SUMMARY: Filamentous axonalmasses, similar to the abnormal enlargements found in the ventral horns, were found in Clarke’s nucleus in six cases of sporadic A LS. Clarke’s nucleus is generally thought to be normal in sporadic A LS, but the present findings, in conjunction with distal spinocerebellar degeneration which is often described, suggest that this system is also pathologically involved.
A clinical challenge for interventional prostate treatments for localized prostate cancer has been to elicit cancer tissue eradication which can avoid undesirable toxicities and irreparable damage to adjacent structures. Fexapotide triflutate (FT) has been shown in human clinical trials to be a well-tolerated pharmaco-ablative agent with therapeutic benefit in patients with prostate enlargement and low-grade prostate cancer.Studies were undertaken in vitro and in the normal male rat to characterize and quantify selective ablation of prostate glandular cells exposed to fexapotide triflutate (FT) injections. N=371 2-month-old Sprague Dawley rats received direct intraprostatic injections under ether anesthesia with laparotomy (n=268 given 0.3 mL FT 0.1-2.0 mg/mL at varied schedules, and n=103 controls), and were sacrificed at intervals of 24 hr-12 months, with measurements of prostate volume, assessments of apoptosis, prostatic nerve structures, connective tissue stroma, and vasculature. In vitro prostate cell lines treated with FT were studied by electron microscopy and RNA quantification.Evidence shows that FT leads to prostate glandular cell loss not found in controls, by apoptosis within 24-72 hrs that is highly selective for achieving near-total loss of glandular epithelium at 6 to 12 months, without any adverse microscopic effects to adjacent periprostatic nerves, vascular elements, and stroma.Histological studies in the rat demonstrate that FT ablative effect is selective for prostate glandular epithelium, sparing adjacent tissues and structures in the prostate including nerves, vasculature, and stroma.
The rate of disappearance of microneurons from the granular layer of the cerebellum of the rat during post-mortem autolysis was measured by image analysis of serial sections of perfusion preparations at various intervals during the first 24 hr after death. The cell population shows a logarithmic decrease during this period. The possible relation to cell death in disease and practical applications of this finding as a gauge of post-mortem interval are discussed.
Spherons are unique brain entities that are causally linked to the amyloid plaques (SPs [senile plaques]) of Alzheimer's disease (AD). SPs are the quantitatively major tissue abnormality of AD. Spherons increase in size (but not in number) gradually throughout life until they reach a size range where they burst and form SPs. Drugs targeted at attenuating the process of spheron transformation into SPs are a logical approach to AD therapy. There are 20 criteria of validity for an SP causal entity that are satisfied by spherons-and no more than a few of these 20 criteria are satisfied by any other known hypothesis. These criteria of validity are reviewed, in addition to common difficulties in understanding spheron theory and a number of common-sense considerations in AD therapeutic research. Spheron-based drug therapy in AD potentially can retard the process of spheron bursting and subsequent plaque formation by: 1) blocking the formation of SPs; 2) reducing the size of SPs; 3) delaying spheron breakdown; and 4) retarding spheron growth. Isolated spherons from human brain are intact human drug targets and can be used as human in vitro or in vivo screening targets. The paramount importance of spherons as a target for drug therapy in AD is emphasized by considering that regardless of any other type of real or potential therapy, there still already exists in every middle-aged adult a full population of spherons in the brain, filled with more than enough amyloid to bring about full-blown AD.
Tissue from L-4 spinal cord, dorsal root ganglia, sural nerve, and intramuscular branches to the gastrocnemius was obtained during 35 random autopsies, embedded in paraffin, and stained with PAS and Holmes Alcian blue and studied for the incidence and distribution of corpora amylacea (CA). Intraaxonal CA in spinal grey matter were commonly found, but the incidence in root ganglia, sural, and intramuscular nerve was low. Clinically insignificant intraneuronal spinal grey CA were found in six of eight men past the age of 60 years. Corpora amylacea in spinal white matter were most common in the region of posterior root entry.
We have isolated a novel Alu sequence-containing cDNA, designated AD7c-NTP, that is expressed in neurons, and overexpressed in brains with Alzheimer's disease (AD). The 1,442-nucleotide AD7c-NTP cDNA encodes an approximately 41-kD protein. Expression of AD7c-NTP was confirmed by nucleic acid sequencing of reverse transcriptase PCR products isolated from brain. AD7c-NTP cDNA probes hybridized with 1. 4 kB mRNA transcripts by Northern blot analysis, and monoclonal antibodies generated with the recombinant protein were immunoreactive with approximately 41-45-kD and approximately 18-21-kD molecules by Western blot analysis. In situ hybridization and immunostaining studies localized AD7c-NTP gene expression in neurons. Using a quantitative enzyme-linked sandwich immunoassay (Ghanbari, K., I. Beheshti, and H. Ghanbari, manuscript submitted for publication) constructed with antibodies to the recombinant protein, AD7c-NTP levels were measured under code in 323 clinical and postmortem cerebrospinal fluid (CSF) samples from AD, age-matched control, Parkinson's disease, and neurological disease control patients. The molecular mass of the AD7c-NTP detected in CSF was approximately 41 kD. In postmortem CSF, the mean concentration of AD7c-NTP in cases of definite AD (9.2+/-8.2 ng/ml) was higher than in the aged control group (1.6+/-0.9; P < 0.0001). In CSF samples from individuals with early possible or probable AD, the mean concentration of AD7c-NTP (4.6+/-3.4) was also elevated relative to the levels in CSF from age-matched (1.2+/-0.7) and neurological disease (1.0+/-0.9) controls, and ambulatory patients with Parkinson's disease (1.8+/-1.1) (all P < 0.001). CSF levels of AD7c-NTP were correlated with Blessed dementia scale scores (r = 0. 66; P = 0.0001) rather than age (r = -0.06; P > 0.1). In vitro studies demonstrated that overexpression of AD7c-NTP in transfected neuronal cells promotes neuritic sprouting and cell death, the two principal neuroanatomical lesions correlated with dementia in AD. The results suggest that abnormal AD7c-NTP expression is associated with AD neurodegeneration, and during the early stages of disease, CSF levels correlate with the severity of dementia.
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