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Biomedical subjects

B H Peters

Publications and source records attributed to B H Peters.

At least 19 recordsLinked to original sources

Characterization of vertebrate cohesin complexes and their regulation in prophase.

In eukaryotes, sister chromatids remain connected from the time of their synthesis until they are separated in anaphase. This cohesion depends on a complex of proteins called cohesins. In budding yeast, the anaphase-promoting complex (APC) pathway initiates anaphase by removing cohesins from chromosomes. In vertebrates, cohesins dissociate from chromosomes already in prophase. To study their mitotic regulation we have purified two 14S cohesin complexes from human cells. Both complexes contain SMC1, SMC3, SCC1, and either one of the yeast Scc3p orthologs SA1 and SA2. SA1 is also a subunit of 14S cohesin in Xenopus. These complexes interact with PDS5, a protein whose fungal orthologs have been implicated in chromosome cohesion, condensation, and recombination. The bulk of SA1- and SA2-containing complexes and PDS5 are chromatin-associated until they become soluble from prophase to telophase. Reconstitution of this process in mitotic Xenopus extracts shows that cohesin dissociation does neither depend on cyclin B proteolysis nor on the presence of the APC. Cohesins can also dissociate from chromatin in the absence of cyclin-dependent kinase 1 activity. These results suggest that vertebrate cohesins are regulated by a novel prophase pathway which is distinct from the APC pathway that controls cohesins in yeast.

Amino Acid Sequence↗

Expression of the CDH1-associated form of the anaphase-promoting complex in postmitotic neurons.

The anaphase-promoting complex/cyclosome (APC) is a tightly cell cycle-regulated ubiquitin-protein ligase that targets cyclin B and other destruction box-containing proteins for proteolysis at the end of mitosis and in G1. Recent work has shown that activation of the APC in mitosis depends on CDC20, whereas APC is maintained active in G1 via association with the CDC20-related protein CDH1. Here we show that the mitotic activator CDC20 is the only component of the APC ubiquitination pathway whose expression is restricted to proliferating cells, whereas the APC and CDH1 are also expressed in several mammalian tissues that predominantly contain differentiated cells, such as adult brain. Immunocytochemical analyses of cultured rat hippocampal neurons and of mouse and human brain sections indicate that the APC and CDH1 are ubiquitously expressed in the nuclei of postmitotic terminally differentiated neurons. The APC purified from brain contains all core subunits known from proliferating cells and is tightly associated with CDH1. Purified brain APC(CDH1) has a high cyclin B ubiquitination activity that depends less on the destruction box than on the activity of mitotic APC(CDC20). On the basis of these results, we propose that the functions of APC(CDH1) are not restricted to controlling cell-cycle progression but may include the ubiquitination of yet unidentified substrates in differentiated cells.

Anaphase↗

Maintenance of cell-type-specific cytoskeletal character in epithelial cells out of epithelial context: cytokeratins and other cytoskeletal proteins in the rests of Malassez of the periodontal ligament.

We have determined the patterns of synthesis of cytokeratins and other epithelial marker proteins in the "rests of Malassez" of the periodontium of rabbits and humans, by immunofluorescence microscopy of cryosections prepared from fixed and decalcified rabbit teeth with attached ligament or from manually isolated human periodontal ligaments. Proteins of the major cell structures characterizing epithelial differentiation are present in Malassez cells: a complex set of cytokeratins as well as desmosomal, hemidesmosomal and basal lamina proteins. In addition, we have shown these cytoskeletal and extracellular matrix structures by electron microscopy. The cytokeratin complement of Malassez cells was found to be highly complex, as 8 of the total of 20 known epithelial cytokeratins were detected (nos. 5, 7, 8, 14, 15, 17, 18, 19). This pattern, together with the presence of the desmosomal cadherins Dsg2 and Dsc2 and the cytoplasmic desmosome plaque-associated protein plakophilin 1, indicates that the cells of the rests of Malassez are derived from the basal cell layer of a stratified squamous epithelium rather than from simple epithelial or neuroendocrine epithelial cells. Our observations show that Malassez cells retain the major characteristics of epithelial cells throughout their differentiation from the root sheath epithelium into the rests of Malassez, even though the surface location and the polar tissue architecture that typify epithelial are lost during this process. From this study we further conclude that the specific cytoskeletal complement of the Malassez cells represents an intrinsic gene expression program that neither depends on nor causes the formation of a stratified epithelium. We also compare the specific cytoskeletal features of Malassez cells with those of other persisting epithelial residues and discuss the potential value of these findings in relation to the histogenesis and diagnostic classification of dental and periodontal cysts and tumors.

Adolescent↗

The tritocerebral commissure 'dwarf' (TCD): a major GABA-immunoreactive descending interneuron in the locust.

The minor branch of the tritocerebral commissure of the locust, Locusta migratoria, contains only two axons which are from interneurons in the brain descending to the ventral cord ganglia. The smaller of these two neurons, the tritocerebral commissure dwarf (TCD), is immunoreactive to GABA, suggesting that it may be an inhibitory interneuron. We have exploited the accessibility of its axon in the commissure, first, to fill it with cobalt to define its morphology, and second, to record its input characteristics. It has a cell body and arborization of fine branches in the deutocerebrum of the brain, its axon passes contralateral through the tritocerebral commissure and it forms bilateral arborizations in the suboesophageal and three thoracic ganglia. It receives mechanosensory input from many regions of the ipsilateral body and head, and it is sensitive to illumination levels, generally showing greater spontaneous activity in the dark. It is one of the largest GABA-immunoreactive descending interneurons in the locust, suggesting it plays a prominent role in behaviour. Since it is easily accessible for physiological recording, its roles in circuits for particular components of behaviour should be amenable to investigation.

Action Potentials↗

Morphology, ultrastructure and synapse distribution of putative serotonergic salivary neurons in the locust.

Neurons innervating the locust salivary glands have been investigated using the electron microscope. We have examined the projections in the suboesophageal ganglion of two identified salivary neurons by differential double labelling with cobalt ions, followed by silver intensification. Numerous synaptic inputs occur on the arborizations of the salivary neurons, particularly on fine branches and on small spines arising from larger branches. Although a few instances occur of common input to both salivary neurons from a single presynaptic element, many of the appositions between branches seen in the light microscope do not represent functional connections. A few structures resembling presynaptic dense bodies have been observed in salivary neuron profiles, but with few synaptic vesicles. Large dense granules are present in some labelled profiles, but not in the vicinity of synapse-like membrane specializations. We have also examined unidentified neuron profiles within the acini of the salivary glands, which contain large dense granules and small vesicles. There is good evidence that these unidentified terminals correspond to the suboesophageal salivary neurons. The central arborizations of the salivary neurons appear to serve largely as sites of synaptic input, whereas the peripheral terminals are likely sites of transmitter release. The results are considered in the context of the known immunoreactivity of the salivary neurons with antibodies to 5-hydroxytryptamine, and compared with analogous systems in other insect groups.

Animals↗

Electron microscopy of serotonin-immunoreactive neuron branches and terminals in the locust central nervous system.

Using a pre-embedding peroxidase technique, we have investigated the ultrastructure of elements that react with antibodies to 5-hydroxytryptamine in the central nervous system of the locust. Reactive neuron profiles are widespread, and contain a variety of vesicle types: small lucent vesicles, some of which are stained only on their outer membranes while others are stained internally, and large dense granules that again differ in the staining properties of their cores. Some of the reactive profiles contain synaptic specializations, while others receive synaptic inputs from unlabelled elements. The heterogeneity of reactive profiles makes it impossible to define ultrastructural characteristics of putative serotonergic terminals that might be generally applicable. The differential reactivity both of small vesicles and of large dense granules may indicate functional differences within these categories.

Animals↗

Spatial segregation of synaptic inputs and outputs in a locust auditory interneurone.

Using intracellular injection of cobalt, processing for electron microscopy, and using on-section silver intensification, we have investigated the distribution of synapses on the metathoracic arborization of the TN1 intersegmental interneurone in the auditory system of the locust. Previous studies have indicated that inputs to this neurone from tympanal afferents are spatially segregated from its outputs to higher-order inhibitory interneurones. Branches in the area of input are characterised by a smooth appearance in Lucifer Yellow preparations, whereas branches in the main output area appear beaded. Sampling different areas of the TN1 arborization, we have found marked differences in the respective densities of input and output synapses. Labelled profiles in areas of beaded branching have an extremely high density of presynaptic sites, with a much smaller number of synaptic inputs. Smooth branches bear many input synapses, but we have found no output synapses on them. Our results indicate a good correlation between branch beading and presynaptic function and between smooth branches and postsynaptic function. These correlations enable us to predict synapse distribution on other insect neurones with a similar division in branch morphology and also extend our knowledge of the functioning of TN1 itself.

Animals↗

Effects of oral physostigmine and lecithin on memory and attention in closed head-injured patients.

In view of the evidence for the role of the central cholinergic pathways in memory and preliminary studies suggesting alteration of neurotransmitters after severe head injury, we completed a double-blind, placebo-controlled study of combined oral physostigmine and lecithin. Sixteen survivors of moderate to severe closed head injury who had unequivocal memory deficit were studied during the course of inpatient rehabilitation. Although the results generally indicated no difference in the effects of the physostigmine-lecithin combination as compared to lecithin alone, sustained attention on the continuous performance test was more efficient under physostigmine than placebo when the drug condition occurred first in the crossover design. Further investigation of neurotransmitter manipulation is warranted in patients with traumatic brain injury.

Administration, Oral↗

Synaptic connections between the hindwing stretch receptor and flight motor neurones in the locust revealed by double cobalt labelling for electron microscopy.

Synaptic interactions between sensory and motor neurones in the locust flight system have been investigated by using intracellular labelling with cobalt and nickel for electron microscopy. Simultaneous axonal filling of two neurones with different concentrations of metal ions produces differential labelling, so that contacts between them in the central nervous system can be recognized. We have investigated the connectivity of the hindwing stretch receptor neurone (SR) with a direct hindwing depressor motor neurone (MN 127) known from physiological experiments to receive monosynaptic input from the SR, and an indirect hindwing depressor motor neurone (MN 112/1), for which no monosynaptic connection with the SR has been reported. We have found no direct synapses between the SR and MN 112/1, although some of their branches lie close together in the neuropile. We have, however, found some evidence for polysynaptic connections between them. There are many synapses of conventional dyadic morphology from both the lateral and mediolateral branches of the SR to MN 127; the medial branch was not examined. Those from the lateral branch contact the motor neurone on branches close to the neuropilar segment, while those from the mediolateral branch contact long, thin distal twigs. We estimate that there are about 600 anatomical synapses between these two neurones. Our results suggest that a large number of widely distributed anatomical synapses constitute the physiological synaptic connection between the SR and MN 127. The dyadic arrangement of these synapses provides an anatomical correlate for the physiologically established divergence of SR outputs onto interneurones and motor neurones.

Animals↗

Neurological complications of hemoglobin SC disease.

The records of 68 patients with hemoglobin SC disease and 68 age- and sex-matched control patients were reviewed for neurological problems. A significant increase in retinopathy, stupor/coma, and seizures was noted in the hemoglobin SC group. Hemiplegia, noted in two young patients, was probably also secondary to hemoglobin SC disease. Hemoglobin SC disease may often go unrecognized as a cause of stupor and coma in older patients without other obvious manifestations of a sickling hemoglobinopathy. Factors known to precipitate sickling crisis and the associated neurological complications should be avoided, especially in patients undergoing surgery or parturition.

Adolescent↗

Comparison of 650 mg aspirin and 1,000 mg acetaminophen with each other, and with placebo in moderately severe headache.

Two-hundred-sixty-nine otherwise healthy persons experiencing periodic, moderately severe headache of a type that had previously responded to nonprescription medications completed this randomized, parallel, double-blind study. The three demographically similar subgroups took either 1,000 mg acetaminophen, 650 mg aspirin, or an identical placebo, for headache. Headache intensity and relief scores over the following six hours were obtained and assessed by sums of pain intensity difference and values of pain relief scores analyses. Responses for the group, and for the subgroup with tension headaches (107 persons) showed no differences between the effects of the active medications. The effects of each medication were strongly superior to placebo. There were no differences in side effects among the three treatment modalities. In persons experiencing tension-vascular headaches (162), only aspirin, at two hours, was superior to placebo, but direct comparison with acetaminophen suggested no real difference. Acetaminophen (1,000 mg) and aspirin (650 mg) are clinically similar in treating the headaches for which they are commonly taken. Recommendations for their use in treating headache should be based on individual patient suitability and on cost factors.

Acetaminophen↗

Rhabdomyolysis during treatment with epsilon-aminocaproic acid.

Severe rhabdomyolysis and acute renal failure occurred in a patient receiving epsilon-aminocaproic acid. The lack of evidence of vascular involvement in the muscle biopsy specimen suggests that epsilon-aminocaproic acid may have direct myotoxicity. This drug may produce a spectrum of muscle disease from mild myopathy to life-threatening rhabdomyolysis.

Adult↗

Biphasic periodic paralysis.

A young man with episodes characteristic of familial normokalemic periodic paralysis was restudied after a change in the nature of his attacks. He now has spontaneously occurring and provokable episodes of both hyperkalemic and hypokalemic periodic paralyses that are superimposed on a persistent myopathy. Hypokalemia seems to be associated with facilitated entry of glucose and potassium into muscles, whereas resistance to glucose and potassium entry accompanies hyperkalemia. The possibility that episodes of both hypokalemic and hyperkalemic weaknesses can occur in one person should be considered in pathogenic postulates regarding periodic paralysis.

Adult↗