Meningeal carcinomatosis from breast carcinoma responsive to trastuzumab.
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Adult↗
Biomedical subjects
M Groves
Publications and source records attributed to M Groves.
Expression of CCR-5/CXCR-4 in spinal cord of patients with AIDS.
The discovery that chemokines and their receptors (in particular CXCR-4 and CCR-5) play a role in HIV infection challenges traditional views on the pathogenesis of HIV infection in man and identifies new potential targets for therapeutic intervention. Several groups as well as our pilot study have found that increased numbers of CCR-5 positive macrophage/microglia correlate with disease severity in brains of patients with AIDS. Among HIV-related disorders, vacuolar myelopathy (VM) is the most common spinal cord disorder in patients with AIDS. The purpose of this study was to investigate the possible relationship between the expression of CCR-5/CXCR-4 and spinal cord pathology in patients with AIDS. Thirty-four spinal cords (forming two groups: without and with VM) of patients with AIDS and 6 HIV-1-negative controls were investigated by routine histological examination and immunohistochemistry. Elevated expression of CXCR-4 was found in most AIDS cases with/without neuropathological disorders (8/17 and 13/16, respectively). No CCR-5 expression was detected in HIV-1-negative controls. Among 34 cases with AIDS, expression of CCR-5 was detected in 1/16 HIV-1-positive normal spinal cords and 5/18 with VM. Despite the lack of statistical significance between the two groups (P=0.1019), our results suggest that CCR-5/CXCR-4 are present in spinal cord of patients with AIDS and that CCR-5 is more frequently found in association with VM.
Acquired Immunodeficiency Syndrome↗
Retargeting of adenoviral vectors to neurons using the Hc fragment of tetanus toxin.
The Hc fragment of tetanus toxin (Hc) retains the specific nerve cell binding and transport properties of the holotoxin, but lacks any toxicity. We are investigating the potential for utilising its neurotropism for targeted gene delivery to the central nervous system. Previously we reported the use of Hc-polylysine conjugates for selective gene transfer into neuronal cells in vitro. However, as attempts to apply these constructs in vivo were not successful, we have extended these studies to modification of the tropism of adenoviral vectors. Either Hc-polylysine conjugates or the Fab fragment of a neutralising anti-knob antibody covalently bound to Hc were attached to the virus. Infection of neuronal and non-neuronal cell lines with retargeted virus showed highly increased neuronal cell selectivity, but no significant enhancement of gene delivery into these cells. High concentrations of free Hc blocked the infectivity of the retargeted vector efficiently. Intramuscular injection of retargeted virus into mouse tongues resulted in selective gene transfer to the neurons of the hypoglossal nucleus, where no pathological changes were observed. As differentiated neurons do not undergo cell division, appropriate vectors carrying a thymidine kinase gene, which allows selective elimination of dividing cells, may be exploitable for the treatment of tumours of the central nervous system. The demonstrated suitability of the Hc fragment of tetanus toxin as targeting moiety for viral vectors also indicates a potential for gene therapy of inherited neurodegenerative diseases such as spinal muscular atrophy.
Adenoviridae↗
Analysis of mutants of tetanus toxin Hc fragment: ganglioside binding, cell binding and retrograde axonal transport properties.
Tetanus toxin binds neuronal tissue prior to internalization and trafficking to the central nervous system. Binding of the carboxy-terminal 50 kDa HC fragment of tetanus toxin to polysialogangliosides is important for this initial cell binding step. Using the three-dimensional structure of HC, mutants were designed to investigate the role of individual residues in ganglioside binding. Mutant proteins were tested for binding to GT1b gangliosides, to primary motoneurons and for their ability to undergo retrograde transport in mice. Two classes of mutant were obtained: (i) those containing deletions in loop regions within the C-terminal beta-trefoil domain which showed greatly reduced ganglioside and cell binding and did not undergo retrograde transport and (ii) those that showed reduced ganglioside binding, but retained primary neuronal cell binding and retrograde transport. The second class included point mutants of Histidine-1293, previously implicated in GT1b binding. Our deletion analysis is entirely consistent with recent structural studies which have identified sugar-binding sites in the immediate vicinity of the residues identified by mutagenesis. These results demonstrate that ganglioside binding can be severely impaired without abolishing cell binding and intracellular trafficking of tetanus toxin.
Animals↗
Detection and localisation of HIV-1 DNA and RNA in fixed adult AIDS brain by polymerase chain reaction/in situ hybridisation technique.
In the brain of patients with AIDS, HIV-1 is localised in a productive form in mononuclear cells. One issue that still needs clarification is whether HIV is localised in cells other than those of mononuclear lineage. Gene amplification by polymerase chain reaction/in situ hybridisation (PCR-IS) could shed light on it. In this study, formalin-fixed, paraffin-embedded brain tissue from ten adult AIDS sufferers was used. Five of them showed evidence of HIV encephalitis (HIVE), five did not show any abnormality. Nested PCR revealed HIV-1 DNA in all HIVE cases and in three of the group without HIVE. HIV-1 DNA and RNA were also detected in situ in seven cases (all seven were also HIV-1 DNA positive in tube). A higher signal was located in the white than in the grey matter. HIV-1 DNA was found in microglia, macrophages, perivascular cells, multinucleated gaint cells (MGC) and in CD68-negative cells. Some of them were identified as endothelial cells, astrocytes and oligodendrocytes. Reverse transcriptase-PCR-IS was positive in macrophages, MGC, endothelial and glial cells. These results confirm infection of endothelial cells and other glial cells and give clues about the route of entry of virus into the central nervous system and the pathogenesis of the disease. This study did not give any convincing evidence supporting an infection of neurons by HIV-1.
AIDS Dementia Complex↗
Early entry and widespread cellular involvement of HIV-1 DNA in brains of HIV-1 positive asymptomatic individuals.
There is overwhelming evidence that invasion of the central nervous system (CNS) by HIV-1 takes place at an early stage of the infection. It has been demonstrated that HIV-1 DNA is present in brains of asymptomatic individuals. Evidence of immune activation and increased expression of cytokines suggested that neuropathological changes and neuronal and axonal damage could be the effect of the presence of the virus. The purpose of the study is to ascertain whether target cells for HIV-1 in brain of patients at early stage of the infection are the same as those found in AIDS sufferers or if the distribution seen in AIDS patients results from the late spreading of the infection from cells considered traditionally the reservoir of the virus, i.e. microglial cells. Eighteen brains, all HIV-1 DNA positive, as shown by nested polymerase chain reaction (PCR), were selected among the group of HIV-1 positive asymptomatic cases. In 6 of them, HIV-1 DNA was detected by PCR in situ. Positive cells included astrocytes and endothelial cells, in addition to microglial cells. We conclude that astrocytes and endothelial cells are already infected at an early (asymptomatic) stage of the infection and suggest that they might contribute to the damage of the CNS.
Acquired Immunodeficiency Syndrome↗
The neuropathology of paraneoplastic syndromes.
The term "paraneoplastic neurological syndromes" encompasses a number of uncommon disorders associated with systemic malignancies. In order to be classified a paraneoplastic neurological syndrome, the malignancies must not invade, compress, or metastasize to the nervous system. They can either focally or diffusely involve the central and peripheral nervous system or the neuromuscular junction. This paper reviews the neuropathology of the syndrome. It will first describe the clinical presentation and give an account of the systemic tumors most commonly associated with the various types of disorders. Then it will review the general pathological features that consist of an inflammatory process predominantly affecting the gray matter. Finally, it will describe in detail the main clinico-pathological types, including 1) encephalomyelitis, 2) cortical cerebellar degeneration, 3) peripheral neuropathy, 4) opsoclonus-myoclonus and 5) retinopathy. The Lambert-Eaton myasthenic syndrome will be dealt with separately in another paper in this symposium.
Autoantibodies↗
Poor response rate to a continuous schedule of Amifostine therapy for 'low/intermediate risk' myelodysplastic patients.
Ineffective haemopoiesis leading to cytopenia presents the major clinical management problem for patients with myelodysplasia (MDS). Preliminary studies have demonstrated that the synthetic aminothiol Amifostine stimulates multilineage haemopoiesis both in vitro and in vivo in patients with MDS. We have treated 12 patients with an uninterrupted 8-week schedule of thrice-weekly intravenous Amifostine with a starting dose of 300 mg/m2 escalating to 450 mg/m2 in non-responders. No patients satisfied response criteria on study but two patients showed minor responses. We conclude that therapeutic response to Amifostine in MDS may be schedule dependent.
Amifostine↗
Protein engineering aspartic proteinases. Site-directed mutagenesis, biochemical characterisation, and X-ray analysis of chymosins with substituted single amino acid substitutions and loop replacements.
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Amino Acids↗
Accumulation of beta-amyloid precursor protein in HIV encephalitis: relationship with neuropsychological abnormalities.
The pathogenesis of neuropsychological abnormalities in patients with human immunodeficiency virus type 1 (HIV-1) encephalitis is obscure because neurons are not the target of infection and severe neuronal loss occurs only late during the disease. Moreover, there is evidence indicating that HIV dementia is not a homogeneous entity and could partially reverse after treatment with zidovudine. The finding that impaired axonal flow, evidenced by beta-amyloid precursor protein immunoreactivity, could contribute to the neuropsychological deficits prompted the present study. Brains of patients with full-blown acquired immunodeficiency syndrome (AIDS) were studied and findings compared with those of normal and abnormal control subjects. The presence of HIV-1 DNA was investigated by nested polymerase chain reaction; axonal abnormalities were detected by beta-amyloid precursor protein, ubiquitin immunohistochemistry, and silver staining. Accumulation of beta-amyloid precursor protein was observed in all the HIV encephalitis brains studied; the appearance of the immunostaining varied from globular structures to bundles of parallel formations. In 2 AIDS brains without pathological abnormalities, only the latter pattern was detected. The brains with trauma were strongly reactive with beta-amyloid precursor protein antibody and the different reactivity within them correlated with posttrauma survival, only globular structures being detected in the older cases. No correlation was found between the different pattern of beta-amyloid precursor protein reactivity and dementia in AIDS patients. These results show that widespread axonal injury is a constant feature in AIDS brains and suggest that it could play a role in the pathogenesis of the neuropsychological abnormalities of these patients.
AIDS Dementia Complex↗
Axonal damage revealed by accumulation of beta-APP in HIV-positive individuals without AIDS.
The presence of neuropsychological disturbances in HIV-positive, pre-symptomatic individuals is a controversial issue. Neuroimaging studies have not shown brain atrophy or hyperintensity in the white matter, whereas proton magnetic resonance spectroscopy has revealed some abnormality of cerebral biochemistry. Using an antibody to beta-amyloid precursor protein (beta-APP), we previously demonstrated frequent and widespread axonal changes in the brains of AIDS patients. In this study, we extended the use of beta-APP to asymptomatic patients in order to establish a possible morphological correlation with neuropsychological disorders. Brain samples from 29 patients were examined. Results showed bundles of beta-APP-positive axons in 8/29 cases (27%). The changes, seen in both superficial and deep white matter, were either focal or diffuse, could not be visualized by silver or ubiquitin stains, and did not coexist with any change in distribution or morphology of astrocytes and microglial cells. We conclude that in HIV-positive asymptomatic individuals, axonal changes: (a) may be related to the state of immune activation with consequent presence of toxic substances, including cytokines, observed in these patients; (b) may represent mild changes that could undergo repair, unless other pathological events, such as the supervening of the AIDS stage and the specific encephalitis, make them permanent.
Amyloid beta-Protein Precursor↗
Radiological case of the month. Sinusitis osteo-meatal unit (OMU) disease.
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Acute Disease↗
Detection of paraneoplastic anti-neuronal autoantibodies on paraffin-embedded tissues.
Anti-neuron-specific autoantibodies are widely recognised as useful, though non-specific, diagnostic markers of paraneoplastic neurological disorders. However, controversies on the best way to detect these autoantibodies have recently arisen, and the use of different procedures for their detection by different laboratories has made results difficult to compare. The aim of this study was to adapt the existing immunohistochemical techniques used for the detection of anit-neuron autoantibodies to improve their visualisation and to facilitate a wide application of these procedures. Sera and cerebrospinal fluid (CSF) were obtained from 15 patients known to carry paraneoplastic anti-neuronal autoantibodies; in addition, one serum with "atypical" anti-neuron autoantibody and 18 control sera were studied. Paraformaldehyde-fixed, paraffin-embedded rat nervous tissue and formalin-fixed, paraffin-embedded human nervous tissue treated in a microwave oven were used as substrate; the reactions were developed by immunoperoxidase methods. At the dilutions used for diagnostic purposes, all the sera and CSFs showed staining whose intensity and specificity was comparable to that obtained using frozen tissue; the end-point dilutions were, however, reduced. The atypical pattern of staining of one serum was confirmed and better emphasised using these procedures; all control sera and CSFs were negative. The morphology was improved by the use of paraffin-embedded tissues; moreover, the results obtained are permanent because of peroxidase staining, which makes it possible to use them as standards for further investigations and for comparison between different laboratories. The convenience of using paraffin-embedded material could facilitate a wide application of these procedures in clinical neurology.
Animals↗
The effects of formalin fixation on the detection of apoptosis in human brain by in situ end-labelling of DNA.
The technique of DNA in situ end-labelling (ISEL) for the detection of apoptotic cells has recently become the method of choice. The incorporation of a labelled nucleotide to facilitate detection into the single-stranded region of DNA cleaved by endogenous nucleases has proved to be a sensitive and straightforward technique. Previous reports have applied the technique to the study of apoptotic cells in brain tissue, which is normally subjected to relatively long-term formalin fixation. In this study we have examined the effects of long-term formalin fixation on the ability to detect apoptosis using ISEL in a variety of pathologies and in a normal rat testis. In the tissues which had been treated with overnight formalin fixation, apoptotic cells were readily identified in those pathologies where it might be expected to occur. However, in tissue which had been fixed for several weeks or more, apoptotic cells were not detectable. Samples of brain lymphoma tissue and rat testis subjected to a prospective analysis with respect to fixation time showed that the ability to detect apoptotic cells tailed off at around 3-5 weeks. In order to obviate the risk of false negative results it would be desirable to use ISEL in tissues formalin fixed for less than this period.
Acquired Immunodeficiency Syndrome↗
Effect of concurrent chest pain assessment on retrospective reports by cardiac patients.
The purpose of this study was to examine the effect of a concurrent record of chest pain episodes on later completeness and accuracy of verbal recall. Patients included 23 men and eight women, ages 43 to 76 years from a private cardiology practice who were randomized into experimental (n = 16) and control (n = 15) groups. Following an initial interview, experimental patients were instructed in using a Chest Discomfort Diary in the home setting to record eight categories of information about each episode of chest pain experienced during the next 7 to 10 days. At the end of that time, both groups were interviewed about a specific typical episode of chest pain that had occurred; patients who did not have chest pain during the study period described an episode experienced prior to the initial interview. Experimental patients recalled their chest pain more completely than controls (P = 0.007), whether it had occurred during or prior to the study period. Experimental patients who had pain (n = 11), and thus actually used the diary, accurately recalled the duration, intensity, description, and treatment of the typical episode but were often inaccurate regarding their mood and the total number of episodes they had experienced. The findings suggest that a concurrent diary offers one method of teaching patients how to report their chest pain symptoms and may improve the completeness and accuracy of those reports.
Aged↗
Computerizing patient questionnaires.
Hillcrest Baptist Medical Center spent two years perfecting its computerized patient questionnaire system. A look at how the system evolved illustrates some valuable lessons on implementing a computerized system that provides hospitals with fast and accurate analyses of patient opinions.
Computer Systems↗
Extravascular lung water measurement by double indicator dilution in shock and respiratory failure.
Clinical quantitation of water accumulation in the lungs is imprecise. The technique of measuring extravascular lung water (EVLW) with double indicator dilution utilizing cold indocyanine green dye has become practical with the addition of a microprocessor. The technique, insertion of a special thermistor tipped arterial catheter and potential problems are described. Our studies with resuscitation of 27 patients in shock indicate little increase in EVLW at 24 hours. On the other hand 19 patients with Adult Respiratory Distress Syndrome (ARDS) had marked increases in EVLW from normal of 5-8 ml/kg to 10.7 to 14.4 ml/kg. No further increases in EVLW were observed in eight ARDS patients requiring fluid resuscitation for associated hypovolemia and hypoperfusion. We feel that measurement of EVLW in critically ill patients offers an opportunity to study the pathophysiology of pulmonary failure.
Catheterization↗
Two-dimensional impedance studies of BSA buoyant density separated human erythrocytes.
Combined DC (Coulter Volume) and radio frequency impedance studies were performed on human erythrocytes which had been separated by buoyant density in linear, neutral, isotonic bovine serum albumin gradients. The individual buoyant density fractions showed no reproducible shift in volume with buoyant density but did show a shift with opacity, radio frequency impedance divided by dc impedance. This new electronic parameter of opacity can be related to cell age, since both it and cell age are directly related to buoyant density. This increase in opacity with buoyant density is correlated with a change in shape.
Adult↗