virus was similarly tested in vivo and induced thymic atrophy and thymic lymphosarcomas. Most FeLV-T17-induced tumors manifested either v-myc or an activated c-myc allele and had undergone rearrangement of endogenous T-cell antigen receptor beta-chain genes, supporting the proposition that the oncogenic effects of c-myc linked to the FeLV long terminal repeat are targeted to a specific window in T-cell differentiation. However, neither the FeLV-T17-induced tumors nor the T-31 + FeLV-A-induced tumors contained clonally represented v-tcr sequences. Only one of the FeLV-T17-induced tumors contained detectable v-tcr proviruses, at a low copy number. While v-tcr does not have a readily transmissible oncogenic function, a more restricted role is not excluded, perhaps involving antigenic peptide-major histocompatibility complex recognition by the T-cell receptor complex. Such a function could be obscured by the genetic diversity of the outbred domestic cat host.
Animals↗
Use of an ammonia electrode for rapid quantification of Helicobacter pylori urease: its use in the endoscopy room and in the assessment of urease inhibition by bismuth subsalicylate.
The use of an ammonia electrode to quantify ammonia liberated by urease from Helicobacter pylori was assessed in an in vitro study. It was found to be highly sensitive (down to 0.7 ppm NH3) and highly reproducible (coefficient of variation 6.0%). Inhibition of urease by bismuth subsalicylate was evaluated as urease testing is often used to assess clearance of H. pylori in patients treated with bismuth. Concentrations of bismuth subsalicylate up to 5 mg/ml had no inhibitory effect but bismuth subsalicylate at 50 mg/ml resulted in 21% inhibition of the urease activity of an ultrasonicated H. pylori suspension. As a preliminary study, the ammonia electrode was assessed in the endoscopy room in comparison with conventional techniques for H. pylori diagnosis. Antral biopsies from 39 patients attending for routine diagnostic endoscopy were subjected to culture, histology, detection of urease activity with a commercially available slide test (CLO) and with the ammonia electrode to detect ammonia liberated from samples placed in urea solution. 21 patients were positive after 1 h with the ammonia electrode, compared to only 17 with the commercially available slide test. 20 were positive on histology and 19 by culture. All samples positive with the ammonia electrode were either positive by culture or by histology. The ammonia electrode offers a quick, sensitive, quantitative and cheap method for the detection and quantification of H. pylori.
Ammonia↗
Cognitive planning deficit in patients with cerebellar atrophy.
We compared the performance of 12 patients with cerebellar atrophy (CA) and 12 normal controls matched for age and education on the Tower of Hanoi, a nine-problem task that requires cognitive planning. CA patients performed significantly worse than controls on this task despite no difference in planning and between-move pause times. A reanalysis of the data using just the subgroup of patients with pure cerebellar cortical atrophy (CCA) (N = 9) replicated the above results and also showed that CCA patients had significantly increased planning times compared with controls. Neither age, sex, education level, severity of dementia, word fluency, response time, memory, nor visuomotor procedural learning predicted CA or CCA performance. This deficit in cognitive planning suggests a functional link between the cerebellum, basal ganglia, and the frontal lobe concerning specific cognitive processes. However, the exact role of the cerebellum in cognitive planning remains undetermined.
Adult↗