Advantages and disadvantages of an essential drugs programme.
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Community Pharmacy Services↗
Biomedical subjects
L M Levy
Publications and source records attributed to L M Levy.
Down-regulation of glial glutamate transporters after glutamatergic denervation in the rat brain.
Membrane-localized transporter proteins, expressed in both neurons and glial cells, are responsible for removal of extracellular glutamate in the mammalian CNS. The amounts and activities of these transporters may be under regulatory control. We demonstrate here that cortical lesions, which decrease striatal glutamate uptake in synaptosome-containing homogenates by approximately 50%, also decrease the striatal concentrations of the astrocytic glutamate transporter proteins, GLT-1 and GLAST by approximately 20-30%. Since GABA uptake activity was not decreased and glial fibrillary acidic protein was increased in the same samples, the lesion-induced losses of GLT-1 and GLAST were not caused by a general impairment of neuronal or glial function. The observed reduction in the two astrocytic glutamate transporters after corticostriatal nerve terminal degeneration indicates that their levels of expression are dependent on glutamatergic innervation.
ATP-Binding Cassette Transporters↗
Reduced postischemic expression of a glial glutamate transporter, GLT1, in the rat hippocampus.
Perturbations of the synaptic handling of glutamate have been implicated in the pathogenesis of brain damage after transient ischemia. Notably, the ischemic episode is associated with an increased extracellular level of glutamate and an impaired metabolism of this amino acid in glial cells. Glutamate uptake is reduced during ischemia due to breakdown of the electrochemical ion gradients across neuronal and glial membranes. We have investigated, in the rat hippocampus, whether an ischemic event additionally causes a reduced expression of the glial glutamate transporter GLT1 (Pines et al. 1992) in the postischemic phase. Quantitative immunoblotting, using antibodies recognizing GLT1, revealed a 20% decrease in the hippocampal contents of the transporter protein, 6 h after an ischemic period lasting 20 min induced by four vessel occlusion. In situ hybridization histochemistry with 35S labelled oligonucleotide probes or digoxigenin labelled riboprobes directed to GLT1 mRNA showed a decreased signal in the hippocampus, particularly in CA1. This reduction was more pronounced at 3 h than at 24 h after the ischemic event. We conclude that the levels of GLT1 mRNA and protein show a modest decrease in the postischemic phase. This could contribute to the delayed neuronal death typically seen in the hippocampal formation after transient ischemia.
ATP-Binding Cassette Transporters↗
Cell cycle-dependent disruption of E2F-p107 complexes by human papillomavirus type 16 E7.
The human papillomavirus type 16 (HPV-16) E7 and adenovirus (Ad) E1A oncoproteins share a common pathway of transformation. They disrupt the cell cycle G1 phase-specific protein complex containing the E2F transcription factor and the regulatory protein Rb1, the retinoblastoma tumour suppressor gene product. In the G1 and S phases of the cell cycle, E7 and E1A bind two other cellular complexes containing the Rb1-related protein p107 and E2F. Ad E1A disrupts both complexes and releases active E2F. In contrast, HPV-16 E7, although it efficiently binds both E2F-p107 complexes, causes dissociation of the G1 phase complex only. Using chimeric proteins of HPV-16 E7 and Ad E1A we were able to demonstrate that the ability of E1A to disrupt both G1 and S phase E2F-p107 complexes is not due to the higher concentration of Ad E1A in the cell, but is an intrinsic property of the Ad E1A transforming region. These data suggest that E1A and E7 may function in cellular transformation in similar, but not identical ways.
3T3 Cells↗
Predicting outcome in the tethered cord syndrome: a study of cord motion.
Thirty-two children with spinal dysraphism have been studied with phase MRI to assess longitudinal cord motion. Seventeen children who were asymptomatic and who had normal or slightly decreased motion were not operated. Fifteen had signs and symptoms of spinal cord tethering as well as decreased cord motion and underwent surgery. None of the nonsurgical patients have become symptomatic. The children with markedly decreased cord motion did not improve after surgery. A trend was seen toward a better outcome in younger patients with slight or moderate decrease in cord motion. All children with worse outcome were previously operated meningomyeloceles who had markedly decreased cord motion and who were greater than 10 years old.
Adolescent↗
Differential expression of two glial glutamate transporters in the rat brain: quantitative and immunocytochemical observations.
Glutamate, the major excitatory neurotransmitter in brain, is almost exclusively intracellular due to the action of the glutamate transporters in the plasma membranes. To study the localization and properties of these proteins, we have raised antibodies specifically recognizing parts of the sequences of two cloned rat glutamate transporters, GLT-1 (Pines et al., 1992) and GLAST (Storck et al., 1992). On immunoblots the antibodies against GLT-1 label a broad heterogeneous band with maximum density at around 73 kDa, while the antibody against GLAST labels a similarly broad band at around 66 kDa in the cerebellum and a few kilodaltons lower in other brain regions. GLT-1 is expressed at the highest concentrations in the hippocampus, lateral septum, cerebral cortex, and striatum, while GLAST is preferentially expressed in the molecular layer of the cerebellum. However, both transporters are present throughout the brain, and have roughly parallel distributions in the cerebral hemispheres and brainstem. Preembedding light and electron microscopical immunocytochemistry shows that both GLT-1 and GLAST are restricted to astrocytes, which appear to express both proteins concomitantly, but in different proportions in different parts of the brain. Nerve terminal labeling was not observed. Both the amino and carboxyl terminals of GLT-1 and GLAST are located intracellularly, indicating an even number of transmembrane segments. Antibodies against a synthetic peptide corresponding to amino acid residues 2-11 of the proposed sequence of GLT-1 recognize the native rat brain GLT-1 protein, confirming that the translation initiation site is at the first ATG.
ATP-Binding Cassette Transporters↗
Flow-sensitive magnetic resonance imaging in the evaluation of cerebrospinal fluid leaks.
Cerebrospinal fluid (CSF) leaks involving the skull base are associated with considerable morbidity and mortality, and often present a diagnostic challenge. Current diagnostic methods are invasive and cumbersome and involve substantial radiation exposure of the patient. The authors identified seven patients with clinically suspected CSF leaks and evaluated them with a flow-sensitive magnetic resonance imaging (MRI) sequence in addition to more conventional studies. In cases with active CSF leakage, flow characteristics were documented with slow-flow and diffusion-weighted MRI. Unlike current approaches, MRI offers the advantages of rapidity, non-invasiveness, and absence of ionizing radiation. Preliminary results suggest that flow-sensitive MRI may have a role in the evaluation of CSF leaks involving the skull base and temporal bone.
Adult↗
A monoclonal antibody raised against an [Na(+)+K+]coupled L-glutamate transporter purified from rat brain confirms glial cell localization.
A monoclonal antibody (9C4) shows that an [Na(+)+K+]coupled glutamate transporter protein purified from rat brain runs electrophoretically as a wide band and is localized in neuroglial cell bodies and processes, but not in neurons. This confirms the findings with polyclonal antibodies [Neuroscience 51 (1992) 295-310], and shows that the apparent heterogeneity in relative molecular mass is accounted for by a single antigenic epitope. By testing several synthetic peptides derived from the deduced amino acid sequences of two cloned rat brain glutamate transporters, the antigenic epitope was identified as residing within the peptide TQSVYDDTKNHRESNSNQC (residues 518-536) of one of these [Nature 360 (1992) 464-467].
Amino Acid Sequence↗
Sacral meningeal cysts: evaluation with MR imaging.
It is often difficult for the radiologist to determine if a given sacral meningeal cyst is causing symptoms. Radiographic criteria for identifying cysts likely to be symptomatic are needed. Using conventional magnetic resonance (MR) imaging along with a specifically designed flow-sensitive sequence, the authors characterized 24 cysts (19 patients) with respect to diameter and communication with the subarachnoid space. They found no significant difference in size between symptomatic and asymptomatic cysts (P > .05) but did observe a clear-cut disparity in the context of communication: Five of five asymptomatic cysts were shown to communicate on MR flow studies, while seven of seven symptomatic cysts were not shown to communicate. The authors propose that flow-sensitive MR imaging is useful in differentiating communicating from noncommunicating sacral meningeal cysts and that this information may be of value in classifying these lesions as more or less likely to be symptomatic.
Adult↗
Advances in lymphoma treatment.
There have been considerable advances in the management of patients with lymphoma over the past three decades. In Hodgkin's disease, there was a major break-through in the late 1960s with the development of the MOPP combination regimen. Using this and other more recent combinations, remission rates of up to 80 pc may be achieved overall with many patients having durable remissions. In non-Hodgkin's lymphoma there have been few advances in therapy of the indolent low-grade varieties which remain largely incurable. In the aggressive high-grade lymphomas, some subtypes have proved highly responsive to intensive cytotoxic programmes, giving remission rates and relapse-free survival rates of 70-80 pc. Certain categories, however, such as lymphoblastic lymphoma, remain a problem. Bone marrow transplantation and biological response modifiers have been important recent developments. The search for treatment strategies that improve survival and have relatively low toxicity is a continuing challenge.
Antineoplastic Combined Chemotherapy Protocols↗
Zimbabwe National Cancer Registry: summary data 1986-1989. National Cancer Registry Advisory Committee.
The Zimbabwe National Cancer Registry began operation in 1986. Between 1986-1989, a total of 8 276 cases were identified. Among men of African descent, oesophageal (11.2 pc) and liver cancer (11.0 pc) were most common. Cervical cancer was by far the most common among women of African descent (34.5 pc). Among both males and females of non-African descent, skin cancers (other than melanoma) accounted for one-third of cancers followed by prostate cancer (7.7 pc) in males and breast cancer (18.5 pc) in females. These findings are comparable to earlier reports of the epidemiology of cancer in Zimbabwe.
Causality↗
MR phase imaging and cerebrospinal fluid flow in the head and spine.
Motion of the cerebrospinal fluid (CSF) in and around the brain and spinal cord was examined in healthy subjects and in a number of patients with abnormalities of the CSF circulation. The pulsatile motion of the CSF was determined by spin echo phase (velocity) imaging, sometimes in combination with gradient echo phase contrast cine. Differences in flow patterns across CSF spaces were observed: flow reversal in the cerebellomedullary cistern and lumbar area relative to cervical CSF, and in the posterior versus the anterior subarachnoid space in the spinal canal. Flow communication was demonstrated in known communicating cysts or cavities. Differences in flow were also noted across spinal narrowing or block, and across the walls of a variety of cystic lesions in the brain and spinal cord. MR phase imaging of CSF flow provides pathophysiological information of potential clinical importance for the assessment of diseases affecting the CSF circulation.
Brain↗
Stereospecificity of C4 nicotinamide hydrogen transfer of the NADP-dependent glyceraldehyde-3-phosphate dehydrogenase.
The stereospecificity of the reaction catalysed by the spinach chloroplast enzyme NADP-dependent glyceraldehyde-3-phosphate dehydrogenase (D-glyceraldehyde-3-phosphate: NADP+ oxidoreductase (phosphorylating), EC 1.2.1.13) with respect to the C4 nicotinamide hydrogen transfer was investigated. NADPH deuterated at the C4 HA position was synthesized using aldehyde dehydrogenase. 1H-NMR spectroscopy was used to examine the NADP+ product of the GPDH reaction for the presence or absence of the C4 deuterium atom. Chloroplast NADP-dependent glyceraldehyde-3-phosphate dehydrogenase retains the deuterium at the C4 HA position (removing the hydrogen atom), and is therefore a B (pro-S) specific dehydrogenase.
Chloroplasts↗
Interaction of NADPH and triazine dyes with ferredoxin-NADP+ oxidoreductase.
The ability of NADPH to compete for binding with other ligands of known affinity has been used to provide values for the Kd of NADPH with ferredoxin-NADP+ oxidoreductase (EC 1.18.1.2) (FNR). When the competing ligand is procion red, which binds with a red-shift in spectrum, or Woodwards reagent K(N-ethyl-5-phenylisoxazolium 3'-sulfonate), which covalently modifies an active site carboxyl residue, the calculated Kd for the NADPH-FNR complex is greater than 8 or 0.08 mM, respectively. Because of the feeble (or non-existent) ability of NADPH to dislodge procion red, we propose that this dye and NADPH are not binding at the same site. Procion red must, however, bind additionally at the active site (presumably without spectral perturbation) as it is a competitive inhibitor of NADPH in ferricyanide reduction assays and more crucially proves to be a novel substrate itself, being reduced to a leuco form which can be reoxidised by oxygen. Although a Kd for the NADPH-FNR complex of 0.08 mM is reasonable, we point out the difficulty of interpreting this value and question its physiological significance.
Ferredoxin-NADP Reductase↗
Hodgkin's disease in black Zimbabweans. A study of epidemiologic, histologic, and clinical features.
A 3-year prospective study of the histologic and clinical features of patients with Hodgkin's disease presenting to the medical units in Harare, Zimbabwe, was undertaken. The histologic pattern of disease was similar to that of other African countries with mixed cellularity and lymphocyte depleted patterns prevailing (58% and 21%, respectively). Unlike most African countries, however, disease occurred most commonly in teenagers and young adults. Nutritional status was poor in just under 50% of the patients. Clinically, the extent of disease at presentation was striking, with over 90% of patients having advanced stage disease in spite of the stated duration of symptoms being moderate. The histologic and clinical findings resembled those reported from other African countries, but in certain aspects the epidemiologic pattern was intermediate between those of affluent and underprivileged communities.
Adolescent↗
Spinal cord artifacts from truncation errors during MR imaging.
The significance of linear regions of altered signal intensity that appear in sagittal magnetic resonance (MR) images along the length of the spinal cord was investigated. Examinations were performed on ten healthy volunteers and one patient with spinal cord edema. A 0.5-T or a 1.5-T MR system was used. Sampling-related effects (Gibbs phenomenon) at spinal cord edges and cerebrospinal fluid interfaces can lead to different signal patterns within the spinal cord and canal. These artifacts cause problems in interpretation, especially with the use of small object-to-pixel size ratios, by obscuring anatomy and simulating pathologic conditions such as pseudosyringes. Analysis of these intensity variations and of their dependence on sampling may improve the clinical accuracy of MR imaging.
Humans↗
Fixed spinal cord: diagnosis with MR imaging.
Pulsatile motion of the spinal cord was examined with phase imaging techniques. Sagittal images of the spinal cord were obtained at different times of the cardiac cycle in healthy volunteers, as well as in patients in whom the spinal cord either was tethered, was compressed, or contained an intramedullary lesion. Pulsatile velocity changes of the spinal cord, observed on the phase images, were most marked at the cervical-upper thoracic level. Cord motion was found to be significantly decreased in cases in which the cord was either tethered or compressed. Cord enlargement due to an intramedullary lesion generally did not lead to decreased cord motion. Imaging of pulsatile cord motion may be clinically useful in evaluating diseases restricting cord motion or changing the status of parenchymal compliance.
Adult↗
Low-grade non-Hodgkin's lymphoma in Zimbabwe: clinical features and stage.
Fifteen patients with low-grade non-Hodgkin's lymphoma were seen in Harare over a 3-year period, and this group constituted approximately 17% of all non-Hodgkin's lymphoma. All but one were of type A (Working Formulation), i.e. small lymphocytic. This low proportion of lesser grades of malignancy and virtual absence of follicular histology was similar to findings in other parts of Africa. The clinical features, however, resembled those reported worldwide with the sex ratio equal, older patients affected, and most patients (87%) having advanced stage disease, often with extranodal spread.
Humans↗