Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Incubation of murine spleen cells, or enriched T-cell populations, with the T-cell-dependent polyclonal mitogens Con-A or PHA resulted in a dose-dependent increase in 45Ca2+ uptake. This effect was observed after a delay of about 30 to 60 min, reached a maximum after 2-4 h and lasted up to 6 h. Similarly, the calcium ionophore A23187 caused an increased Ca2+ uptake, although this was faster, occurring within a few minutes, reaching a maximum at 15 min and lasting for about 2-4 h. No change in Ca2+ uptake was observed using a specific B-cell mitogen (lipopolysaccharide) or B-cell preparations. Nifedipine, a calcium channel-blocking agent, inhibited activation of lymphocytes in a primary immune response (mixed lymphocyte reaction and formation of plaque forming cells in vitro) but was unable to interfere with proliferating cell lines or a secondary immune response. Incubation of Con-A-activated lymphocytes with the immunosuppressive agent CS-A caused an additional increase in calcium uptake, whereas no change in calcium uptake was observed when resting lymphocytes or B-cells activated by LPS were incubated with cyclosporin. A similar potentiation of Con-A-induced calcium uptake was seen with hydrocortisone, but not with cytostatic agents or anti-lymphocyte serum. Submaximal calcium uptake induced by the ionophore A23187 was potentiated by CS-A and hydrocortisone as well as by cytostatic agents and ALS.
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PMID:Cyclosporin A (Sandimmun) modulates the Ca2+ uptake of mitogen-stimulated lymphocytes. 644 37

The effect of ALS (I), a heterologous anti-lymphocyte serum prepared against lymph node cells from rats pre-immunised with sheep erythrocytes (SRBC), on plaque forming cells (PFC) to SRBC was studied in vitro. ALS (I) reduced the number of both IgM and IgG PFC when complement was included in the reaction. This ability of ALS (I) to inhibit PFCs in vitro was absorbed out by the IgG fraction of anti-SRBC serum. Thus ALS (I) was thought to possess and anti-idiotypic antibody directed against B-cells at a later stage of differentiation.
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PMID:In vitro studies on the effect of anti-lymphocyte serum on the humoral immune response. 698 31

The clinical and neuropathological features of a case of a neurodegenerative disorder with pronounced and progressive head drooping, in Japanese Kubisagari, are reported. This female patient died at the age of 72 years after an approximately 20-year history of peculiar posture with progressive head drooping (Kubisagari) and lordosis (bowed posture), parkinsonism, dysphonia and slight muscle wasting of the face, tongue, neck, and distal portions of the upper extremities. She did not display mental deterioration until the terminal stage of the illness. A simple macroscopic inspection formalin-fixed sections of the central nervous system (CNS) showed prominent atrophic frontal and temporal lobes, brownish discoloration of the putamen and an atrophic pyramidal tract. Light microscopy revealed severe neuron loss with fibrillary gliosis at both the above-mentioned lobes and the putamen. Both the facial and hypoglossal nuclei had almost disappeared. Motor neurons in the spinal cord were moderately to markedly decreased. Neither Bunina nor Lewy bodies, senile plaque, nor Pick's argyrophilic neuronal inclusions were observed, but very occasionally ubiquitin-positive neurons were found in the temporal cortex. In conclusion, the hitherto-unrecognized neuropathological findings in the CNS corresponding to progressive head drooping (Kubisagari) suggest that this is a neurodegenerative disorder of the CNS, possibly an atypical form of amyotrophic lateral sclerosis.
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PMID:Clinical and neuropathological features of a neurodegenerative disorder in the central nervous system with progressive head drooping (Kubisagari). 748 99

The Guamanian amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is characterized by abundant neurofibrillary pathology and neuron loss. In contrast to Alzheimer's disease (AD), where extensive neurofibrillary lesions always occur with deposits of A beta in numerous amyloid plaques, A beta-rich amyloid plaques are absent or rare in most ALS/PDC patients. To characterize the amyloid plaques in the latter patients, we probed plaque-rich sections of their brains by immunohistochemistry using well-characterized antibodies to specific epitopes in the N and C termini of A beta as well as to defined epitopes in hyperphosphorylated tau (PHFtau). The results indicate that the species of A beta in the amyloid plaques of ALS/PDC patients resemble those detected in the amyloid plaques of cognitively intact subjects with pathological aging as well as patients with AD. However, the paucity of PHFtau-positive neurites in the ALS/PDC plaques suggests that they reflect pathological aging rather than AD.
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PMID:Amyloid plaques in Guam amyotrophic lateral sclerosis/parkinsonism-dementia complex contain species of A beta similar to those found in the amyloid plaques of Alzheimer's disease and pathological aging. 949 44

Identification of genetic mechanisms that promote the onset of stroke and transient cerebral ischemic attack symptoms in carotid atherosclerotic patients would further our understanding of the pathophysiology of this disease and could lead to new pharmacological and molecular therapies. Using Affymetrix Human Genome 230 GeneChip set, the present study evaluated the gene expression differences in geometrically similar carotid artery plaque samples extricated from six symptomatic stroke patients and four asymptomatic patients. There was no significant difference in the degree of stenosis between the two groups. Of the 44,860 transcripts analyzed, 289 (approximately 0.6% of the total transcripts) were differentially expressed between the plaques from the symptomatic and asymptomatic groups (236 were expressed more abundantly and 53 were expressed less abundantly in the symptomatic group). Of the 236 transcripts expressed more abundantly in the symptomatic plaques, 71% (167 transcripts) indicate an active cell proliferation and neoplastic process. These include oncogenes, growth factors, tumor promoters, tumor markers, angiogenesis promoters, transcription factors, RNA splicing factors, RNA processing proteins, signal transduction mediators and those that control the metabolism. Real-time polymerase chain reaction confirmed the increased expression of 63 transcripts in the symptomatic plaques. The other groups of transcripts expressed more abundantly in the symptomatic plaques are those that control ionic homeostasis, those that participate in the progression of degenerative neurological diseases (Alzheimer's disease, amyotrophic lateral sclerosis and Huntington's disease) and epilepsy. This indicates that symptomatic plaques are molecularly and biochemically more active than the asymptomatic plaques, or active plaque growth precipitates stroke symptoms.
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PMID:Carotid atherosclerotic plaques from symptomatic stroke patients share the molecular fingerprints to develop in a neoplastic fashion: a microarray analysis study. 1570 79

Although Enteroviruses are mainly described as responsible for acute diseases, their role in severe chronic pathology has been also established. Echovirus 6-like sequences have been detected by PCR analysis in central nervous system specimens from patients presenting with Amyotrophic Lateral Sclerosis. These findings suggested a persistent infection with viruses that underwent, genetic changes precluding viral particle release. To support this hypothesis, we developed a model system of Echovirus 6 chronic infection in precursors of glial cells. The nucleotide sequences of the 5'non-translated region (5'NTR), 2A and 3C regions of the virus developing persistent genome were analysed during establishment of the chronic phenotype. This study revealed that at day 160 of chronic infection, several mutations were observed: one mutation at nucleotide 108 upstream the domain II of the internal ribosome entry site (IRES) structure, one mutation at nucleotide 30 in the cloverleaf, and two mutations in the 2A region (translated in His48 to Tyr, and Ile 123 to Met). No mutations were detected in the 3C region. The impact of these mutations on viral replication have been analysed in a rabbit reticulocyte lysate (RRL) translation assay supplemented with HeLa cell lysate, and by plaque assay. Viruses with these mutations displayed a phenotype with a significant reduction of replication, while in vitro translation was not affected by the nucleotide 108 mutation. This model allowed the description of molecular changes observed in the genome of Echovirus 6 during the establishment of a chronic infection phenotype, and may be helpful for the understanding of the mechanisms leading Enteroviruses to develop chronic infections in man.
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PMID:Cumulative mutations in the genome of Echovirus 6 during establishment of a chronic infection in precursors of glial cells. 1574 68

Here is proposed a hypothesis that a completely unsuspected biology exists for pathogenic spirochetes, namely that the cystic spirochetal forms (long thought to be static and resting or just a dormant cohort) actually are capable of killing mammalian host cells. At least two "lethal" scenarios are proposed; first, the host cell destruction from the "inside out" by small caliber cystic forms invading the host cell cytoplasm, and second host cell destruction by engulfment of entire host cells by large caliber cystic spirochetal forms. Conventional thinking about spirochetal cyst forms is divided between two polar spheres of influence; one a majority community that completely denies the existence of spirochetal cyst forms, and a second group of academically persecuted individuals who accepts the precepts of such antebellum scientists as Schaudinn, Hoffman, Dutton, Levaditi, Balfour, Fantham, Noguchi, McDonough, Hindle, Steiner, Ingraham, Coutts, Hampp, Warthin, Ovcinnikov, and Delamater. Microscopic images of cystic spirochetes are difficult to ignore, but as has been the case in this century, academic "endowments" have nearly expunged all cystic spirochetal image data from the current textbook versions of what is the truth about the spirochetaceae. If the image database from the last century is obliterated; many opportunities to diagnose will be lost. Variously sized cystic spirochetal profiles within diseased nerve cells explain the following structures: Lewy body of Parkinson's disease, Pick body, ALS spherical body, Alzheimer plaque. Borrelia infection is therefore a unifying concept to explain diverse neurodegenerative diseases, based not entirely on a corkscrew shaped profile in diseased tissue, but based on small, medium and large caliber rounded cystic profiles derived from pathogenic spirochetes which are..."hiding in plain sight".
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PMID:Spirochetal cyst forms in neurodegenerative disorders,...hiding in plain sight. 1682 36

Statin drugs are widely prescribed to achieve aggressive low-density lipoprotein lowering in order to decrease cardiovascular disease. Although some of the immunomodulatory effects of statins may stabilize atherosclerotic plaque, they may be harmful in certain segments of the population. Recently, statins have been shown to increase the concentration of regulatory T cells (Tregs), in vivo. There is evidence that this increases the risk of many cancers, particularly in the elderly. Furthermore, a statin induced increase in Tregs may be detrimental in neurodegenerative disorders, such as amyotrophic lateral sclerosis; and a myriad of infectious diseases. These include, but are not limited to, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, and varicella zoster virus. These issues need our attention, and call for a heightened state of vigilance among those prescribing statins.
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PMID:The double-edged sword of statin immunomodulation. 1857 Dec 56

Pathologic TAR-DNA-binding protein 43 (TDP-43) is a disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis. We studied the presence, frequency, and distribution of TDP-43 pathology by immunohistochemistry and biochemistry in a series of clinically well-characterized tauopathy patient brains, including 182 Alzheimer disease (AD), 39 corticobasal degeneration, 77 progressive supranuclear palsy, and 12 Pick disease cases and investigated the clinical impact of concomitant TDP-43 pathology in these cases. TAR-DNA-binding protein 43 pathology was found in 25.8% of AD cases. It was restricted to the dentate gyrus and entorhinal cortex in approximately 75% of cases; approximately 25% showed more widespread TDP-43 pathology in frontal and temporal cortices, resembling the FTLD-U subtype associated with progranulin mutations. TAR-DNA-binding protein 43 pathology in AD was associated with significantly longer disease duration, but there was no association with the clinical presentation (148 cases diagnosed as AD and 34 cases diagnosed as frontotemporal lobar degeneration). Progressive supranuclear palsy and Pick disease cases showed no TDP-43 inclusions and no biochemical alterations of TDP-43. There was, however, a unique, predominantly glial TDP-43 pathology with staining of astrocytic plaque-like structures and coiled bodies in 15.4% of corticobasal degeneration cases; this was associated with biochemical TDP-43 changes similar to those in FTLD-U. These findings provide further insight into the burden and clinical significance of TDP-43 pathology in disorders other than FTLD-U and amyotrophic lateral sclerosis.
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PMID:Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies. 1852 Jul 74

The TAR DNA-binding protein-43 (TDP-43) has been identified as a major constituent of inclusions found in frontotemporal dementia with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). To determine a possible role for TDP-43 in Alzheimer's disease (AD), a site-directed caspase-cleavage antibody to TDP-43 based upon a known caspase-3 cleavage consensus site within TDP- 43 at position D219 was designed. In vitro, this antibody labeled the predicted 25 kDa caspase-cleavage fragment of TDP-43 without labeling full-length TDP-43 following digestion of recombinant TDP-43 with caspase-3 or treatment of HeLa cells with staurosporine. Application of this antibody in postmortem brain sections indicated the presence of caspase-cleaved TDP-43 in Hirano bodies, tangles, reactive astrocytes and neuritic plaques of the AD brain. Caspase-cleaved TDP-43 also co-localized with ubiquitin labeled neurons as well as dystrophic neurites within plaque regions. These results suggest that caspase-cleaved TDP-43 is a major pathological finding in AD and may contribute to the neurodegeneration associated with this disease.
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PMID:Caspase-cleaved TAR DNA-binding protein-43 is a major pathological finding in Alzheimer's disease. 1863 62


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