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Biomedical subjects

G J Siegel

Publications and source records attributed to G J Siegel.

At least 19 recordsLinked to original sources
PubMed2003

Effect of PPF and ALCAR on the induction of NGF- and p75-mRNA and on APP processing in Tg2576 brain.

Amyloidogenic processing of beta-amyloid precursor protein (APP) leading to Abeta accumulation is critical in Alzheimer's disease (AD). Abeta leads to pre-synaptic molecular changes in hippocampus of the AD mutant transgenic mouse model Tg2576 prior to plaque formation. Since NGF is critical to neuronal growth and is involved in regulating APP processing, we tested the hypothesis that NGF expression is altered early in this model of AD. We measured APP products and mRNAs for NGF and its low-affinity receptor p75 in 10-month-old Tg2576 whole brain after dietary propentofylline (PPF) or acetyl-L-carnitine (ALCAR) for 4 weeks to induce NGF- or p75-expression, respectively. The results (all P<0.0002) show that compared to wild-type or littermate controls, the transgene leads to decreases of 44% in NGF-mRNA, 25% in p75-mRNA, 64% in sAPPalpha, and 21-fold increases in Abeta40/42. PPF increased NGF-mRNA by 20% and sAPPalpha by 42% while decreasing Abeta40/42 by 45/48%, with no effect on p75-mRNA in Tg animals. ALCAR increased p75-mRNA by 16% and decreased Abeta40/42 by 46/26% with no significant effect on sAPPalpha or NGF-mRNA in Tg animals. The results indicate that NGF expression is reduced early in the Tg brain, that this reduction potentiates further Abeta formation in a vicious cycle, and that inducing NGF shifts the balance toward secretory processing of APP. To a lesser extent, p75 decreases Abeta peptides, possibly via peptidases since sAPPalpha level is not changed.

Acetylcarnitine↗
PubMed2001

Distribution of intraventricularly administered antiamyloid-beta peptide (Abeta) antibody in the mouse brain.

There is considerable interest in utilizing the intracerebroventricular (icv) route of administration of antibodies in the brain for various studies and for the therapy of malignancies, but very little is known about the anatomic extent of distribution of the antibody in brain after injection into the third ventricle. To explore the potential for icv administration of antiamyloid-beta peptide (Abeta) in reducing Abeta toxicity in brain in Alzheimer's disease, we first mapped the time course and path of transit of horseradish peroxidase (HRP)-labeled antibody. The results show that, after a single injection into the mouse third venticle, the HRP-labeled antibody is localized within the microvasculature, first that of the corticohippocampal region close to the site of injection at 3 hr. By 24 hr, the antibody is distributed throughout the hippocampus and frontoparietal cortex close to the injection site, as well as in the deep and outer cerebral cortex and cerebellar cortex remote from the injection site. The injected antibody is almost entirely removed by 4 days. Therefore, the antibody had diffused throughout all the brain by 24 hr, showing the feasibility of small quantities of anti-Abeta antibody infused into the third ventricle to reach extracellular epitopes throughout the brain parenchyma rapidly.

Alzheimer Disease↗
PubMed2001

Depletion of glial cell line-derived neurotrophic factor in substantia nigra neurons of Parkinson's disease brain.

The distribution of nerve growth factor (NGF), ciliary neurotrophic factor (CNTF), glial cell line-derived neurotrophic factor (GDNF), brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) in substantia nigra pars compacta (SNc) of Parkinson's disease (PD) brains was investigated by immunofluorescence. Cases studied included four 69-77 year old neurologically normal male controls and four 72-79 year old male PD patients. Integrated optical densities (IODs) of immunofluorescence over individual neuromelanin-containing neurons and in areas of neuropil and the number of neurons on H & E stained adjacent sections were quantitated with the use of the BioQuant Image Analyzer. Data were statistically analyzed by ANOVA, including the unpaired two-tailed Student t-test and the Mann-Whitney test. The results showed 55.8% (P<0.0001) dropout of SNc neurons in PD brains compared to age-matched controls. Despite considerable neuronal dropout, immunofluorescent NTFs in the PD brains showed differential reductions that were consistent within the group as compared to age-matched controls: reductions were GDNF, 19.4%/neuron (P<0.0001), 20.2%/neuropil (P<0.0001); CNTF, 11.1%/neuron (P<0.0001), 9.4%/neuropil (P<0.0001); BDNF, 8.6%/neuron (P<0.0001), 2.5%/neuropil. NGF, NT-3 and NT-4 showed no significant differences within surviving neurons or neuropil. Since the depletion of GDNF both within surviving neurons and neuropil was twice as great as that of CNTF and BDNF and since the other NTFs showed no changes, GDNF, of the tested NTFs, is probably the most susceptible and the earliest to decrease in the surviving neurons of SNc. These observations suggest a role for decreased availability of GDNF in the process of SNc neurodegeneration in PD.

Aged↗
PubMed2000

Neurotrophic factors in Alzheimer's and Parkinson's disease brain.

The biomedical literature on the subject of neurotrophic growth factors has expanded prodigiously. This essay reviews neurotrophic factors (NTF) and their receptors in Alzheimer's disease (AD) and Parkinson's disease (PD) brain and recent updates on receptor signaling. The hypotheses for specific NTF involvement in neurodegenerative diseases in human and as potential therapy are based mainly on experimental animal and in vitro models. There are wide gaps in information on regional synthesis and cell contents of NTFs and their receptors in human brain. Observations on AD brain indicate increases in NGF and decreases in BDNF in surviving neurons of hippocampus and certain neocortical regions and decreases in TrkA in cortex and nucleus basalis. In PD brain, the few data available indicate decreases in neuronal content of GDNF and bFGF in surviving substantia nigra dopaminergic neurons. There are very few data regarding age-dependent effects on NTFs and on their receptors in human brain. Since NTFs in neurons are subject to retrograde and, in at least some cases, to anterograde transport from and to target neurons, their effects may be related to synthesis in local or remote sites or to changes in axoplasmic transport. Also, certain NTFs and their receptors are found to be expressed in activated glia. Thus, comparative in situ data for transcription levels and protein contents for NTFs and their receptors in both sites of neuronal origin and termination in human brain are needed to understand their potential roles in treating human diseases.

Alzheimer Disease↗
PubMed2000

Description of an office technique for laser ventilation of the ears.

The author presents a description of a technique he developed called laser office ventilation of ears (LOVE). LOVE, an office-based procedure performed under local anesthesia, can provide intermediate-term ventilation for middle ear disease. This procedure has potential to change the standard of care for otitis media. Such changes might include a decrease in the need for antibiotics (and thus antibiotic resistance), a decrease in hearing loss associated with otitis media, and a decrease in the overall cost of treatment.

Ambulatory Care↗
PubMed1998

Anti-tubulin antibodies in a sensorimotor neuropathy patient alter tubulin polymerization.

The effect of anti-tubulin antibodies present in the serum of a patient with a progressive sensorimotor neuropathy on microtubule assembly was examined. The patient's serum was reactive on immunoblots with a single band of proteins of 55-kDa from homogenates of neural tissues. Tubulin was identified as the quantitatively major component of these 55-kDa proteins. Polymerization of tubulin in vitro was significantly enhanced by the patient's serum. A monoclonal antibody to nerve-specific class III beta-tubulin precisely duplicated the immunoreactive profile of the patient's serum, while an antibody to class (I + II) beta-tubulins also reacted with tubulins in non-neural tissues. The results indicate for the first time that human antisera reactive with nerve specific beta-tubulin can alter tubulin polymerization-depolymerization dynamics.

Aged↗
PubMed1997

Na,K-ATPase mRNA levels and plaque load in Alzheimer's disease.

UNLABELLED: The expression of Na,K-ATPase alpha 1- and alpha 3-mRNAs was analyzed by in situ hybridization in the superior frontal cortex and cerebellum of brains from five Alzheimer's disease (AD), five nondemented age-matched, and three young control subjects. Brains with well-preserved RNA, tested by Northern hybridization of immobilized RNA with [32P]-labeled human beta-actin riboprobe, were chosen for analysis. In situ hybridization was performed on formalin-fixed, 5 microns-thick Paraplast sections with [35S]-labeled riboprobes prepared by in vitro transcription of the respective linearized clones: a 537-bp EcoRI-PstI fragment of alpha 1-cDNA and a 342-bp PstI-EcoRI fragment of alpha 3-cDNA. In cortex, grains related to mRNA were measured by density per unit area in five cortical columns separated by 1.0-1.2 cm in each of two adjacent sections. Each cortical column of 180-micron width was divided into four depths orthogonal to the pial surface between the pia and the white matter. Amyloid plaques were counted in the same regions of adjacent sections. In addition, alpha 3-mRNA grain clusters over individual pyramidal neurons within depth 4 were analyzed. We found the following significant changes (p < 0.05): 1. Increases in total alpha 1-mRNA by 13-19% in AD compared to young and by 7-12% in AD compared to age-matched controls. 2. Decrease in total alpha 3-mRNA by 31-38% in AD compared to young and age-matched controls. 3. Decrease in alpha 3-mRNA content over individual pyramidal perikarya by 14% in normal aged brains without plaques compared to young controls, and by 44% in AD relative to young controls and by 35% compared to age-matched controls. No significant difference (p < 0.2) was found with respect to alpha 1- or alpha 3-mRNA in cerebellar cortex or individual Purkinje cells among any of the groups. In addition, there was a trend toward an inverse correlation between the levels of alpha 3-mRNA and of diffuse plaques, but not of neuritic plaques, in AD cases. IN CONCLUSION: 1. The increases in alpha 1-mRNA in AD may be related to an increased reactive gliosis. 2. The declines in alpha 3-mRNA per individual neuron found in normal aging occur prior to the formation of diffuse plaques and are greatly accelerated in AD. 3. The declines in alpha 3-mRNA per neuron found in normal aging may predispose to or potentiate AD pathogenesis.

Adult↗
PubMed1996

In situ analysis of Na, K-ATPase alpha1- and alpha3-isoform mRNAs in aging rat hippocampus.

Age-related changes in the expression of Na, K-ATPase alpha1- and alpha3-isoform mRNAs were analyzed by in situ hybridization in the Fischer-344 rat hippocampus. Quantification of signal density with cRNA probes in rat hippocampus at 3 months of age showed (a) alpha1 content is 1.5 times higher in granule than in pyramidal cell layers, whereas alpha3 content shows the opposite ratio and (b) alpha3 label is found in large clusters related to mossy cells and basket cells and in medium clusters corresponding to interneurons within the dendritic fields of CA1-3. In the 24-month-old rats as compared with the young animals, the alpha1 signal is increased more than sevenfold in the dendritic fields and is not significantly changed in the perikaryal layers. The alpha3 signal is reduced about threefold (p<0.0001, ANOVA, n=6) in perikaryal layers, is almost completely absent over interneurons, basket cells, and mossy cells, and is not significantly changed in dendritic fields. These data indicate age-related, cell- and isoform-specific alterations in pretranslational regulation of Na,K-ATPase a isoforms. The striking changes in the dendritic fields, mossy cells, and GABAergic basket cells and interneurons may constitute early and sensitive markers for age related alterations in hippocampal function, before cell loss.

Aging↗
PubMed1994

Distribution of alpha 1 subunit isoform of (Na,K)-ATPase in the rat spinal cord.

Three isoforms of the alpha subunit of (Na,K)-ATPase have been identified in the rat central nervous system. Using a probe specific for the alpha 1 isoform, mRNA levels were measured from five sections of the rat spinal cord using slot blot techniques. Assigning a value of 1 to the slope obtained from the cervical section, the upper thoracic section was 2.6 times higher; the midthoracic section was 4.5 times higher; the lower thoracic section was 2.6 times higher; and the lumbar section was 1.7 times higher. The results suggest that alpha 1 isoform mRNA levels are not uniform throughout the spinal cord. In situ hybridization techniques showed that alpha 1 isoform mRNA was diffusely abundant in glial and central canal ependymal cells, while labeled neurons were localized exclusively in laterally located anterior horn neurons in cervical, thoracic, and lumbar segments and in ventromedial neurons in mid-thoracic spinal cord. Also, dorsal root ganglia neurons were extensively labeled at all segments.

Animals↗
PubMed1991

Differential distribution of (Na,K)-ATPase alpha isoform mRNAs in the peripheral nervous system.

mRNA transcripts for 3 isoforms of the alpha subunit of (Na,K)-ATPase have been previously identified in the nervous system (designated alpha 1, alpha 2, and alpha 3). In order to study the localization and expression of the different alpha isoforms in the peripheral nervous system, we prepared probes from the unique 3' untranslated region of alpha 1 cDNA, and from the translated region of alpha 3 cDNA. These probes were used in dot blot and in situ hybridization assays of rat spinal cord, dorsal root ganglia (DRG), and sciatic nerve. Within the ventral horn of lumbar spinal cord, alpha 1 mRNA was found in a discrete set of laterally placed motor neurons, while alpha 3 was found in all the identified neurons of the spinal cord, including those motor neurons containing alpha 1. In the lumbar DRG, alpha 3 was uniformly distributed in DRG neurons, while alpha 1 was abundant in some neurons but little or none was found in other neurons. Satellite cells contained neither isoform. Schwann cells in sciatic nerve were labeled with the alpha 1 probe in a perinuclear distribution, but contained no detectable alpha 3. Dot blot analysis showed alpha 1 and alpha 3 in spinal cord and DRG, but only alpha 1 in peripheral nerve.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Differential distribution of (Na, K)-ATPase alpha isoforms in the central nervous system.

1. mRNA transcripts for three isoforms of the alpha subunit of (Na,K)-ATPase have been previously identified in the rat nervous system and designated alpha 1, alpha 2 and alpha 3. 2. In order to study the localization and expression of the different alpha isoform mRNAs on a regional and cellular level in the brain, we prepared probes from the unique 3' untranslated region of rat alpha 1 cDNA and from a segment containing a portion of the translated region of rat alpha 3 cDNA. These probes were used in dot blot and in situ hybridization assays of rat brain. 3. alpha 1 mRNA was found predominantly in cerebral cortex, dentate gyrus of hippocampus, and specific isolated brain-stem nuclei such as locus ceruleus and motor nuclei V and VII. In contrast alpha 3 mRNA was found predominantly in pyramidal neurons in the deep layers of cerebral cortex, in both pyramidal and dentate gyrus neurons of the hippocampus, and in neurons of most subcortical structures of the thalamus, basal ganglia, and brain-stem nuclei. 4. In the cerebellum, Purkinje cells showed predominantly alpha 3, as did stellate and basket cells. The granule cells contained predominantly alpha 1. 5. These experiments show that mRNAs for both alpha 1 and alpha 3 isoforms of (Na,K)-ATPase are found in neurons of the CNS. The isoforms have unique cellular and regional distributions, which in some cases overlap.

Animals↗
PubMed1991

Measurement of phenytoin and carbamazepine in an ultrafiltrate of saliva.

We have introduced a method of collecting a prepurified sample of saliva in the mouth for the quantitative determination of phenytoin and carbamazepine. The patient places in the mouth an osmotic device that accumulates in greater than 8 min a volume of approximately 1.2 ml clear ultrafiltrate devoid of molecules greater than 12,000 daltons. The concentrations of phenytoin and carbamazepine in serum (total and free fractions), whole saliva, and the salivary ultrafiltrate from patients receiving anticonvulsant treatment were measured and correlated. The correlation coefficients r (p less than 0.001) for phenytoin were: total in serum and ultrafiltrate r = 0.92; free in serum and ultrafiltrate r = 0.93; whole saliva and ultrafiltrate r = 0.95. The correlation coefficients for carbamazepine were (in the same order) 0.90, 0.92, and 0.93. It is concluded that the use of an ultrafiltrate as a biological medium simplifies the diagnostic evaluation of free circulating phenytoin and carbamazepine concentrations for monitoring therapy.

Adolescent↗
PubMed1991

Immunocytochemical demonstration of Na+,K(+)-ATPase in internodal axolemma of myelinated fibers of rat sciatic and optic nerves.

We used postembedding electron microscopic immunocytochemistry with colloidal gold to determine the ultrastructural distribution of Na+,K(+)-ATPase in the sciatic and optic nerves of the rat. Using a polyclonal antiserum raised against the denatured catalytic subunit of brain Na+,K(+)-ATPase, we found immunoreactivity along the internodal axolemma of myelinated fibers in both nerves. This antiserum did not produce labeling of nodal axolemma. These results suggest that an important site of energy-dependent sodium-potassium exchange is along the internodal axolemma of myelinated fibers in the mammalian CNS and PNS and that there may be differences between the internodal and nodal forms of the enzyme.

Animals↗
PubMed1991

Immunocytochemical localization of carbonic anhydrase, NaK-ATPase and the bicarbonate chloride exchanger in the anterior segment of the human eye.

We examined immunohistochemically the localization of three transport enzymes (carbonic anhydrase, Ca-II; sodium-potassium-activated adenosine triphosphatase, NaK-ATPase; bicarbonate-chloride exchanger, band III) in the anterior segment of the human eye. In accord with earlier studies, NaK-ATPase was primarily found in the corneal endothelium, but also in the corneal basal epithelial cell membranes. In addition, immunoreactivity for NaK-ATPase was observed in the non-pigmented epithelium of the ciliary processes and between the two epithelial cell layers. Ca-II immunoreactivity was found in the corneal endothelium as well as in the non-pigmented epithelial layer of the ciliary processes. Interestingly, band III immunoreactivity was found in the corneal endothelium, as similar to Ca-II, but not in the ciliary processes. These results show that, similar to many other tissues, Ca-II and band III immunoreactivities colocalize in the same cytologic site in the human corneal endothelium. Immunocytochemical detection of these key transport enzymes not only gives their accurate and reliable anatomical distribution, but also provides information on the electrolyte transport at these sites.

Anion Exchange Protein 1, Erythrocyte↗
PubMed1990

Differences between lateral and mesial temporal metabolism interictally in epilepsy of mesial temporal origin.

We performed interictal [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography in 17 patients with well-defined unilateral anterior mesial temporal epileptogenic foci as determined by EEG procedures. Sixteen of these patients subsequently underwent surgical resection of the epileptogenic focus. We measured local cerebral metabolic rates for glucose in mesial and lateral temporal structures and compared them with metabolic rates for analogous regions in 16 healthy normal volunteers and the contralateral hemisphere of the epileptic patients. We found relative hypometabolism ipsilateral to the seizure focus more frequently and to a greater degree in the lateral than in the mesial temporal cortex. Since the physiologic abnormalities involved mesial temporal structures, this observation suggests that functional pathways exist between mesial and lateral temporal cortex normally and that these pathways are altered in epilepsy of mesial temporal origin. Hypometabolism did not correlate well with histologic abnormalities in the surgical specimens.

Adolescent↗
PubMed1990

Hemangiopericytoma of the nasal cavity.

Hemangiopericytomas are unusual vascular tumours that rarely occur in the paranasal sinuses and nasal cavity. They are thought to arise from pericytes that surround capillaries, however, there is no proven etiology of these tumours. The diagnosis cannot be made based on gross morphologic characteristics nor on frozen section biopsy. Instead, the diagnosis is dependent on careful histologic examination and reticulum staining. The diagnosis can be confirmed by electron microscopy. The histologic picture is greatly varied from tumour to tumour and within a given tumour itself. The clinical course of hemangiopericytomas ranges from benign to malignant with possible distant metastases and cannot be reliably predicted by histologic criteria. Hemangiopericytomas of the nose and paranasal sinuses are thought to behave less aggressively than those occurring in other parts of the body. Lymph node metastasis is rare and elective neck dissection is not indicated. The accepted treatment of these tumours is wide surgical excision, however adequate surgical margins are usually difficult in the sinonasal region. As a result, hemangiopericytomas can exhibit a high recurrence rate. Therefore, it is mandatory that these patients be followed carefully for the remainder of their lives.

Adult↗