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Biomedical subjects

R E Mrak

Publications and source records attributed to R E Mrak.

At least 55 records · Page 3Linked to original sources
PubMed1996

Nitric oxide synthase (NOS) in schizophrenia: increases in cerebellar vermis.

A high proportion of neurons in the cerebellum and in cholinergic brainstem nuclei stain positive for nicotinamide adenine dinucleotide phosphate-diaphorase (NADPHd), which is a nitric oxide synthase (NOS). Recent evidence suggests that schizophrenia may involve increased numbers of NADPHd-stained neurons in different areas of the subcortex. This led us to examine the actual concentration of NOS in postmortem brain specimens of cerebellum, and the relevant regions of brainstem tegmentum, to see if NOS concentrations were also increased in schizophrenia. Postmortem brain tissue was obtained at autopsy from schizophrenics and controls who did not have other brain disease. In patients with schizophrenia, NOS concentration was higher.

Aged↗
PubMed1996

Correlation of astrocytic S100 beta expression with dystrophic neurites in amyloid plaques of Alzheimer's disease.

The neurite extension factor S100 beta is overexpressed by activated astrocytes associated with amyloid-containing plaques in Alzheimer's disease, and has been implicated in dystrophic neurite formation in these plaques. This predicts (a) that the appearance of S100beta- immunoreactive (S100beta+) astrocytes precedes that of dystrophic neurites in diffuse amyloid deposits and (b) that the number of these astrocytes correlates with the degree of dystrophic neurite proliferation in neuritic plaques. As a test of the first prediction, we determined the number of S100beta+ astrocytes associated with different plaque types: diffuse non-neuritic, diffuse neuritic, dense-core neuritic, and dense-core non-neuritic. Diffuse non-neuritic plaques had small numbers of associated S100beta+ astrocytes (1.3 +/- 0.1 S100beta astrocytes per plaque [mean +/- SEM]; 80% of plaques had one or more). These astrocytes were most abundant in diffuse neuritic plaques (4.2 +/- 0.2; 100%), were somewhat less numerous in dense-core neuritic plaques (1.6 +/- 0.2; 90%), and were only rarely associated with dense-core non-neuritic plaques (0.15 +/- 0.05; 12%). As a test of the second prediction, we correlated the number of S100beta+ astrocytes per plaque with the area of beta-amyloid precursor protein (beta-APP) immunoreactivity per plaque (an index of the size of the plaques' dystrophic neurite shells) and found a significant positive correlation (r = 0.74, p < 0.001). This correlation was also evident at the tissue level: the numbers of S100beta+ astrocytes per plaque-rich field correlated with the total area beta-APP immunoreactivity in these fields (r = 0.66, p < 0.05). These correlations support the idea that astrocytic activation and S100 beta overexpression are involved in the induction and maintenance of dystrophic neurites in amyloid deposits, and support the concept of a glial cytokine-mediated cascade underlying the progression of neuropathological changes in Alzheimer's disease.

Aged↗
PubMed1996

Apolipoprotein E distribution among different plaque types in Alzheimer's disease: implications for its role in plaque progression.

We sought to determine the pattern of ApoE immunoreactivity in mesial temporal lobe tissue from 12 Alzheimer patients, age 66-88, and to determine the distribution of this immunoreactivity among different plaque types representing hypothesized stages of plaque evolution. In these patients, the cortical area of ApoE immunoreactivity was 30% that of beta-amyloid. Only 6% of diffuse non-neuritic amyloid deposits were even weakly ApoE immunoreactive (ApoE+). This is in contrast to our previous demonstration that microglia overexpressing interleukin-1 (IL-1) are present in most diffuse non-neuritic deposits. Eighty-three per cent of diffuse neuritic plaques and 86% of dense-core neuritic plaques were highly ApoE+, consistent with IL-1-induced astrocyte activation and synthesis of ApoE resulting in the appearance of ApoE immunoreactivity in neuritic plaques. Dense-core non-neuritic ('burned out') plaques were only rarely (6%) ApoE+. These results, together with the known trophic and toxic effects of ApoE on neurites, suggest that plaque-associated ApoE contributes to the formation of overgrown degenerating (dystrophic) neurites in plaques. However, the fact that some neuritic plaques are not ApoE+ suggests contributions by additional trophic and toxic factors. Our results are also consistent with a role for ApoE in the condensation of diffuse amyloid deposits into a beta-pleated-sheet form that occurs concomitant with dystrophic neurite formation in the neuritic beta-amyloid plaques of Alzheimer's disease.

Aged↗
PubMed1996

Cranial chordomas in children and adolescents.

Chordomas are rare tumors that usually occur in adults. This report describes four cases of intracranial chordomas treated in patients 20 years of age or younger by the senior author (O.A.M.) during a 4-year period. The authors also reviewed the literature on pediatric patients, which revealed that the clinical presentations, histological patterns, and behaviors of these tumors differ considerably depending on whether the patient is younger or older than 5 years of age. The younger population had a wider range of presenting symptoms, a greater prevalence of atypical histological findings with aggressive behavior, a greater range of cellularity than the classic chordomas, and a higher instance of metastasis; it showed no chondroid component compared to a 17.1% instance in the older patients. The prognosis for patients with a chordoma is related directly to the histological pattern of the tumor; the atypical chordoma carries a poor prognosis. The prognoses for children older than 5 years of age with a classic or chondroid tumor were not significantly different (p=0.788). At follow up, the difference in survival rates between patients undergoing surgery plus radiation therapy and those who had surgery alone was statistically significant (p=0.00446). No correlation was found between radical resection or radiation therapy and an improved prognosis for patients younger than 5 years of age who had a tumor with an atypical histological pattern. This study identifies and delineates the distinction between these age groups and provides a review of the potential prognostic factors.

Adolescent↗
PubMed1995

Detached single cilia: another potential pseudomicrobe seen in bronchoalveolar lavage specimens.

High magnification examination of Romanovsky-stained bronchoalveolar lavage (BAL) material may be needed, if one is to confidently exclude small organisms such as toxoplasmosis, histoplasmosis, and the negative images of mycobacteria. Pseudomicrobes have been described, and detailed criteria must be carefully applied, if incorrect diagnoses are to be avoided. We recently noted numerous free-lying, uniform, eosinophilic, straight or slightly curved bacilliform structures in such a specimen. These were seen on Diff-Quik-stained material, but were extremely pale on Papanicolaou-stained slides. Comparison with the cilia of contaminating bronchial cells showed these pseudomicrobes to have similar length, diameter, and tinctorial properties. Electron microscopy of the sedimented cell pellet showed isolated, detached single cilia (DSC) far removed from any bronchial cells. Twenty BAL's from 13 males and seven females (median age = 48.5) undergoing infection surveillance were then retrospectively reviewed. DSC were present in 16 specimens (80%), but were rare in three of these. Although present in cases with prominent bronchial cell contamination (n = 6 cases), DSC were also encountered when ciliated cells were rare (n = 13), or absent (n = 1). Familiarity with these distinctive structures should make it unlikely that they will be mistaken for infectious organisms.

Adolescent↗
PubMed1995

Glial cytokines in Alzheimer's disease: review and pathogenic implications.

The roles of activated glia and of glial cytokines in the pathogenesis of Alzheimer's disease are reviewed. Interleukin-1 (IL-1), a microglia-derived acute phase cytokine, activates astrocytes and induces expression of the astrocyte-derived cytokine, S100 beta, which stimulates neurite growth (and thus has been implicated in neuritic plaque formation) and increases intracellular free calcium levels. Interleukin-1 also upregulates expression and processing of beta-amyloid precursor proteins (beta-APPs) (thus favoring beta-amyloid deposition) and induces expression of alpha 1-antichymotrypsin, thromboplastin, the complement protein C3, and apolipoprotein E, all of which are present in neuritic plaques. These cytokines, and the molecular and cellular events that they engender, form a complex of interactions that may be capable of self-propagation, leading to chronic overexpression of glial cytokines with neurodegenerative consequences. Self-propagation may be facilitated by means of several reinforcing feedback loops. beta-Amyloid, for instance, directly activates microglia, thus inducing further IL-1 production, and activates the complement system, which also leads to microglial activation with IL-1 expression. Self-propagation also could result when S100 beta-induced increases in intraneuronal free calcium levels lead to neuronal injury and death with consequent microglial activation. Such chronic, self-propagating, cytokine-mediated molecular and cellular reactions would explain the progressive neurodegeneration and dementia of Alzheimer's disease.

Alzheimer Disease↗
PubMed1995

Mesopontine neurons in schizophrenia.

Findings reported here show that there is a significant increase in the number of neurons in the pedunculopontine nucleus in most schizophrenic patients compared to age-matched controls. Nicotinamide adenine dinucleotide phosphate diaphorase histochemistry was used to label putative cholinergic neurons in the pedunculopontine nucleus and laterodorsal tegmental nucleus, while noradrenergic locus coeruleus neurons were labeled immunocytochemically using an antibody to tryosine hydroxylase. Cell counts of these neuronal groups were carried out using a Biographics image analysis system. We found significantly increased cell numbers in the pedunculopontine nucleus of schizophrenic patients compared to controls. The number of laterodorsal tegmental nucleus neurons was increased but this was not statistically significant. However, the total cell counts for pedunculopontine and laterodorsal tegmental nuclei were significantly higher in schizophrenic subjects. The number of locus coeruleus noradrenergic neurons was similar in both groups. These results implicate the brainstem reticular formation as a pathophysiological site in at least some patients with schizophrenia. In addition, these findings suggest a developmental etiology for the disease and account for some, but not all, of the symptoms of schizophrenia, including sensory gating abnormalities, sleep-wake disturbances and, perhaps, hallucinations. Overdriving of thalamic and substantia nigra function by cholinergic afferents from the midbrain may account for some of the symptoms seen in schizophrenia. These findings suggest that, at least in some schizophrenic patients, there is an increased number of neurons in the cholinergic arm of the reticular activating system. This may explain some of the symptoms of schizophrenia and points to a prenatal disturbance as one of the possible causes of the disease.

Aged↗
PubMed1995

Overexpression of the neurotrophic cytokine S100 beta in human temporal lobe epilepsy.

Neuritic sprouting and disturbances of calcium homeostasis are well described in epilepsy. S100 beta is an astrocyte-derived cytokine that promotes neurite growth and induces increases in levels of intracellular calcium in neurons. In sections of neocortex of surgically resected temporal lobe tissue from patients with intractable epilepsy, we found that the number of S100 beta-immunoreactive astrocytes was approximately threefold higher than that found in control patients (p < 0.001). These astrocytes were activated, i.e., enlarged, and had prominent processes. Temporal lobe tissue levels of S100 beta were shown by ELISA to be fivefold higher in 21 epileptics than in 12 controls (p < 0.001). The expression of the astrocyte intermediate filament protein, glial fibrillary acidic protein, was not significantly elevated in epileptics, suggesting a selective up-regulation of S100 beta expression. Our findings, together with established functions of S100 beta, suggest that this neurotrophic cytokine may be involved in the pathophysiology of epilepsy.

Adolescent↗
PubMed1995

Interleukin-1 expression in different plaque types in Alzheimer's disease: significance in plaque evolution.

The histologically apparent polymorphism of plaques containing beta-amyloid in Alzheimer's disease is thought to represent different stages in plaque evolution. beta-amyloid-immunopositive plaques were classified according to the pattern of beta-amyloid distribution (diffuse vs dense-core) and the presence or absence of dystrophic beta-amyloid precursor protein-immunopositive (beta-APP+) neurites (neuritic vs non-neuritic). The potential contribution of microglia-derived interleukin-1 (IL-1), an immune response cytokine that induces synthesis and processing of beta-APP, to the possible sequential development of these plaque types was examined through determination of the number of IL-1 alpha+ microglia associated with each of four identified plaque types. Diffuse non-neuritic plaques had the least dense and most widely dispersed beta-amyloid, did not exhibit beta-APP+ dystrophic neurites, but most (78%) contained activated IL-1 alpha+ microglia (2 +/- 0.2/plaque; mean +/- SEM). Diffuse neuritic plaques had more dense, but still widely dispersed beta-amyloid, displayed a profusion of beta-APP+ dystrophic neurites, and had the greatest numbers of associated activated IL-1 alpha+ microglia (7 +/- 0.8/plaque). Dense-core neuritic plaques had both compact and diffuse beta-amyloid and had fewer IL-1 alpha+ microglia (4 +/- 0.4/plaque). Dense-core, non-neuritic plaques had compact beta-amyloid, lacked associated diffuse beta-amyloid, and were devoid of both IL-1 alpha+ microglia and beta-APP+ dystrophic neurites. These results suggest an important immunological component in the evolution of amyloid-containing plaques in Alzheimer's disease and further suggest that IL-1-expressing cells are necessary to initiate dystrophic neurite formation in diffuse beta-amyloid deposits.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1995

Microglial interleukin-1 alpha expression in brain regions in Alzheimer's disease: correlation with neuritic plaque distribution.

Interleukin-1 alpha-immunoreactive (IL-1 alpha+) microglia are prominent components of neuritic plaques in Alzheimer's disease, and may be important in the evolution of neuritic plaques from diffuse amyloid deposits. Neuritic plaques show a characteristic distribution across cerebral regions and are absent in the cerebellum of patients with Alzheimer's disease. We used single- and dual-immunohistochemical labelling to investigate the possibility that the expression of IL-1 alpha is correlated with this regional distribution of neuritic (tau 2-immunoreactive, tau 2+) plaques. In Alzheimer's disease, tau 2+ neuritic plaques occurred with increasing frequency in grey matter of frontal and occipital lobes, temporal lobe, and hippocampus. There were positive correlations between the regional patterns of distribution of activated IL-1 alpha+ microglia and tau 2+ neuritic plaques as well as between activated IL-1 alpha+ microglia and activated astrocytes. No activated IL-1 alpha+ microglia, tau 2+ neuritic plaques, or activated astrocytes were observed in cerebellum of these Alzheimer patients. These regional relationships between activated IL-1 alpha+ microglia, tau 2+ neuritic plaques, and activated astrocytes, together with the established functions of IL-1, support a causal association between the overexpression of IL-1 and the evolution of beta-amyloid deposits into neuritic plaques in Alzheimer's disease.

Aged↗
PubMed1994

S100 beta protein expression in Alzheimer disease: potential role in the pathogenesis of neuritic plaques.

Increased synthesis and release of S100 beta protein from activated astrocytes has been implicated in the overgrowth of dystrophic neurites in neuritic plaques in Alzheimer disease (AD). To evaluate the quantitative relationships between tissues levels of S100 beta and the numbers of neuritic plaques in AD patients, we counted neuritic plaques, by Tau-2 immunoreactive (Tau-2+) labeling, in tissue sections of hippocampus and adjacent temporal cortex and measured the levels of S100 beta protein, by Western immunoblot labeling, in samples of analogous regions from contralateral hemisphere of the same patients. In AD, tissue levels of S100 beta (two- to fivefold that of controls) were significantly correlated with the number of Tau-2+ plaques (R = 0.82, P < .01). Dual-label immunohistochemical analysis showed that most S100 beta+ cells were activated GFAP+ astrocytes. These results were substantiated by a significant correlation between S100 beta and GFAP tissue levels (R = 0.81, P < .05). Many of the S100 beta+ astrocytes were clustered around and within Tau-2+ plaques. Indeed, no Tau-2+ plaques were found without associated activated S100 beta+ astrocytes. Our findings provide further evidence of a role for S100 beta protein in dysregulation of neurons that leads to apparently nonsensical growth of imperfect neurites in AD, a potential key element in early stages of neuritic plaque pathogenesis.

Aged↗
PubMed1994

Microglial interleukin-1 alpha expression in human head injury: correlations with neuronal and neuritic beta-amyloid precursor protein expression.

Activated microglia containing IL-1 alpha-immunoreactive (IL-1 alpha +) product were increased 3-fold in number in the acute phase following head injury, a risk factor for later development of Alzheimer's disease, and this increase was correlated with a 7-fold increase in the number of neurons with elevated beta-amyloid precursor protein (beta-APP) levels (R = 0.78; P < 0.05). Furthermore, clusters of beta-APP+ dystrophic neurites present in these patients were invariably associated with activated IL-1 alpha + microglia. These findings suggest that early overexpression of IL-1 alpha and beta-APP is a priming event for later neuropathological changes evident at end stages of Alzheimer's disease.

Adult↗
PubMed1994

n-Amyl alcohol partitioning in synaptic plasma membranes.

Nuclear magnetic resonance and fluorescence polarization techniques were used to determine n-amyl alcohol partitioning between, and effects on, lipid microdomains of isolated rat cerebral synaptic plasma membranes. n-Amyl alcohol binding to the hydrophobic membrane core had an unchanging binding constant over an aqueous alcohol concentration range of 2.5-22.5 mM, indicating a linear relationship between membrane core and aqueous alcohol concentrations. Binding to the membrane surface, in contrast, was cooperative with a steadily increasing binding constant over this alcohol concentration range. Membrane lipid order was determined using various fluorescent probes with preferences for the membrane core, for the mid-acyl regions of the exofacial or cytofacial bilayer leaflets and for ordered or bulk microdomains. All these probes showed steady decreases in membrane order with increasing alcohol concentration, at least for the nanosecond time scale sampled by this technique. These results further demonstrate the complexity of interaction between natural membranes and membrane disordering agents.

Animals↗
PubMed1994

Metastatic myxopapillary ependymoma: report of a case with fine-needle aspiration findings.

A case of recurrent and metastasizing myxopapillary ependymoma of the sacral region in a 35-yr-old man is reported. Fifteen years after the original diagnosis, he presented with an abdominal mass, subcutaneous nodules in the previous surgical excision line, and bilateral inguinal lymph node enlargement. FNA cytology of the inguinal lymph nodes showed a poorly cohesive, highly cellular smear pattern exhibiting papillary formations and rosette-like structures composed of slim columnar cells having cytoplasmic processes without evidence of atypia. Histologic and ultrastructural findings confirmed the diagnosis. Chromosomal analysis was also done.

Adult↗
PubMed1994

Gastrointestinal autonomic nerve tumor presenting as high-grade sarcoma. Case report and review of the literature.

Gastrointestinal autonomic nerve (GAN) tumors, also known as plexosarcomas, are a rare distinct subtype of the gastrointestinal stromal tumors. These tumors are usually histologically low-grade, epithelioid or spindle-cell neoplasms that can be distinguished from the other gastrointestinal stromal tumors on the basis of their unique ultrastructural features. A 66-year-old female presented with a histologically high-grade sarcoma of the small bowel. Ultrastructural studies showed features of a GAN tumor. The light microscopic and ultrastructural features are described. The tumor cells gave strong, diffuse staining for vimentin and synaptophysin, and weak focal staining for neuron-specific enolase and S100. While usually presenting as low-grade neoplasms on histologic examination, this case demonstrates that GAN tumors should be considered in the differential diagnosis of a histologically high-grade sarcoma of the gastrointestinal tract, especially when evidence of smooth muscle, peripheral nerve sheath, or neuroblastic origin is not forthcoming.

Aged↗
PubMed1994

Malignant neurocytic tumor.

Two patients, 14 and 46 years of age, presented with diffuse, rapidly growing intracerebral tumors leading to death 6 1/2 and 9 1/2 months, respectively, after diagnosis. Histological examination showed sheets of moderate-sized tumor cells with clear cytoplasm and central nuclei interrupted by delicate arciform vasculature, an appearance distinctly different from that of neuroblastoma. Malignant features were present in the form of significant nuclear pleomorphism, numerous mitotic figures, and small foci of necrosis with some suggestion of adjacent pseudo-palisading in one case. Ultrastructural examination showed neuronal differentiation, including prominent neuritic processes, microtubules, dense-core neurosecretory-type granules, and synaptic bouton-like structures containing small, empty-appearing synaptic-type vesicles and synapse-like membrane "thickenings." Immunohistochemistry showed focal immunopositivity for synaptophysin, neurofilaments, neuron-specific enolase, and S100 protein. Immunoreactivity for glial fibrillary acidic protein (GFAP) was found at the margins of the tumors adjacent to some intratumoral blood vessels and in some tumor cells. These tumors seem to occupy a nosological "middle ground" between neuroblastoma and central neurocytoma.

Adolescent↗
PubMed1994

Increased neuronal beta-amyloid precursor protein expression in human temporal lobe epilepsy: association with interleukin-1 alpha immunoreactivity.

Levels of immunoreactive beta-amyloid precursor protein and interleukin-1 alpha were found to be elevated in surgically resected human temporal lobe tissue from patients with intractable epilepsy compared with postmortem tissue from neurologically unaffected patients (controls). In tissue from epileptics, the levels of the 135-kDa beta-amyloid precursor protein isoform were elevated to fourfold (p < 0.05) those of controls and those of the 130-kDa isoform to threefold (p < 0.05), whereas those of the 120-kDa isoform (p > 0.05) were not different from control values. beta-Amyloid precursor protein-immunoreactive neurons were 16 times more numerous, and their cytoplasm and proximal processes were more intensely immunoreactive in tissue sections from epileptics than controls (133 +/- 12 vs. 8 +/- 3/mm2; p < 0.001). However, neither beta-amyloid precursor protein-immunoreactive dystrophic neurites nor beta-amyloid deposits were found in this tissue. Interleukin-1 alpha-immunoreactive cells (microglia) were three times more numerous in epileptics than in controls (80 +/- 8 vs. 25 +/- 5/mm2; p < 0.001), and these cells were often found adjacent to beta-amyloid precursor protein-immunoreactive neuronal cell bodies. Our findings, together with functions established in vitro for interleukin-1, suggest that increased expression of this protein contributes to the increased levels of beta-amyloid precursor protein in epileptics, thus indicating a potential role for both of these proteins in the neuronal dysfunctions, e.g., hyperexcitability, characteristic of epilepsy.

Adolescent↗