Temporal lobe destruction with microvascular dissections following irradiation for rhinopharyngeal carcinoma.
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Aortic Dissection↗
Biomedical subjects
D Troost
Publications and source records attributed to D Troost.
Upregulation of metabotropic glutamate receptor subtype mGluR3 and mGluR5 in reactive astrocytes in a rat model of mesial temporal lobe epilepsy.
Reactive gliosis is a prominent morphological feature of mesial temporal lobe epilepsy. Because astrocytes express glutamate receptors, we examined changes in metabotropic glutamate receptor (mGluR) 2/3, mGluR5 and transforming growth factor (TGF)-beta in glial cells of the hippocampal regions in an experimental rat model of spontaneous seizures. Rats that exhibited behavioural status epilepticus (SE) directly after 1 h of electrical angular bundle stimulation, displayed chronic spontaneous seizures after a latent period of 1-2 weeks as observed using continuous electrographic monitoring. SE resulted in hypertrophy of astrocytes and microglia activation throughout the hippocampus as revealed by immunolabelling studies. A dramatic, seizure intensity-dependent increase in vimentin immunoreactivity (a marker for reactive astrocytes) was revealed in CA3 and hilar regions where prominent neuronal loss occurs. Increased vimentin labelling was first apparent 24 h after onset of SE and persisted up to 3 months. mGluR2/3 and mGluR5 protein expression increased markedly in glial cells of CA3 and hilus by 1 week after SE, and persisted up to 3 months after SE. Double immunolabelling of brain sections with vimentin confirmed co-localization with glial fibrillary acidic protein (GFAP), mGluR2/3 and mGluR5 in reactive astrocytes. TGF-beta, a cytokine implicated in mGluR3-mediated neuroprotection, was also upregulated during the first 3 weeks after SE throughout the hippocampus. This study demonstrates seizure-induced upregulation of two mGluR subtypes in reactive astrocytes, which - together with the increased production of TGF-beta - may represent a novel mechanism for modulation of glial function and for changes in glial-neuronal communication in the course of epileptogenesis.
Animals↗
Nitric oxide synthase expression and apoptotic cell death in brains of AIDS and AIDS dementia patients.
OBJECTIVES: To determine the occurrence and cellular localization of inducible nitric oxide synthase (iNOS), NOS activity and its association with cell death in brains of AIDS and AIDS dementia complex (ADC) patients. DESIGN AND METHODS: Post-mortem cerebral cortex tissue of eight AIDS patients, eight ADC patients and eight control subjects was processed for iNOS immunocytochemistry, NADPH-diaphorase activity staining as an index of NOS activity, and in situ end-labelling to detect cell death. RESULTS: iNOS-positive cells were present in the white matter of 14 out of 16 AIDS and ADC patients, whereas two out of eight control subjects showed iNOS-positive cells. iNOS immunoreactivity was exclusively localized in activated macrophages and microglial cells that both showed NADPH-diaphorase activity. In addition, NADPH-diaphorase activity, not related to iNOS immunoreactivity, was observed in astrocytes in both white and grey matter of AIDS and ADC patients. All AIDS and ADC patients, and only one control subject showed characteristic features of apoptotic cell death. CONCLUSIONS: Different forms of NOS are present in microglial cells and astrocytes of AIDS and ADC patients but are largely absent in control subjects. Although more NOS-expressing cells occur in ADC than in AIDS patients, apoptotic cell death was found in both patient groups to the same extent. We postulate that NO production in brains of AIDS patients results in cumulative cortical cell loss, which becomes neurologically evident at later stages of disease and is expressed as ADC.
AIDS Dementia Complex↗
Genetic sub-types of human malignant astrocytoma correlate with survival.
In human malignant astrocytoma, age of the patient and histological grade of the tumor are important prognostic variables. Several genetic changes have been reported to occur in these tumors, which may be of additional and independent prognostic relevance. To determine their prognostic significance, we analyzed 75 high-grade tumors, 12 anaplastic astrocytomas and 63 glioblastomas multiforme, for the presence of genetic changes that occur frequently in high-grade astrocytoma, i.e., loss of heterozygosity (LOH) for chromosome 10, p53-gene alteration (mutation and/or LOH), and EGFR-gene amplification. We defined 4 groups of patients who showed a specific combination of genetic changes in the tumor: group 1, p53-gene alteration without complete LOH 10; group 2, complete LOH 10 only; group 3, p53-gene alteration + complete LOH 10; group 4, complete LOH 10 + EGFR-gene amplification. In univariate analysis, the log-rank test revealed significant differences in survival between patients of group 1 (median survival of 13 months) and group 3 (median survival of 5.2 months, p = 0.0058) and between patients of group 1 and group 4 (median survival of 4 months, p = 0.0033). In multivariate analysis, age and genetic sub-type proved to be important prognostic variables, whereas histological grading was less important. The age-corrected survival time for group-4 patients is significantly shorter than that for group-1 patients (relative risk = 3.79, p = 0.0075). Our data indicate that genetic sub-type is an important prognostic variable in human high-grade astrocytoma.
Adult↗
Dynamics of genetic alterations associated with glioma recurrence.
We investigated the dynamics of the genetic changes that are associated with two types of glioma recurrence, that is, progression from a lower-grade to a high-grade tumor (7 cases) and development of a same high-grade recurrence (15 cases). Each pair of tumors was analyzed for TP53 mutation, EGFR amplification, and loss of heterozygosity for tumor suppressor genes (TP53, RB1, CDKN2A, PTEN, DMBT1) and tumor suppressor gene regions (1p36, 19q13, 11p15, 10p15) known to be frequently implicated in glioma tumorigenesis. By comparing the genetic changes in the primary and corresponding secondary tumors, we found that additional loss of CDKN2A and/or RB1, encoding important components of the cell cycle regulatory pathway, was the most frequent genetic change in both types of recurrence development (10 of 22 cases, 45%). Additional loss of heterozygosity for the 10p15 region, for PTEN, and/or for DMBT1 in the recurrent tumor was noted in 7 of 22 cases (32%), suggesting that additional inactivation of tumor suppressor genes on chromosome 10 is another important feature of glioma relapse. Less frequent additional losses were detected for chromosome regions 11p15 and 19q13 (3 of 22 cases, 14%, each). We conclude that glioma recurrences are characterized by an increased involvement of tumor suppressor genes, even in those cases in which the primary and secondary tumor are of the same high malignancy grade.
Adult↗
5-year survival and clinical prognostic factors in progressive supratentorial diffuse "low-grade" astrocytoma: a retrospective analysis of 46 cases.
In order to study survival and identify prognostic factors in progressive supratentorial low grade astrocytoma, 46 cases of diffusely growing glioma (1982-1989), in which stereotactic biopsy revealed a diagnosis of astrocytoma grade II according to Kernohan, were evaluated. Only patients with definite tumour growth on consecutive CT scans were included. All patients received a full course of fractionated radiotherapy. All tumour biopsy specimens were re-evaluated according to both the Kernohan and Daumas-Duport grading systems. Follow-up for at least 5 years showed a median survival of 47.5 months (1 year 71%, 5 year 41%). In Cox' multivariate analysis 4 factors turned out to give the best fitting prognostic model for survival: age, duration of symptoms, pre-operative neurological examination and CT-contrast enhancement. Numerical scoring was performed by giving either 1 or 0 for: age > or < 40 years, symptom duration < or > 1 year, presence or absence of focal deficit, and presence or absence of CT-contrast enhancement. Combining these factors in a score ranging from 0-4 resulted in 3 distinct groups with respect to median survival (< 2:66.5 months, 2:40 months, > 2:10 months, P = 0.0015). Although 17 cases with Kernohan grade II were upgraded using Daumas-Duport criteria (13 grade III, 4 grade IV), these cases did not form a separate survival-group. Additional parameters are needed to assess prognosis by neuropathological means, as some "low-grade" tumours are less benign than others, giving rise to a variable natural history.
Adolescent↗
Differential expression of CD44 splice variants in the normal human central nervous system.
Cluster of differentiation 44 (CD44) is a broadly distributed group of glycoproteins that are involved in many functions related to cell-cell and cell-matrix interactions. In the present study, the expression of the standard form of CD44 (CD44s) and of CD44 variants (CD44v) was explored immunohistochemically on frozen sections of various areas of the human CNS. The results demonstrate that CD44s epitopes are expressed predominantly by white matter astrocytes, whereas different CD44 variant molecules are present in neurons, on axonal membranes, on endothelium or on choroid plexus epithelium. Interestingly, neurons and axons differentially expressed CD44 variant epitopes but consistently lack immunoreactivity for CD44s epitopes. Another interesting finding was that some CD44 variant epitopes expressed by neurons were localized in the cytoplasm instead of on the cell membrane. The broad distribution of variant CD44 molecules in the human CNS suggests that CD44 may play an important role in many biological processes in the CNS.
Aged↗
Hypofractionated radiation induces a decrease in cell proliferation but no histological damage to organotypic multicellular spheroids of human glioblastomas.
The aim of this study was to examine the effect of radiation on glioblastoma, using an organotypic multicellular spheroid (OMS) model. Most glioblastoma cell lines are, in contrast to glioblastomas in vivo, relatively radiosensitive. This limits the value of using cell lines for studying the radiation effect of glioblastomas. The advantage of OMS is maintenance of the characteristics of the original tumour, which is lost in conventional cell cultures. OMS prepared from four glioblastomas were treated with hypofractionated radiation with a radiobiologically equivalent dose to standard radiation treatment for glioblastoma patients. After treatment, the histology as well as the cell proliferation of the OMS was examined. After radiation, a significant decrease in cell proliferation was found, although no histological damage to the OMS was observed. The modest effects of radiation on the OMS are in agreement with the limited therapeutic value of radiotherapy for glioblastoma patients. Therefore, OMS seems to be a good alternative for cell lines to study the radiobiological effect on glioblastomas.
Cell Division↗
Treatment of ependymomas. Clinical and non-clinical factors influencing prognosis: a review.
We review the epidemiological and clinical features of ependymomas as described in published series as well as the effect on outcome of various treatment strategies.
Adolescent↗
c-Jun, JNK/SAPK kinases and transcription factor NF-kappa B are selectively activated in astrocytes, but not motor neurons, in amyotrophic lateral sclerosis.
There is increasing evidence that oxidative damage plays a major role in amyotrophic lateral sclerosis (ALS), but how it contributes to motor neuron degeneration and astrocytic gliosis, two pathologic hallmarks of the disease, is unknown. A few studies have suggested that ALS motor neurons die via apoptosis and show upregulation of c-jun, an immediate early gene that is necessary for neuronal apoptosis. In order to elucidate the mechanisms of cell damage induced by oxidant stress, we have studied in ALS and control spinal cord the immunohistochemical expression of c-Jun, of JNK/SAPK, a kinase that activates c-Jun following various types of stress, and of NF-kappa B, a transcription factor that is induced by oxidant stress and has prominent neuroprotective functions. An in situ end-labeling assay was performed for detecting apoptotic cells. We show that (a) the JNK/SAPK-c-Jun pathway is dramatically overexpressed in ALS spinal cord; (b) the strongest activation occurs in astrocytes, while motor neurons show unusually low expression of the pathway; (c) increased JNK/SAPK expression in glial cells is accompanied by NF-kappa B activation, indicating the presence of a protective response to oxidant sress, which is deficient in motor neurons; (d) activation of JNK/SAPK, c-Jun and NF-kappa B is unrelated to apoptotic cell death. These results support the view that astrocytes are directly involved in the pathologic process of ALS, and might explain the selective vulnerability of motor neurons by their relative lack of antioxidant defenses.
Amyotrophic Lateral Sclerosis↗
Autosomal dominant cerebellar ataxia with retinal degeneration (ADCA II): clinical and neuropathological findings in two pedigrees and genetic linkage to 3p12-p21.1.
OBJECTIVES: To investigate relations between clinical and neuropathological features and age of onset, presence of anticipation, and genetic linkage in autosomal dominant cerebellar ataxia type II (ADCA II). METHODS: The natural history of ADCA II was studied on the basis of clinical and neuropathological findings in two pedigrees and genetic linkage studies were carried out with polymorphic DNA markers in the largest, four generation, pedigree. RESULTS: Ataxia was constant in all age groups. Retinal degeneration with early extinction of the electroretinogram constituted an important component in juvenile and early adult (< 25 years) onset but was variable in late adult presentation. Neuromuscular involvement due to spinal anterior horn disease was an important contributing factor to illness in juvenile cases. Postmortem findings in four patients confirm the general neurodegenerative nature of the disease, which includes prominent spinal anterior horn involvement and widespread involvement of grey and white matter. Genetic linkage was found with markers to chromosome 3p12-p21.1 (maximum pairwise lod score 4.42 at D3S1285). CONCLUSIONS: The sequence of clinical involvement seems related to age at onset. Retinal degeneration is variable in late onset patients and neuromuscular features are important in patients with early onset. Strong anticipation was found in subsequent generations. Linkage of ADCA II to chromosome 3p12-p21.1 is confirmed.
Adolescent↗
Vascular expression of endothelial antigen PAL-E indicates absence of blood-ocular barriers in the normal eye.
The endothelium-specific antigen PAL-E is expressed in capillaries and veins throughout the body with the exception of the brain, where the antigen is absent from anatomical sites with a patent blood-brain barrier. In this study we determined vascular endothelial staining for PAL-E in the normal eye in relation to the ocular blood-tissue barriers. Immunohistochemical staining of frozen tissue sections of eyes from 22 cornea donors and a number of normal animal autopsy eyes was performed for the PAL-E antigen and the blood-brain barrier marker glucose transporter 1. In normal human and animal eyes, endothelial PAL-E staining was absent from the microvasculature in iris, ciliary muscle, optic nerve and retina. In a few normal human eyes, some weakly stained capillaries were observed in the retina and nerve fiber layer, mostly in the peripapillary area. Marked staining of capillaries and venules with PAL-E was observed in the conjunctiva, episclera, sclera, ciliary processes, choriocapillaris and optic nerve head. In general, the endothelial antigen PAL-E is absent from microvessels involved in the blood-ocular and the blood-retinal barriers. PAL-E may therefore be a useful marker to identify pathological breakdown of blood-ocular barriers.
Animals↗
Induction of c-Jun immunoreactivity in spinal cord and brainstem neurons in a transgenic mouse model for amyotrophic lateral sclerosis.
Transgenic mice carrying amyotrophic lateral sclerosis (ALS)-linked superoxide dismutase 1 (SOD1) mutations develop a motoneuron disease resembling human ALS. c-Jun is a transcription factor frequently induced in injured neurons. In this study we have examined the distribution of c-Jun-immunoreactivity in the brainstem and spinal cord of transgenic SOD1 mice with a glycine 93 alanine (G93A) mutation. In non-transgenic littermates c-Jun immunostaining was predominantly situated in motoneurons. The number of c-Jun immunoreactive motoneuron was reduced in SOD1(G93A) mice due to pronounced loss of motoneurons. In SOD1(G93A) mice, however, c-Jun-immunoreactivity was strongly induced in neurons in the intermediate zone (Rexed's laminae V-VIII and X) of the spinal cord and throughout the brainstem reticular formation. These findings are of interest since increased levels of c-jun also have been found in the intermediate zone of the spinal cord of ALS patients. This c-Jun may be involved in the neurodegenerative processes both in ALS and in motoneuron disease in SOD1(G93A) mice.
Amyotrophic Lateral Sclerosis↗
Enhanced superoxide dismutase-2 immunoreactivity of astrocytes and occasional neurons in amyotrophic lateral sclerosis.
The recent discovery of missense mutations in the superoxide dismutase (SOD)-1 gene as a cause of familial amyotrophic lateral sclerosis (ALS) and the ensuing description of transgenic SOD-1 mutant mouse models have focussed scientific interest on free radical scavenging mechanisms in all other familial (FALS) and sporadic (SALS) forms of the disease. We have compared the presence of intracellular cytosolic copper-zinc SOD-1 and mitochondrial manganese SOD-2 in the CNS from FALS and SALS patients and from non-neurological controls by immunohistochemical assessment, in the knowledge that no SOD-1 mutations have been found in any of 18 Dutch ALS pedigrees. ALS specimens from the motor cortex and the spinal cord presented enhanced SOD-2 immunoreactivity, especially of astrocytes and occasionally of neurons. Astrocyte staining appeared to be increased at the cerebral cortical and the spinal cervical and lumbar levels, but was only slightly increased in the thoracic anterior horns and not at all in the brain stem. This indicates that, by the time of death, the disease had burnt out in the brain stem and thoracic cord. Increased staining of neurons was limited to the small lateral and dorsal nuclei of the spinal cord. FALS and SALS cases exhibited the same staining patterns. SOD-1 immunoreactivity did not differ between disease and control specimens. SOD-1 and -2 staining was normal in the ALS cortical, brain stem and spinal motoneurons. This suggests that SALS and non-SOD-1 mutant FALS are not accompanied by loss of SOD-1 or -2 protein. An enzyme-linked immunosorbent assay revealed no differences in SOD-1 and SOD-2 levels between ALS patients and controls. Our major finding of locally increased SOD-2 immunoreactivity of astrocytes in FALS and SALS specimens, probably reflects reactive fibrillary and protoplasmatic gliosis in areas of ongoing degeneration but may also result from an attempt at compensation for free radical injury.
Adult↗
[Cerebrospinal fluid diagnosis using polymerase chain reaction].
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DNA, Bacterial↗
A newly recognized autosomal dominant limb girdle muscular dystrophy with cardiac involvement.
Sixty-five members of three families with limb girdle muscular dystrophy (LGMD) underwent neurological, cardiological, and ancillary investigations. Thirty-five individuals were diagnosed as having slowly progressive autosomal dominant LGMD. Symmetrical weakness started in the proximal lower limb muscles, and gradually upper limb muscles also became affected. Early contractures of the spine were absent. Contractures of elbows and Achilles tendons were either minimal or late. Serum creatine kinase activity was normal to moderately elevated. Electromyogram and muscle biopsy were consistent with a mild muscular dystrophy. Cardiological abnormalities, found in more than one-half the patients, included dysrhythmias and atrioventricular (AV) conduction disturbances presenting as bradycardia, syncopal attacks necessitating pacemaker implantation, and sudden cardiac death. There was a significant relation between the severity of AV conduction disturbances and age. In nearly all patients, neuromuscular symptomatology preceded cardiological involvement. The early recognition of this previously not described, autosomal dominant LGMD with life-threatening cardiac involvement offers an opportunity for therapeutic intervention.
Adolescent↗
Expression of different metallothionein messenger ribonucleic acids in motor cortex, spinal cord and liver from patients with amyotrophic lateral sclerosis.
In earlier studies of sporadic amyotrophic lateral sclerosis (ALS), a disease of unknown etiology, the amount of metallothioneins (MTs), a group of small (6-7 kDa) metal-binding proteins, appeared higher in liver, kidney and spinal cord from patients than from non-neurologic controls. Immunohistochemically, the expression of MT in the central nervous system appeared limited to glia. Since the highly conserved MTs isotypes share antigenic epitopes, they could not be distinguished by immunological methods. It thus proved necessary to estimate the expression of each individual MT messenger ribonucleic acid (mRNA) by performing reverse transcriptase polymerase chain reaction (RT-PCR)-mediated analysis of tissue samples. Tissues selected included liver, motor cortex and cervical cord at C6; MT mRNAs analyzed included MT1A, 1B, 1E, 1F, 1G, 2A, and 3. Also, special care was taken to avoid interference by amplification of the 6 MT pseudogenes. Except of MT3, already known as brain-specific, and MT1B which was not expressed in any tissue, mRNA levels of the other MT genes tended to be higher in ALS than in control liver samples, but the differences did not attain statistical significance. In the nervous system, the diverse MT genes were expressed over a greater range in ALS than in controls, but exhibited no change in a consistent direction. At the motor cortex, changes seemed to be less pronounced than at C6. MT3 was expressed in the motor cortex and the cord. The results provide no evidence for either the induction of a specific MT repertoire, or for the inability of glia to express any MT gene in ALS. Because the semi-quantitative RT-PCR technique does not permit detailed comparisons between the subtypes of MT expressed in the various tissues, the question whether a single inductor may be held responsible for the elevation of MT in the ALS liver and nervous system remains open. In conclusion, ALS tissue remains capable of expressing all the major MT genes. MT, present in protoplasmic glia, arises locally and is not secondary to increases of hepatic or renal MT. Because MT3 is also expressed by the normal and ALS spinal cord, it is a central nervous system-specific and not only a brain-specific protein. Thus, the excess of MT in ALS liver seems to be an effect of slower catabolism rather than faster synthesis of protein.
Adult↗
Daunorubicin and doxorubicin but not BCNU have deleterious effects on organotypic multicellular spheroids of gliomas.
In the present study organotypic multicellular spheroids (OMS) were used to study the effects of chemotherapeutic agents on malignant gliomas. Compared with the frequently used cell line models, OMS have several advantages with respect to the preservation of the cellular heterogeneity and the structure of the original tumour. OMS prepared from seven glioma specimens were treated with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), daunorubicin or doxorubicin. After exposure to these drugs, the histology and cell proliferation of the OMS were analysed by immunohistochemistry and image analysis. Furthermore, the expression of P-glycoprotein (P-gp) and multidrug resistance-related protein (MRP), which both can contribute to resistance to daunorubicin and doxorubicin, were immunohistochemically investigated. We found that OMS from gliomas are sensitive for daunorubicin and doxorubicin but not for BCNU in terms of tissue destruction and decrease in cell proliferation. In addition, all gliomas were P-gp and MRP negative, which is in accordance with the sensitivity for daunorubicin and doxorubicin. Considering the potential use of several new alternative drug delivery methods, such as intratumoural implantation of drug-impregnated polymers or liposomal encapsulation of cytostatic drugs, daunorubicin and doxorubicin might be effective in the treatment of malignant gliomas.
ATP Binding Cassette Transporter, Subfamily B, Mem↗