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Biomedical subjects

J B Schweitzer

Publications and source records attributed to J B Schweitzer.

At least 19 recordsLinked to original sources
PubMed1999

Prediction of presence of hippocampal sclerosis from intracarotid amobarbital procedure memory asymmetry scores and epilepsy on set age.

Identification of the pathological status of the hippocampus prior to surgery is important since the absence of hippocampal sclerosis (HS) carries risks to memory function following anterior temporal lobectomy (ATL). We studied 62 patients undergoing ATL (31 L, 31 R) for intractable epilepsy of temporal lobe origin in whom no pathology was identified apart from HS. An intracarotid amobarbital procedure (IAP) was performed as part of the preoperative evaluation. All patients were left hemisphere dominant for language. IAP memory testing was according to the protocol of Loring. We examined IAP memory asymmetry scores at four levels of difference (<2, > or =2, > or =4, > or =6) as a function of the presence (HS+) or absence (HS-) of HS. A logistic regression analysis was performed with HS+ as the dependent variable, and age at onset of epilepsy, age at time of surgery, gender, side of surgery and significant IAP memory asymmetry as independent variables. At each level of memory asymmetry, onset age and memory asymmetry were the only predictors of HS+. Younger age at onset was associated with HS+. Curves were constructed showing probability of HS+ for age at onset for each level of asymmetry. These can be used to predict the likelihood of presence of HS based on age at onset of epilepsy and the IAP memory asymmetry score. It is concluded that IAP memory asymmetry scores reflect the functional and pathological status of the hippocampus, and greater asymmetry increases the probability of finding HS in the resected hippocampus.

Adult↗
PubMed1998

Synaptophysin immunohistochemistry densitometry measurement in resected human hippocampus: implication for the etiology of hippocampal sclerosis.

Synaptophysin (SY) is a protein expressed at presynaptic vesicles. SY immunohistochemistry (IHC) was undertaken in surgically resected hippocampal specimens from 25 patients with intractable epilepsy. All were investigated with chronic ictal EEG videotelemetry, which showed a temporal onset in each case, and all had normal magnetic resonance imaging (MRI). The density of reaction product of SY IHC was used to generate optical density (OD) measurements as an estimate of synaptic density in CA1 and CA4 fields (ODCA1 and ODCA4), and inner third and outer two-thirds of the molecular layer of the dentate gyrus (ODIML and ODOML). There was significant correlation between ODCA1 (r=0.619, P=0.001) and ODCA4 (r=0.639, P=0.001) and onset age of epilepsy. There was no correlation between ODCA1 and duration of epilepsy. There was correlation between ODCA4 and duration (r=-0.412, P=0.041), but partial correlations showed no significant correlation between ODCA4 and duration when controlling for onset, although correlation between ODCA4 and onset when controlling for duration remained significant (r=0.536, P < 0.01). Univariate ANOVA revealed onset age to be the only predictor of ODCA1 and ODCA4. Chronological age and duration were not predictors. There was no correlation between ODIML or ODOML and either onset age or duration. ODIML and ODOML were not predicted by onset age, duration or chronological age. These findings support the hypothesis that the major cause of hippocampal sclerosis is an age specific insult rather than the result of repeated seizures.

Adult↗
PubMed1997

Effects of cholinergic depletion on glutamic acid decarboxylase immunoreactivity in the somatosensory cortex of rats.

The purpose of these experiments was to determine the effects of cholinergic depletion on the morphology and staining density of barrels formed by glutamic acid decarboxylase-positive neuropil in the posteromedial barrel subfield of the somatosensory cortex. The density and distribution of glutamic acid decarboxylase immunoreactive neuropil were examined after highly selective lesions of cholinergic neurons in the nucleus basalis of Meynert with an immunotoxin, IgG 192-saporin. Glutamic acid decarboxylase immunoreactivity was also examined in animals subjected to a whisker-pairing experience and lesion of acetylcholine inputs from the nucleus basalis of Meynert. Seven to 9 weeks after intraventricular injection of the immunotoxin, animals were perfused with a zinc aldehyde fixative and glutamic acid decarboxylase immunoreactivity was examined in 30-micron tangential sections. Cholinergic depletion caused reduced glutamic acid decarboxylase immunoreactivity in selective regions of the posteromedial barrel subfield. The density of neuropil and cell bodies immunoreactive for glutamic acid decarboxylase was significantly reduced in septa and perimeters of barrel walls. The length, width, and area of barrels were reduced 10-20% in cholinergic-depleted animals compared with controls. The density of glutamic acid decarboxylase immunoreactivity in the hollow of barrels was not affected by this treatment. Whisker pairing did not significantly change the density of glutamic acid decarboxylase immunoreactivity in barrels. These observations are discussed in regard to how long-term cholinergic depletion affects the function of different fiber systems in the posteromedial barrel subfield cortex and how some sensory functions may be comprised.

Acetylcholine↗
PubMed1997

Effects of cholinergic depletion on experience-dependent plasticity in the cortex of the rat.

Clinical and functional studies have strongly suggested that acetylcholine input from the nucleus basalis of Meynert is important for the cortex's adaptive response to experience. The purpose of this study was to investigate the effects of depletion of acetylcholine inputs from nucleus basalis of Meynert on experience-dependent plasticity in the cortex of young adult male rats. The posteromedial barrel subfield in the primary somatosensory cortex was studied. Experience-dependent plasticity was elicited using a whisker-pairing paradigm in which all whiskers except D2 and D3 were trimmed daily. Plasticity within barrel D2 of the posteromedial barrel subfield was measured using the electrophysiological extracellular recording technique. An index of plasticity was determined in two ways: as an increase in the magnitude of evoked activity to stimulation of whisker D2 and as a bias in the ratio of evoked activity for stimulation of paired whisker D3 and cut whisker D1 (D3/D1). Whiskers D2, D3 and D1 were stimulated (deflected) by a Chubbuck electromechanical stimulator. Cholinergic neurons in the nucleus basalis of Meynert were selectively lesioned with an immunotoxin, 192 IgG-saporin, injected into the left lateral ventricle. Lesions of cholinergic neurons in the nucleus basalis of Meynert were verified using choline acetyltransferase immunocytochemistry and radioenzymatic assay. Experience-dependent plasticity was significantly reduced in cholinergic-depleted animals. The magnitude of evoked activity to stimulation of whisker D2 increased by 16-100% in control animals compared with 0-20% in cholinergic-depleted animals. Similarly, compared to a 60-100% increase in the D3/D1 ratio of evoked activity for phosphate-buffered saline-injected control animals, cholinergic-depleted rats showed no significant increase in the D3/D1 ratio (0-15%) after undergoing the whisker-pairing paradigm. After whisker trimming, the D3/D1 response ratio in immunotoxin-treated animals was essentially the same as in control animals that had not been subjected to the whisker-pairing paradigm. This study showed that no significant plasticity response was observed in the absence of cholinergic input from the nucleus basalis of Meynert. The mechanisms of the action of acetylcholine in cortical plasticity are still not known, but we hypothesize that this type of plasticity is activity dependent and is significantly enhanced in the presence of acetylcholine.

Acetylcholine↗
PubMed1997

Differentiating central neurocytoma. Case report.

In 1976 a patient underwent partial resection of an intraventricular tumor that showed central neurocytoma. No other tumor pattern was observed. In 1994 this patient underwent a second operation for removal of the tumor, at which time foci of tumor were diagnosed as central neurocytoma and ganglioglioma. This is the first reported case of differentiation of central neurocytoma into ganglioglioma, a sequence of events termed differentiating central neurocytoma.

Adult↗
PubMed1996

The effects of immunolesions of nerve growth factor-receptive neurons by 192 IgG-saporin on sleep.

Low-affinity nerve growth factor (NGF) receptors are present on the cholinergic neurons of the basal forebrain. We studied the effects of 192 IgG-saporin, a specific immunotoxin for the NGF receptor-positive, cholinergic basal forebrain neurons, on sleep, the power spectrum of the electroencephalogram (EEG), and body temperature. After 3 d baseline recordings, 12 male rats were injected intracerebroventricularly with 4 micrograms 192 IgG-saporin. EEG, motor activity, and brain temperature were recorded for 23 h on the first, third, fifth, and seventh day after the treatment. 192 IgG-saporin did not affect the total daily amounts but altered the circadian distribution of sleep. On days 1 and 3 after the injection of the immunotoxin, the amount of non-rapid-eye-movement sleep (NREMS) and rapid-eye-movement sleep (REMS) increased during the dark period, whereas during the light both NREMS and REMS decreased. On day 5, these changes were less pronounced and sleep completely returned to the baseline by day 7. The EEG was suppressed in each frequency band and each vigilance state, and, in contrast to sleep, these changes in EEG persisted for 7 days. Brain temperature was decreased from day 3. These results suggest that NGF receptor-positive, cholinergic basal forebrain neurons are not necessary for the maintenance of total sleep time but contribute to the generation of normal EEG and the maintenance of brain temperature.

Analysis of Variance↗
PubMed1996

Use of a token economy to increase compliance during hemodialysis.

We report the effects of using a token economy to treat noncompliant behavior in a 10-year-old male hemodialysis patient. The results of an ABAB design indicated that the intervention increased compliant behavior during both treatment phases and that compliance was maintained at 3- and 6-month follow-up observations.

Child↗
PubMed1995

Loss of p75 nerve growth factor receptor mRNA containing neurons in rat forebrain after intraventricular IgG 192-saporin administration.

Cholinergic neurons of the basal forebrain express the p75 (low affinity) nerve growth factor receptor (NGFr) on the cell surface. It has been previously shown that an immunotoxin that recognizes the p75 NGFr, IgG 192-saporin, eliminates these neurons as judged by a variety of techniques after intraventricular injection into rat brain. Here we show that this loss of neurons can also be identified by detecting the disappearance of the p75 NGFr mRNA utilizing a non-radioactive in situ hybridization method.

Animals↗
PubMed1995

DNA end labeling (TUNEL) in Huntington's disease and other neuropathological conditions.

Deoxyribonucleic acid of cells undergoing apoptosis is cleaved by a calcium-dependent endonuclease into oligonucleosomal-sized fragments. These fragments can be labeled using the enzyme terminal deoxynucleotidyl transferase so that the cells can be visualized immunohistochemically. Few investigators have evaluated this method in disease processes of the human central nervous system. The Tdt-mediated dUTP-biotin nick end labeling (TUNEL) technique has been investigated in preliminary studies of a variety of pathologic conditions of the human brain (e.g., gliomas, traumatic brain injury, Parkinson's disease, Parkinson's-Alzheimer's complex, multisystem atrophy, striatonigral degeneration). We focus, however, on Huntington's disease (HD) because of the availability of well-characterized pathological stages for study, and also because of the neurodegenerative diseases studied to date, only Huntington's disease revealed significant and consistent labeling with this method. This implies a possibly unique nature to the mechanism of cell death in Huntington's disease compared to the other neurodegenerative diseases studied. TUNEL+ neurons were found in Grade 1-4 HD neostriatum, while labeled astrocytes were found predominantly in the Grade 1 and 2 cases studied to date. TUNEL+ cells were also found in glioblastoma multiforme and traumatic brain injury. We conclude that while there appear to be several limitations associated with this technique, it may be useful for identifying both apoptosis and necrosis in certain neuropathological conditions.

Brain Injuries↗
PubMed1995

192 IgG-saporin. 2. Neuropathology in the rat brain.

We have previously shown that an immunotoxin (IT) directed against the p75 component of the nerve growth factor receptor (NGFr) selectively abolished cholinergic neurons in the basal forebrain of the rat following intraventricular administration. We now report the neuropathological responses in the rat brain to the IT, with particular emphasis on the cholinergic basal forebrain (CBF) and other known p75NGFr-positive brain regions. Animals received intraventricular injections of IT and were allowed to survive for various times. Sections through the entire brain were evaluated using (1) hematoxylin and eosin; (2) glial fibrillary acidic protein immunohistochemistry; and (3) Griffonia simplicifolia lectin histochemistry. The only clearly degenerating cells following IT treatment were located in the CBF or in the Purkinje cell layer of the cerebellum. A marked microglial response was demonstrated that was tightly linked both topographically and temporally to the loss of neurons in these areas. The astroglial response was mild in the same regions in which the microglial response was obvious. The other areas of rat brain including the terminal fields of CBF projections showed no consistent reactive cellular responses in IT-treated animals. This study extends and corroborates previous work indicating specificity of IT, demonstrates active neuronal degeneration by conventional pathological methods for the first time, and illustrates the unexpected and novel finding that the predominant pathological response to the IT-induced loss of neurons is microglial. Both the high degree of specificity and the distinctive glial response distinguish the IT model from other experimental models of CBF neurodegeneration.

Animals↗
PubMed1995

Self-control in boys with attention deficit hyperactivity disorder: effects of added stimulation and time.

Preference for larger-delayed versus more immediate-smaller rewards was studied in 5- and 6-year-old typical boys with Attention Deficit Hyperactivity Disorder (ADHD) in a repeated measure design. The effect of adding stimulation on preference also was studied. Boys with ADHD chose delayed-larger rewards significantly less than did typical boys. Adding stimulation reduced motoric behavior, but did not affect choice. As rates of motoric activity increased in boys with ADHD, their preference for delayed, larger rewards decreased over time. These findings argue for the external validity of choice tasks in the study of ADHD.

Adolescent↗
PubMed1995

Elements in the 5' flanking sequences of the mouse low-affinity NGF receptor gene direct appropriate CNS, but not PNS, expression in transgenic mice.

We have initiated a characterization of the cis-acting regulatory elements of the murine low-affinity NGF receptor (p75NGFR) gene. Despite studies in cultured cells that suggest the p75NGFR promoter is constitutive, a detailed analysis of this promoter in five lines of transgenic mice demonstrated a high degree of cell-type specificity: 8.4 kb of 5' flanking sequence directs expression of a lacZ reporter to retinal and CNS neurons normally expressing p75NGFR. A transgene with 470 bp of 5' flanking sequence is also expressed in the CNS, but its regulation is aberrant, with a loss of basal forebrain expression. In non-neural tissues, both transgenes were expressed only in the testis, kidney, anterior pituitary, and pancreatic islets; with the exception of the renal pattern of expression, transgene activity was confined to appropriate cells within these tissues. In contrast, although expression of both transgenes was prominent in adrenal medulla and gastrointestinal myenteric neurons, neither construct was active in several sensory or sympathetic ganglia that strongly express the endogenous p75NGFR gene, indicating that genetic elements necessary for expression in these neurons are not present in these promoter sequences. In addition, neither transgene was activated in Schwann cells during Wallerian degeneration of sciatic nerve. We conclude that regulation of the p75NGFR gene is complex, with the first 470 bp of 5' flanking sequence sufficient for expression in enteric and CNS neurons and additional elements within the first 8.4 kb of 5' flanking sequence required for restriction to appropriate CNS neurons. Further regulatory elements are possibly required for expression in at least some sensory and sympathetic neurons in the PNS and in Schwann cells. To identify potential regulatory elements in the 470 bp of 5' flanking sequence from the smaller transgene, we compared the sequences of equivalent regions from the mouse, rat, and human p75NGFR genes. This "phylogenetic footprint" identified conserved motifs potentially important for the regulation of this gene in the CNS.

Animals↗
PubMed1994

Heterogeneity of subcellular localization of p53 protein in human glioblastomas.

Immunohistochemical analysis of the p53 protein in human glioblastomas with known genetic profiles of p53 mutations and allele losses on chromosome 17p demonstrated a heterogeneous pattern of subcellular compartmentalization of the p53 protein. Tumors with a single wild type copy of the p53 gene but with allelic deletions on chromosome 17p exhibit nuclear and/or cytoplasmic accumulation of p53, whereas tumors with both copies of the wild type gene and no allele losses on chromosome 17 do not accumulate p53. Glioblastomas with one normal and one mutated copy of the p53 gene and allelic deletions on 17p distal to p53, on the other hand, show predominantly cytoplasmic staining, probably originating from the wild type p53 protein. Furthermore, tumors with mutations in the same codon of p53 display quite different intracellular distribution suggesting that, in addition to the genotype of p53, the intracellular microenvironment of a particular tumor is important in determining the subcellular localization of the p53 protein.

Base Sequence↗
PubMed1994

192 IgG-saporin causes a major loss of synaptic content in rat olfactory bulb.

An immunotoxin composed of a monoclonal antibody that recognizes the p75 nerve growth factor (NGF) receptor disulfide-linked to the ribosome-inactivating protein saporin selectively eliminates p75-expressing cholinergic neurons in the basal forebrain, while sparing other neurons in the forebrain, both cholinergic and noncholinergic. We now report the effect that intraventricular administration of this immunotoxin has on the synaptic content of the olfactory bulb, one of the major terminal fields of the cholinergic basal forebrain system. Control substances or immunotoxin were given to rats followed by a 2-week survival. Unilateral transection of the olfactory tract and peduncle was also studied. Both qualitative and quantitative evaluation of olfactory bulbs processed for synaptophysin immunohistochemistry indicated dramatic loss of synapses in the four regions of neuropil evaluated (glomeruli, outer and inner halves of the external plexiform layer, and internal plexiform layer) compared with the administration of control substances. Surgical transection of the bulb produced a visually similar decrement, but quantitative studies showed synaptic loss to be consistently greater following tract transection. The effects of these two insults on the glial response were remarkably different. Transection produced an obvious hyperplasia and hypertrophy of both astrocyte and microglial elements, while immunotoxin produced small, almost undetectable reactions by these two cell types. The results in the glomeruli strongly suggest an effect of the immunotoxin on either periglomerular cells or olfactory nerve terminals, whether directly by NGF receptor (+) structures or by trans-synaptic mechanisms. We conclude that the immunotoxin produces a specific and large loss of synapses that does not produce much glial response.

Animals↗
PubMed1994

192 IgG-saporin: I. Specific lethality for cholinergic neurons in the basal forebrain of the rat.

An immunotoxin (IT) composed of a monoclonal antibody to the nerve growth factor (NGF) receptor, 192 IgG, chemically linked to saporin, 192 IgG-saporin, was shown to selectively reduce forebrain choline acetyltransferase (ChAT) activity in the rat brain following intraventricular administration. In order to determine if the IT was killing NGF receptor-positive neurons in the CBF (rather than simply suppressing the cholinergic phenotype in these cells), a population of neurons in the nucleus basalis magnocellularis (NBM) was prelabeled by an intracortical injection of the neurotracer Fluoro-Gold (FG) 1 week before intraventricular injections of IT or control substances (reduced IT or phosphate-buffered saline). We found that there were very few double-labeled (i.e. FG-labeled and ChAT-positive) neurons remaining in the NBM of IT-treated animals. The absolute number of FG-labeled neurons in the NBM of IT-treated animals was reduced by a number similar to the counts of double-labeled neurons in the NBM of control animals. Our conclusion is that the IT is preferentially lethal to cholinergic neurons in the NBM. Due to its ability to selectively kill cholinergic neurons in the CBF and concomitantly spare noncholinergic neurons with similar morphology and projections, 192 IgG-saporin can be used to produce a selective model of CBF deficit in the rat.

Animals↗
PubMed1993

Ubiquitin marks the reactive swellings of diffuse axonal injury.

Ubiquitin is a protein that targets proteins for non-lysosomal degradation. It has been found to be present in a number of inclusions characteristic of neurodegenerative diseases. Using the fluid percussion model of closed head injury in the cat, a well-established model of diffuse axonal injury (DAI), we now report that the reactive axonal swellings and the retraction balls produced in this model stain positively with anti-ubiquitin immunohistochemistry. Furthermore, the affected axons become ubiquitin positive quickly (within the first 6 h after injury). Anti-ubiquitin immunohistochemistry compares well with the recently reported ability of antibodies to low molecular weight neurofilament proteins to demonstrate reactive axonal change in DAI, and it could provide additional clues to the pathogenesis of axonal transection.

Animals↗