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1

Novel monoclonal antibodies to normal and pathologically altered human TDP-43 proteins.  

Science.gov (United States)

The RNA/DNA-binding protein, TDP-43, is the key component of ubiquitinated inclusions characteristic of amyotrophic lateral sclerosis (ALS) and the majority of frontotemporal lobar degeneration (FTLD-TDP) referred to collectively as TDP-43 proteinopathies. To further elucidate mechanisms of pathological TDP-43 processing and identify TDP-43 epitopes that could be useful as potential biomarkers of TDP-43 proteinopathies, we developed a panel of novel monoclonal antibodies (MAbs) directed at regions extending across the length of TDP-43. Here, we confirm previous observations that there is no or minimal accumulation of TDP-43 N-terminal domains in neocortical inclusions in human TDP-43 proteinopathy tissues and we identify a subset of these MAbs that are specific for human versus mouse TDP-43. Notably, one of these MAbs recognized an epitope that preferentially detected pathological TDP-43 inclusions with negligible reactivity for normal nuclear TDP-43 resembling anti-phospho-TDP-43 specific antibodies that only bind pathological TDP-43. Hence, we infer that this new MAb recognizes a phosphorylation independent but disease-specific pathologic conformation in abnormal TDP-43. These data suggest that the novel MAbs reported here will be useful for patient-oriented research as well as for studies of animal and cell-based models of TDP-43 proteinopathies including ALS and FTLD-TDP. PMID:24690345

Kwong, Linda K; Irwin, David J; Walker, Adam K; Xu, Yan; Riddle, Dawn M; Trojanowski, John Q; Lee, Virginia M Y

2014-01-01

2

Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice  

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Full Text Available Abstract Background Abnormal distribution, modification and aggregation of transactivation response DNA-binding protein 43 (TDP-43 are the hallmarks of multiple neurodegenerative diseases, especially frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U and amyotrophic lateral sclerosis (ALS. Researchers have identified 44 mutations in the TARDBP gene that encode TDP-43 as causative for cases of sporadic and familial ALS http://www.molgen.ua.ac.be/FTDMutations/. Certain mutant forms of TDP-43, such as M337V, are associated with increased low molecular weight (LMW fragments compared to wild-type (WT TDP-43 and cause neuronal apoptosis and developmental delay in chick embryos. Such findings support a direct link between altered TDP-43 function and neurodegeneration. Results To explore the pathogenic properties of the M337V mutation, we generated and characterized two mouse lines expressing human TDP-43 (hTDP-43M337V carrying this mutation. hTDP-43M337V was expressed primarily in the nuclei of neurons in the brain and spinal cord, and intranuclear and cytoplasmic phosphorylated TDP-43 aggregates were frequently detected. The levels of TDP-43 LMW products of ~25 kDa and ~35 kDa species were also increased in the transgenic mice. Moreover, overexpression of hTDP-43M337V dramatically down regulated the levels of mouse TDP-43 (mTDP-43 protein and RNA, indicating TDP-43 levels are tightly controlled in mammalian systems. TDP-43M337V mice displayed reactive gliosis, widespread ubiquitination, chromatolysis, gait abnormalities, and early lethality. Abnormal cytoplasmic mitochondrial aggregates and abnormal phosphorylated tau were also detected in the mice. Conclusion Our novel TDP-43M337V mouse model indicates that overexpression of hTDP-43M337V alone is toxic in vivo. Because overexpression of hTDP-43 in wild-type TDP-43 and TDP-43M337V mouse models produces similar phenotypes, the mechanisms causing pathogenesis in the mutant model remain unknown. However, our results suggest that overexpression of the hTDP-43M337V can cause neuronal dysfunction due to its effect on a number of cell organelles and proteins, such as mitochondria and TDP-43, that are critical for neuronal activity. The mutant model will serve as a valuable tool in the development of future studies designed to uncover pathways associated with TDP-43 neurotoxicity and the precise roles TDP-43 RNA targets play in neurodegeneration.

Dickson Dennis W

2011-10-01

3

RNP2 of RNA Recognition Motif 1 Plays a Central Role in the Aberrant Modification of TDP-43  

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Phosphorylated and truncated TAR DNA-binding protein-43 (TDP-43) is a major component of ubiquitinated cytoplasmic inclusions in neuronal and glial cells of two TDP-43 proteinopathies, amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Modifications of TDP-43 are thus considered to play an important role in the pathogenesis of TDP-43 proteinopathies. However, both the initial cause of these abnormal modifications and the TDP-43 region responsible for its aggregation remain u...

Takagi, Shinnosuke; Iguchi, Yohei; Katsuno, Masahisa; Ishigaki, Shinsuke; Ikenaka, Kensuke; Fujioka, Yusuke; Honda, Daiyu; Niwa, Jun-ichi; Tanaka, Fumiaki; Watanabe, Hirohisa; Adachi, Hiroaki; Sobue, Gen

2013-01-01

4

Neuronal sensitivity to TDP-43 overexpression is dependent on timing of induction  

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Ubiquitin-immunoreactive neuronal inclusions composed of TAR DNA binding protein of 43 kDa (TDP-43) are a major pathological feature of frontotemporal lobar degeneration (FTLD-TDP). In vivo studies with TDP-43 knockout mice have suggested that TDP-43 plays a critical, although undefined role in development. In the current report, we generated transgenic mice that conditionally express wild-type human TDP-43 (hTDP-43) in the forebrain and established a paradigm to examine the sensitivity of n...

Cannon, Ashley; Yang, Baoli; Knight, Joshua; Farnham, Ian M.; Zhang, Yongjie; Wuertzer, Charles A.; D’alton, Simon; Lin, Wen-lang; Castanedes-casey, Monica; Rousseau, Linda; Scott, Brittany; Jurasic, Michael; Howard, John; Yu, Xin; Bailey, Rachel

2012-01-01

5

Altered distributions of Gemini of coiled bodies and mitochondria in motor neurons of TDP-43 transgenic mice  

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TAR DNA-binding protein-43 (TDP-43), a DNA/RNA-binding protein involved in RNA transcription and splicing, has been associated with the pathophysiology of neurodegenerative diseases, including ALS. However, the function of TDP-43 in motor neurons remains undefined. Here we use both gain- and loss-of-function approaches to determine roles of TDP-43 in motor neurons. Mice expressing human TDP-43 in neurons exhibited growth retardation and premature death that are characterized by abnormal intra...

Shan, Xiu; Chiang, Po-min; Price, Donald L.; Wong, Philip C.

2010-01-01

6

ALS/FTLD-linked TDP-43 regulates neurite morphology and cell survival in differentiated neurons  

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Tar-DNA binding protein of 43 kDa (TDP-43) has been characterized as a major component of protein aggregates in brains with neurodegenerative diseases such as frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). However, physiological roles of TDP-43 and early cellular pathogenic effects caused by disease associated mutations in differentiated neurons are still largely unknown. Here, we investigated the physiological roles of TDP-43 and the effects of missense mutations associated with diseases in differentiated cortical neurons. The reduction of TDP-43 by siRNA increased abnormal neurites and decreased cell viability. ALS/FTLD-associated missense mutant proteins (A315T, Q331K, and M337V) were partially mislocalized to the cytosol and neurites when compared to wild-type and showed abnormal neurites similar to those observed in cases of loss of TDP-43. Interestingly, cytosolic expression of wild-type TDP-43 with mutated nuclear localization signals also induced abnormal neurtie morphology and reduction of cell viability. However, there was no significant difference in the effects of cytosolic expression in neuronal morphology and cell toxicity between wild-type and missense mutant proteins. Thus, our results suggest that mislocalization of missense mutant TDP-43 may contribute to loss of TDP-43 function and affect neuronal morphology, probably via dominant negative action before severe neurodegeneration in differentiated cortical neurons. Highlights: • The function of nuclear TDP-43 in neurite morphology in mature neurons. • Partial mislocalization of TDP-43 missense mutants into cytosol from nucleus. • Abnormal neurite morphology caused by missense mutants of TDP-43. • The effect of cytosolic expression of TDP-43 in neurite morphology and in cell survival

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ALS/FTLD-linked TDP-43 regulates neurite morphology and cell survival in differentiated neurons  

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Tar-DNA binding protein of 43 kDa (TDP-43) has been characterized as a major component of protein aggregates in brains with neurodegenerative diseases such as frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). However, physiological roles of TDP-43 and early cellular pathogenic effects caused by disease associated mutations in differentiated neurons are still largely unknown. Here, we investigated the physiological roles of TDP-43 and the effects of missense mutations associated with diseases in differentiated cortical neurons. The reduction of TDP-43 by siRNA increased abnormal neurites and decreased cell viability. ALS/FTLD-associated missense mutant proteins (A315T, Q331K, and M337V) were partially mislocalized to the cytosol and neurites when compared to wild-type and showed abnormal neurites similar to those observed in cases of loss of TDP-43. Interestingly, cytosolic expression of wild-type TDP-43 with mutated nuclear localization signals also induced abnormal neurtie morphology and reduction of cell viability. However, there was no significant difference in the effects of cytosolic expression in neuronal morphology and cell toxicity between wild-type and missense mutant proteins. Thus, our results suggest that mislocalization of missense mutant TDP-43 may contribute to loss of TDP-43 function and affect neuronal morphology, probably via dominant negative action before severe neurodegeneration in differentiated cortical neurons. Highlights: • The function of nuclear TDP-43 in neurite morphology in mature neurons. • Partial mislocalization of TDP-43 missense mutants into cytosol from nucleus. • Abnormal neurite morphology caused by missense mutants of TDP-43. • The effect of cytosolic expression of TDP-43 in neurite morphology and in cell survival.

Han, Jeong-Ho; Yu, Tae-Hoon; Ryu, Hyun-Hee; Jun, Mi-Hee; Ban, Byung-Kwan [Department of Biotechnology, College of Life Science and Nanotechnology, Hannam University, Dajeon 305-811 (Korea, Republic of); Jang, Deok-Jin [Department of Applied Biology, College of Ecology and Environment, Kyungpook National University, 386, Gajang-dong, Sangju-si, Kyungbuk 742-711 (Korea, Republic of); Lee, Jin-A, E-mail: leeja@hnu.kr [Department of Biotechnology, College of Life Science and Nanotechnology, Hannam University, Dajeon 305-811 (Korea, Republic of)

2013-08-01

8

Loss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis.  

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Abnormal TDP-43 aggregation is a prominent feature in the neuropathology of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. Mutations in TARDBP, the gene encoding TDP-43, cause some cases of ALS. The normal function of TDP-43 remains incompletely understood. To better understand TDP-43 biology, we generated mutant mice carrying a genetrap disruption of Tardbp. Mice homozygous for loss of TDP-43 are not viable. TDP-43 deficient embryos die about day 7.5 of embryonic development thereby demonstrating that TDP-43 protein is essential for normal prenatal development and survival. However, heterozygous Tardbp mutant mice exhibit signs of motor disturbance and muscle weakness. Compared with wild type control littermates, Tardbp (+/-) animals have significantly decreased forelimb grip strength and display deficits in a standard inverted grid test despite no evidence of pathologic changes in motor neurons. Thus, TDP-43 is essential for viability, and mild reduction in TDP-43 function is sufficient to cause motor deficits without degeneration of motor neurons. PMID:20198480

Kraemer, Brian C; Schuck, Theresa; Wheeler, Jeanna M; Robinson, Linda C; Trojanowski, John Q; Lee, Virginia M Y; Schellenberg, Gerard D

2010-04-01

9

RNA targets of TDP-43 identified by UV-CLIP are deregulated in ALS.  

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TDP-43 is a predominantly nuclear DNA/RNA binding protein involved in transcriptional regulation and RNA processing. TDP-43 is also a component of the cytoplasmic inclusion bodies characteristic of amyotrophic lateral sclerosis (ALS) and of frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U). We have investigated the premise that abnormalities of TDP-43 in disease would be reflected by changes in processing of its target RNAs. To this end, we have firstly identified RNA targets of TDP-43 using UV-Cross-Linking and Immunoprecipitation (UV-CLIP) of SHSY5Y cells, a human neuroblastoma cell line. We used conventional cloning strategies to identify, after quality control steps, 127 targets. Results show that TDP-43 binds mainly to introns at UG/TG repeat motifs (49%) and polypyrimidine rich sequences (17.65%). To determine if the identified RNA targets of TDP-43 were abnormally processed in ALS versus control lumbar spinal cord RNA, we performed RT-PCR using primers designed according to the location of TDP-43 binding within the gene, and prior evidence of alternative splicing of exons adjacent to this site. Of eight genes meeting these criteria, five were differentially spliced in ALS versus control. This supports the premise that abnormalities of TDP-43 in ALS are reflected in changes of RNA processing. PMID:21421050

Xiao, Shangxi; Sanelli, Teresa; Dib, Samar; Sheps, David; Findlater, Joseph; Bilbao, Juan; Keith, Julia; Zinman, Lorne; Rogaeva, Ekaterina; Robertson, Janice

2011-07-01

10

Disease-Associated Mutations of TDP-43 Promote Turnover of the Protein Through the Proteasomal Pathway.  

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TAR DNA-binding protein (TDP-43) is a major component of most ubiquitin-positive neuronal and glial inclusions of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). A number of missense mutations in the TARDBP gene have been identified in patients with familial and sporadic ALS, as well as familial FTLD with ALS. In the diseased states, TDP-43 proteins exhibit characteristic alterations, including truncation, abnormal phosphorylation, and altered subcellular distribution. However, the mechanisms by which TDP-43 mutations induce neurodegeneration remain unclear at present. In the current study, we analyzed protein turnover and subcellular distribution of wild-type TDP-43 and two disease-associated mutants (G298S and A382T) in human neuroblastoma SH-SY5Y cells stably expressing TDP-43 with a C-terminal tag. Cycloheximide chase experiments revealed more rapid turnover of TDP-43 mutant proteins than their wild-type counterpart. The decrease in the TDP-43 level after cycloheximide treatment was partially recovered upon co-treatment with the proteasome inhibitor, epoxomicin, but not the lysosomotropic agent, chloroquine, suggesting involvement of the proteasomal pathway in TDP-43 degradation. Analysis of the subcellular distribution of TDP-43 revealed predominant localization in the nuclear fraction, whereas the relative level in the cytoplasm remained unaltered in cells expressing either mutant protein, compared with wild-type protein. Our results suggest that higher turnover of disease-associated mutant TDP-43 proteins through the ubiquitin proteasome system is pathogenetically relevant and highlight the significance of proteolysis in the pathogenetic mechanism of TDP-43 proteinopathy. PMID:24477737

Araki, Wataru; Minegishi, Seiji; Motoki, Kazumi; Kume, Hideaki; Hohjoh, Hirohiko; Araki, Yumiko M; Tamaoka, Akira

2014-12-01

11

Divergent Phenotypes in Mutant TDP-43 Transgenic Mice Highlight Potential Confounds in TDP-43 Transgenic Modeling  

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The majority of cases of frontotemporal lobar degeneration and amyotrophic lateral sclerosis are pathologically defined by the cleavage, cytoplasmic redistribution and aggregation of TAR DNA binding protein of 43 kDa (TDP-43). To examine the contribution of these potentially toxic mechanisms in vivo, we generated transgenic mice expressing human TDP-43 containing the familial amyotrophic lateral sclerosis-linked M337V mutation and identified two lines that developed neurological phenotypes of differing severity and progression. The first developed a rapid cortical neurodegenerative phenotype in the early postnatal period, characterized by fragmentation of TDP-43 and loss of endogenous murine Tdp-43, but entirely lacking aggregates of ubiquitin or TDP-43. A second, low expressing line was aged to 25 months without a severe neurodegenerative phenotype, despite a 30% loss of mouse Tdp-43 and accumulation of lower molecular weight TDP-43 species. Furthermore, TDP-43 fragments generated during neurodegeneration were not C-terminal, but rather were derived from a central portion of human TDP-43. Thus we find that aggregation is not required for cell loss, loss of murine Tdp-43 is not necessarily sufficient in order to develop a severe neurodegenerative phenotype and lower molecular weight TDP-43 positive species in mouse models should not be inherently assumed to be representative of human disease. Our findings are significant for the interpretation of other transgenic studies of TDP-43 proteinopathy. PMID:24466128

D’Alton, Simon; Altshuler, Marcelle; Cannon, Ashley; Dickson, Dennis W.; Petrucelli, Leonard; Lewis, Jada

2014-01-01

12

Mitochondrial dysfunction in human TDP-43 transfected NSC34 cell lines and the protective effect of dimethoxy curcumin.  

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TAR-DNA-binding protein of 43kDa (TDP-43) was recently found to be one of the major disease proteins in the pathological inclusions of amyotrophic lateral sclerosis (ALS). The effect of TDP-43 on mitochondrial function remains poorly understood. Here, we show that human TDP-43 caused mitochondrial morphologic abnormality, decrease of mitochondrial complex I activity and mitochondrial transmembrane potential, and increased expression of mitochondrial uncoupling protein 2 (UCP2) in human TDP-43 stably transfected NSC-34 cells by using flow cytometric analysis, spectrophotometric assays, electron microscopy and Western blotting. We also show that dimethoxy curcumin (DMC) could ameliorate mitochondrial dysfunction in mutated TDP-43 stably transfected cell lines. DMC could be potentially useful for neurodegenerative diseases linked with mutated TDP-43. PMID:22986236

Lu, Jinsheng; Duan, Weisong; Guo, Yansu; Jiang, Hong; Li, Zhongyao; Huang, Jing; Hong, Kun; Li, Chunyan

2012-12-01

13

Astrocytic TDP-43 pathology in Alexander disease.  

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Alexander disease (AxD) is a rare neurodegenerative disorder characterized pathologically by the presence of eosinophilic inclusions known as Rosenthal fibers (RFs) within astrocytes, and is caused by dominant mutations in the coding region of the gene encoding glial fibrillary acidic protein (GFAP). GFAP is the major astrocytic intermediate filament, and in AxD patient brain tissue GFAP is a major component of RFs. TAR DNA binding protein of 43 kDa (TDP-43) is the major pathological protein in almost all cases of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and ?50% of frontotemporal lobar degeneration (FTLD), designated as FTLD-TDP. In ALS and FTLD-TDP, TDP-43 becomes insoluble, ubiquitinated, and pathologically phosphorylated and accumulates in cytoplasmic inclusions in both neurons and glia of affected brain and spinal cord regions. Previously, TDP-43 was detected in RFs of human pilocytic astrocytomas; however, involvement of TDP-43 in AxD has not been determined. Here we show that TDP-43 is present in RFs in AxD patient brains, and that insoluble phosphorylated full-length and high molecular weight TDP-43 accumulates in white matter of such brains. Phosphorylated TDP-43 also accumulates in the detergent-insoluble fraction from affected brain regions of Gfap(R236H/+) knock-in mice, which harbor a GFAP mutation homologous to one that causes AxD in humans, and TDP-43 colocalizes with astrocytic RF pathology in Gfap(R236H/+) mice and transgenic mice overexpressing human wild-type GFAP. These findings suggest common pathogenic mechanisms in ALS, FTLD, and AxD, and this is the first report of TDP-43 involvement in a neurological disorder primarily affecting astrocytes. PMID:24806671

Walker, Adam K; Daniels, Christine M LaPash; Goldman, James E; Trojanowski, John Q; Lee, Virginia M-Y; Messing, Albee

2014-05-01

14

TDP-43 in Alzheimer's disease is not associated with clinical FTLD or Parkinsonism.  

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Widespread deposition of TAR DNA-binding protein of 43 kDa (TDP-43), a major protein inclusion commonly found in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) can also be seen in a subset of cases with Alzheimer's disease (AD). Some of these AD cases have TDP-43 immunoreactivity in basal ganglia (BG) and substantia nigra (SN), regions that when affected can be associated with parkinsonian signs or symptoms, or even features suggestive of frontotemporal dementia. Here, we examined the presence of clinical features of FTLD, parkinsonian signs and symptoms, and BG atrophy on MRI, in 51 pathologically confirmed AD cases (Braak neurofibrillary tangle stage IV-VI) with widespread TDP-43 deposition, with and without BG and SN involvement. All 51 cases had presented with progressive cognitive impairment with prominent memory deficits. None of the patients demonstrated early behavioral disinhibition, apathy, loss of empathy, stereotyped behavior, hyperorality, and/or executive deficits. Furthermore, TDP-43 deposition in BG or SN had no significant association with tremor (p = 0.80), rigidity (p = 0.19), bradykinesia (p = 0.19), and gait/postural instability (p = 0.39). Volumes of the BG structures were not associated with TDP-43 deposition in the BG. The present study demonstrates that TDP-43 deposition in pathologically confirmed AD cases is not associated with a clinical manifestation suggestive of FTLD, or parkinsonian features. PMID:24760339

Jung, Youngsin; Dickson, Dennis W; Murray, Melissa E; Whitwell, Jennifer L; Knopman, David S; Boeve, Bradley F; Jack, Clifford R; Parisi, Joseph E; Petersen, Ronald C; Josephs, Keith A

2014-07-01

15

Mutant TDP-43 Deregulates AMPK Activation by PP2A in ALS Models  

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Bioenergetic abnormalities and metabolic dysfunction occur in amyotrophic lateral sclerosis (ALS) patients and genetic mouse models. However, whether metabolic dysfunction occurs early in ALS pathophysiology linked to different ALS genes remains unclear. Here, we investigated AMP-activated protein kinase (AMPK) activation, which is a key enzyme induced by energy depletion and metabolic stress, in neuronal cells and mouse models expressing mutant superoxide dismutase 1 (SOD1) or TAR DNA binding protein 43 (TDP-43) linked to ALS. AMPK phosphorylation was sharply increased in spinal cords of transgenic SOD1G93A mice at disease onset and accumulated in cytoplasmic granules in motor neurons, but not in pre-symptomatic mice. AMPK phosphorylation also occurred in peripheral tissues, liver and kidney, in SOD1G93A mice at disease onset, demonstrating that AMPK activation occurs late and is not restricted to motor neurons. Conversely, AMPK activity was drastically diminished in spinal cords and brains of presymptomatic and symptomatic transgenic TDP-43A315T mice and motor neuronal cells expressing different TDP-43 mutants. We show that mutant TDP-43 induction of the AMPK phosphatase, protein phosphatase 2A (PP2A), is associated with AMPK inactivation in these ALS models. Furthermore, PP2A inhibition by okadaic acid reversed AMPK inactivation by mutant TDP-43 in neuronal cells. Our results suggest that mutant SOD1 and TDP-43 exert contrasting effects on AMPK activation which may reflect key differences in energy metabolism and neurodegeneration in spinal cords of SOD1G93A and TDP-43A315T mice. While AMPK activation in motor neurons correlates with progression in mutant SOD1-mediated disease, AMPK inactivation mediated by PP2A is associated with mutant TDP-43-linked ALS. PMID:24595038

Perera, Nirma D.; Sheean, Rebecca K.; Scott, John W.; Kemp, Bruce E.; Horne, Malcolm K.; Turner, Bradley J.

2014-01-01

16

Mitochondrial dysfunction and decrease in body weight of a transgenic knock-in mouse model for TDP-43.  

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The majority of amyotrophic lateral sclerosis (ALS) cases as well as many patients suffering from frontotemporal lobar dementia (FTLD) with ubiquitinated inclusion bodies show TDP-43 pathology, the protein encoded by the TAR DNA-binding protein (Tardbp) gene. We used recombinase-mediated cassette exchange to introduce an ALS patient cDNA into the mouse Tdp-43 locus. Expression levels of human A315T TDP-43 protein were 300% elevated in heterozygotes, whereas the endogenous mouse Tdp-43 was decreased to 20% of wild type levels as a result of disturbed feedback regulation. Heterozygous TDP-43(A315TKi) mutants lost 10% of their body weight and developed insoluble TDP-43 protein starting as early as 3 months after birth, a pathology that was exacerbated with age. We analyzed the splicing patterns of known Tdp-43 target genes as well as genome-wide gene expression levels in different tissues that indicated mitochondrial dysfunction. In heterozygous mutant animals, we observed a relative decrease in expression of Parkin (Park2) and the fatty acid transporter CD36 along with an increase in fatty acids, HDL cholesterol, and glucose in the blood. As seen in transmission electron microscopy, neuronal cells in motor cortices of TDP-43(A315TKi) animals had abnormal neuronal mitochondrial cristae formation. Motor neurons were reduced to 90%, but only slight motoric impairment was detected. The observed phenotype was interpreted as a predisease model, which might be valuable for the identification of further environmental or genetic triggers of neurodegeneration. PMID:24515116

Stribl, Carola; Samara, Aladin; Trümbach, Dietrich; Peis, Regina; Neumann, Manuela; Fuchs, Helmut; Gailus-Durner, Valerie; Hrab? de Angelis, Martin; Rathkolb, Birgit; Wolf, Eckhard; Beckers, Johannes; Horsch, Marion; Neff, Frauke; Kremmer, Elisabeth; Koob, Sebastian; Reichert, Andreas S; Hans, Wolfgang; Rozman, Jan; Klingenspor, Martin; Aichler, Michaela; Walch, Axel Karl; Becker, Lore; Klopstock, Thomas; Glasl, Lisa; Hölter, Sabine M; Wurst, Wolfgang; Floss, Thomas

2014-04-11

17

Widespread RNA metabolism impairment in sporadic inclusion body myositis TDP43-proteinopathy.  

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TDP43 protein mislocalization is a hallmark of the neurodegenerative diseases amyotrophic lateral sclerosis and frontotemporal dementia, and mutations in the gene encoding TDP43 cause both disorders, further highlighting its role in disease pathogenesis. TDP43 is a heterogenous ribonucleoprotein, therefore suggesting that alterations in RNA metabolism play a role in these disorders, although direct evidence in patients is lacking. Sporadic inclusion body myositis (sIBM) is the most common acquired myopathy occurring in adults aged older than 50 years and abnormal cytoplasmic accumulations of TDP43 have been consistently described in sIBM myofibers. Here, we exploit high quality RNA from frozen sIBM muscle biopsies for transcriptomic studies on TDP43-proteinopathy patient tissue. Surprisingly, we found widespread sIBM-specific changes in the RNA metabolism pathways themselves. Consistent with this finding, we describe novel RNA binding proteins to mislocalize in the cytoplasm of sIBM myofibers and splicing changes in MAPT, a gene previously shown to play a role in sIBM. Our data indicate widespread alterations of RNA metabolism are a novel aspect of disease pathogenesis in sIBM. These findings also document an association, in TDP43-proteinopathy patients, between heterogenous ribonucleoprotein pathology and RNA metabolism alterations and carry importance for neurodegenerative diseases, such as amyotrophic lateral sclerosis and frontotemporal dementia. PMID:24462217

Cortese, Andrea; Plagnol, Vincent; Brady, Stefen; Simone, Roberto; Lashley, Tammaryn; Acevedo-Arozena, Abraham; de Silva, Rohan; Greensmith, Linda; Holton, Janice; Hanna, Michael G; Fisher, Elizabeth M C; Fratta, Pietro

2014-06-01

18

Curcumin abolishes mutant TDP-43 induced excitability in a motoneuron-like cellular model of ALS.  

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Mutation of TAR DNA-binding protein-43 (TDP-43) is detected in familial and sporadic amyotrophic lateral sclerosis (FALS and SALS). TDP-43-positive cytoplasmic inclusions are present in both neuron and glia of ALS, although not in mutant Cu/Zn-superoxide dismutase (mSOD1)-related or RNA binding protein Fused in sarcoma (FUS)-related ALS. Previous studies have established that cortical hyper-excitability is common to both FALS and SALS patients. Much of our current understanding of neuron excitability has come from studying the subtype of mSOD1-related ALS. Thus, we evaluated the excitable capability through analyzing properties of action potentials (APs) and voltage-gated sodium (Nav) channels on the cellular model, motoneuron-like cell lines that were steadily transfected with mutant Q331K and wild-type TDP-43. We found that wild-type TDP-43 increased firing frequency of APs, but the presence of mutant Q331K TDP-43 enhanced firing frequency and decreased the threshold of APs to a higher level. Further, we observed that mutant Q331K and wild-type TDP-43 induced more rapid speed of recovery from fast and slow inactivation of Nav channels and resulted in a reduction of voltage dependency of slow inactivation. These results provide evidence for high excitability that resulted from the presence of mutant and wild-type TDP-43, and more toxicity of mutant TDP-43 than wild-type. Other studies suggest that Nav channel activity can be increased directly by different oxidative species and, we have shown previously that oxidative stress and mitochondrial dysfunction occurs simultaneously in the cellular model of mutant TDP-43 and can be ameliorated by dimethoxy curcumin (DMC), a safe and effective antioxidant. In the present study we found that the abnormities of APs and Nav channels were significantly ameliorated when treated with DMC (15?M) for 24h, suggesting a dropping-excitability state. Taken together, mutant Q331K TDP-43 induces high excitability in a motoneuron-like cellular model, and this abnormal state is rescued by DMC which may act through alleviation of oxidative stress and mitochondrial dysfunction. PMID:24785678

Dong, H; Xu, L; Wu, L; Wang, X; Duan, W; Li, H; Li, C

2014-07-11

19

Reversible Behavioral Phenotypes in a Conditional Mouse Model of TDP-43 Proteinopathies.  

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Transactive response DNA-binding protein 43 (TDP-43) mislocalization and aggregation are hallmark features of amyotrophic lateral sclerosis and frontotemporal dementia (FTD). We have previously shown in mice that inducible overexpression of a cytoplasmically localized form of TDP-43 (TDP-43-?NLS) in forebrain neurons evokes neuropathological changes that recapitulate several features of TDP-43 proteinopathies. Detailed behavioral phenotyping could provide further validation for its usage as a model for FTD. In the present study, we performed a battery of behavioral tests to evaluate motor, cognitive, and social phenotypes in this model. We found that transgene (Tg) induction by doxycycline removal at weaning led to motor abnormalities including hyperlocomotion in the open field test, impaired coordination and balance in the rotarod test, and increased spasticity as shown by a clasping phenotype. Cognitive assessment demonstrated impaired recognition and spatial memory, measured by novel object recognition and Y-maze tests. Remarkably, TDP-43-?NLS mice displayed deficits in social behavior, mimicking a key aspect of FTD. To determine whether these symptoms were reversible, we suppressed Tg expression for 14 d in 1.5-month-old mice showing an established behavioral phenotype but modest neurodegeneration and found that motor and cognitive deficits were ameliorated; however, social performance remained altered. When Tg expression was suppressed in 6.5-month-old mice showing overt neurodegeneration, motor deficits were irreversible. These results indicate that TDP-43-?NLS mice display several core behavioral features of FTD with motor neuron disease, possibly due to functional changes in surviving neurons, and might serve as a valuable tool to unveil the underlying mechanisms of this and other TDP-43 proteinopathies. PMID:25392493

Alfieri, Julio A; Pino, Natalia S; Igaz, Lionel M

2014-11-12

20

Profiling the genes affected by pathogenic TDP-43 in astrocytes.  

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Mutation in TAR DNA binding protein 43 (TDP-43) is a causative factor of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Neurodegeneration may not require the presence of pathogenic TDP-43 in all types of relevant cells. Rather, expression of pathogenic TDP-43 in neurons or astrocytes alone is sufficient to cause cell-autonomous or non-cell-autonomous neuron death in transgenic rats. How pathogenic TDP-43 in astrocytes causes non-cell-autonomous neuron death, however, is not clear. Here, we examined the effect of pathogenic TDP-43 on gene expression in astrocytes. Microarray assay revealed that pathogenic TDP-43 in astrocytes preferentially altered expression of the genes encoding secretory proteins. Whereas neurotrophic genes were down-regulated, neurotoxic genes were up-regulated. Representative genes Lcn2 and chitinase-3-like protein 1 were markedly up-regulated in astrocytes from primary culture and intact transgenic rats. Furthermore, synthetic chitinase-3-like protein 1 induced neuron death in a dose-dependent manner. Our results suggest that TDP-43 pathogenesis is associated with the simultaneous induction of multiple neurotoxic genes in astrocytes, which may synergistically produce adverse effects on neuronal survival and contribute to non-cell-autonomous neuron death. Restricted expression of pathogenic TDP-43 in astrocytes causes non-cell-autonomous motor neuron death in transgenic rats. As revealed by microarray assay, pathogenic TDP-43 in astrocytes preferentially altered expression of the genes encoding secretory proteins. Whereas neurotrophic genes were down-regulated, neurotoxic genes were up-regulated. Therefore, TDP-43 pathogenesis is associated with simultaneous induction of neurotoxic genes and repression of neurotrophic genes in astrocytes. PMID:24447103

Huang, Cao; Huang, Bo; Bi, Fangfang; Yan, Linda H; Tong, Jianbin; Huang, Jufang; Xia, Xu-Gang; Zhou, Hongxia

2014-06-01

 
 
 
 
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Oxidative stress induced by glutathione depletion reproduces pathological modifications of TDP-43 linked to TDP-43 proteinopathies.  

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TAR DNA-binding protein 43 (TDP-43) is a major component of ubiquitin-positive inclusion of TDP-43 proteinopathies including amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitinated inclusions, which is now referred to as FTLD-TDP. TDP-43 in the aberrant inclusion is known to be hyperphosphorylated at C-terminal sites, to be truncated at the N-terminal region, and to re-distribute from nucleus to cytoplasm or neurite. The pathogenic role of these modifications, however, has not been clarified. Furthermore, there is no evidence about the initial cause of these modifications. Herein we show that ethacrynic acid (EA), which is able to increase cellular oxidative stress through glutathione depletion, induces TDP-43 C-terminal phosphorylation at serine 403/404 and 409/410, insolubilization, C-terminal fragmentation, and cytoplasmic distribution in NSC34 cells and primary cortical neurons. In the investigation using a nonphosphorylable mutant of TDP-43, there was no evidence that C-terminal phosphorylation of TDP-43 contributes to its solubility or distribution under EA induction. Our findings suggest that oxidative stress induced by glutathione depletion is associated with the process of the pathological TDP-43 modifications and provide new insight for TDP-43 proteinopathies. PMID:22198567

Iguchi, Yohei; Katsuno, Masahisa; Takagi, Shinnosuke; Ishigaki, Shinsuke; Niwa, Jun-ichi; Hasegawa, Masato; Tanaka, Fumiaki; Sobue, Gen

2012-03-01

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Therapeutic modulation of eIF2? phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models.  

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Amyotrophic lateral sclerosis (ALS) is a fatal, late-onset neurodegenerative disease primarily affecting motor neurons. A unifying feature of many proteins associated with ALS, including TDP-43 and ataxin-2, is that they localize to stress granules. Unexpectedly, we found that genes that modulate stress granules are strong modifiers of TDP-43 toxicity in Saccharomyces cerevisiae and Drosophila melanogaster. eIF2? phosphorylation is upregulated by TDP-43 toxicity in flies, and TDP-43 interacts with a central stress granule component, polyA-binding protein (PABP). In human ALS spinal cord neurons, PABP accumulates abnormally, suggesting that prolonged stress granule dysfunction may contribute to pathogenesis. We investigated the efficacy of a small molecule inhibitor of eIF2? phosphorylation in ALS models. Treatment with this inhibitor mitigated TDP-43 toxicity in flies and mammalian neurons. These findings indicate that the dysfunction induced by prolonged stress granule formation might contribute directly to ALS and that compounds that mitigate this process may represent a novel therapeutic approach. PMID:24336168

Kim, Hyung-Jun; Raphael, Alya R; LaDow, Eva S; McGurk, Leeanne; Weber, Ross A; Trojanowski, John Q; Lee, Virginia M-Y; Finkbeiner, Steven; Gitler, Aaron D; Bonini, Nancy M

2014-02-01

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Therapeutic modulation of eIF2?-phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models  

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Amyotrophic lateral sclerosis (ALS) is a fatal, late-onset neurodegenerative disease primarily impacting motor neurons. A unifying feature of many proteins associated with ALS, including TDP-43 and Ataxin-2, is that they localize to stress granules. Unexpectedly, we found that genes that modulate stress granules are striking modifiers of TDP-43 toxicity in Saccharomyces cerevisiae and Drosophila melanogaster, eIF2? phosphorylation is upregulated by TDP-43 toxicity in flies, and TDP-43 interacts with a central stress granule component polyA binding protein (PABP). In human ALS spinal cord neurons, PABP accumulates abnormally, suggesting that prolonged stress granule dysfunction may contribute to pathogenesis. We investigated the efficacy of a small molecule inhibitor of eIF2?-phosphorylation in ALS models. This treatment mitigated TDP-43 toxicity in flies and mammalian neurons. These findings indicate that dysfunction induced by prolonged stress granule formation may contribute directly to ALS and that compounds that mitigate this process may represent a novel therapeutic approach. PMID:24336168

Kim, Hyung-Jun; Raphael, Alya R.; LaDow, Eva S.; McGurk, Leeanne; Weber, Ross; Trojanowski, John Q.; Lee, Virginia M.-Y.; Finkbeiner, Steven; Gitler, Aaron D.; Bonini, Nancy M.

2014-01-01

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Subcortical TDP-43 pathology occurs infrequently in multiple system atrophy  

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Aims and Methods The ?-synucleinopathy multiple system atrophy (MSA) and diseases defined by pathological TDP-43 or FUS aggregates such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration show overlapping clinico-pathological features. Consequently, we examined MSA for evidence of TDP-43 or FUS pathology utilizing immunohistochemical studies in autopsy material from 29 MSA patients. Results TDP-43 pathology was generally rare, and there were no FUS lesions. The TDP-43 lesions were located predominantly in medio-temporal lobe structures and subcortical brain areas and were comprised mainly of dystrophic processes and perivascular (and subpial) lesions. Conclusions The multisystem clinical symptoms and signs of MSA, and in particular the neurobehavioural/cognitive and pyramidal features, appear not to result from concomitant TDP-43 or FUS pathology, but rather from widespread white matter ?-synuclein positive glial cytoplasmic inclusions and neurodegeneration in keeping with a primary ?-synuclein mediated oligodendrogliopathy. The gliodegenerative disease MSA evidently results from different pathogenetic mechanisms than neurodegenerative diseases linked to pathological TDP-43. PMID:20942898

Geser, Felix; Malunda, Joseph A.; Hurtig, Howard I.; Duda, John E.; Wenning, Gregor K.; Gilman, Sid; Low, Phillip A.; Lee, Virginia M.-Y.; Trojanowski, John Q.

2010-01-01

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Wild-type human TDP-43 expression causes TDP-43 phosphorylation, mitochondrial aggregation, motor deficits and early mortality in transgenic mice  

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Transactivation response DNA-binding protein 43 (TDP-43) is a principal component of ubiquitinated inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis (ALS). Mutations in TARDBP, the gene encoding TDP-43, are associated with sporadic and familial ALS, yet multiple neurodegenerative diseases exhibit TDP-43 pathology without known TARDBP mutations. While TDP-43 has been ascribed a number of roles in normal biology, including mR...

Xu, Ya-fei; Gendron, Tania F.; Zhang, Yong-jie; Lin, Wen-lang; D’alton, Simon; Sheng, Hong; Casey, Monica Castanedes; Tong, Jimei; Knight, Joshua; Yu, Xin; Rademakers, Rosa; Boylan, Kevin; Hutton, Mike; Mcgowan, Eileen; Dickson, Dennis W.

2010-01-01

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Concomitant accumulation of ?-synuclein and TDP-43 in a patient with corticobasal degeneration.  

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Pathological changes in corticobasal degeneration (CBD) consist of abnormal deposition of the microtubule-associated protein tau. However, the simultaneous accumulation of different misfolded proteins in the brain can be observed in many neurodegenerative diseases with significantly longer disease durations. We encountered a patient with CBD who survived for an extremely long period (18 years) after the diagnosis. We performed an autopsy to elucidate the effect of the longer survival on the pathology of CBD. We observed abnormal aggregation of trans-activating response region DNA-binding protein of 43 kDa (TDP-43) and ?-synuclein, as well as phosphorylated tau, in neurons of broader regions of the brain, beyond the amygdala and other limbic areas. We found that phosphorylated tau, ?-synuclein, and TDP-43 partially co-existed in the same cellular aggregates. The triple pathologic changes might be related to the longer survival of the patient compared with the typical clinical course of patients with CBD. Further investigations are required to support the hypothesis that tauopathy, synucleinopathy, and TDP-43 proteinopathy might share common pathogenic mechanisms in terms of cross-seeding of the pathologic proteins. PMID:25209854

Yamashita, Satoshi; Sakashita, Naomi; Yamashita, Taro; Tawara, Nozomu; Tasaki, Masayoshi; Kawakami, Kensuke; Komohara, Yoshihiro; Fujiwara, Yukio; Kamikawa, Masashi; Nakagawa, Takenobu; Hirano, Teruyuki; Maeda, Yasushi; Hasegawa, Masato; Takeya, Motohiro; Ando, Yukio

2014-11-01

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ALS-Linked Mutations Enlarge TDP-43-Enriched Neuronal RNA Granules in the Dendritic Arbor  

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Trans-activating response region (TAR) DNA-binding protein of 43 kDa (TDP-43) is an RNA-binding protein that is mutated in familial amyotrophic lateral sclerosis (ALS). Disease-linked mutations in TDP-43 increase the tendency of TDP-43 to aggregate, leading to a corresponding increase in formation of stress granules, cytoplasmic protein/RNA complexes that form in response to stress. Although the field has focused on stress granules, TDP-43 also forms other types of RNA granules. For example, TDP-43 is associated with RNA granules that are prevalent throughout the dendritic arbor in neurons. Because aggregation of TDP-43 is also important for the formation of these neuronal RNA granules, we hypothesized that disease-linked mutations might alter granule formation even in the absence of stress. We now report that ALS-linked mutations in TDP-43 (A315T and Q343R) increase the size of neuronal TDP-43 granules in the dendritic arbor of rat hippocampal neurons. The mutations correspondingly reduce the granule density, movement, and mobility of TDP-43 granules. Depolarization of rat hippocampal neurons with KCl stimulates TDP-43 granule migration into dendrites, but A315T and Q343R TDP-43 granules migrate shorter distances and into fewer dendrites than wild-type TDP-43. These findings highlight novel elements of TDP-43 biology that are affected by disease-linked mutations and suggest a neuronally selective mechanism through which TDP-43 mutations might elicit neuronal dysfunction. PMID:24647938

Liu-Yesucevitz, LiQun; Lin, Amy Y.; Ebata, Atsushi; Boon, Joon Y.; Reid, Whitney; Xu, Ya-Fei; Kobrin, Kendra; Murphy, George J.; Petrucelli, Leonard

2014-01-01

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A nonsense mutation in mouse Tardbp affects TDP43 alternative splicing activity and causes limb-clasping and body tone defects.  

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Mutations in TARDBP, encoding Tar DNA binding protein-43 (TDP43), cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Attempts to model TDP43 dysfunction in mice have used knockouts or transgenic overexpressors, which have revealed the difficulties of manipulating TDP43, whose level is tightly controlled by auto-regulation. In a complementary approach, to create useful mouse models for the dissection of TDP43 function and pathology, we have identified a nonsense mutation in the endogenous mouse Tardbp gene through screening an N-ethyl-N-nitrosourea (ENU) mutant mouse archive. The mutation is predicted to cause a Q101X truncation in TDP43. We have characterised Tardbp(Q101X) mice to investigate this mutation in perturbing TDP43 biology at endogenous expression levels. We found the Tardbp(Q101X) mutation is homozygous embryonic lethal, highlighting the importance of TDP43 in early development. Heterozygotes (Tardbp(+/Q101X) ) have abnormal levels of mutant transcript, but we find no evidence of the truncated protein and mice have similar full-length TDP43 protein levels as wildtype littermates. Nevertheless, Tardbp(+/Q101X) mice have abnormal alternative splicing of downstream gene targets, and limb-clasp and body tone phenotypes. Thus the nonsense mutation in Tardbp causes a mild loss-of-function phenotype and behavioural assessment suggests underlying neurological abnormalities. Due to the role of TDP43 in ALS, we investigated potential interactions with another known causative gene, mutant superoxide dismutase 1 (SOD1). Tardbp(+/Q101X) mice were crossed with the SOD1(G93Adl) transgenic mouse model of ALS. Behavioural and physiological assessment did not reveal modifying effects on the progression of ALS-like symptoms in the double mutant progeny from this cross. In summary, the Tardbp(Q101X) mutant mice are a useful tool for the dissection of TDP43 protein regulation, effects on splicing, embryonic development and neuromuscular phenotypes. These mice are freely available to the community. PMID:24465814

Ricketts, Thomas; McGoldrick, Philip; Fratta, Pietro; de Oliveira, Hugo M; Kent, Rosie; Phatak, Vinaya; Brandner, Sebastian; Blanco, Gonzalo; Greensmith, Linda; Acevedo-Arozena, Abraham; Fisher, Elizabeth M C

2014-01-01

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UBE2E ubiquitin-conjugating enzymes and ubiquitin isopeptidase Y regulate TDP-43 protein ubiquitination.  

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Trans-activation element DNA-binding protein of 43 kDa (TDP-43) characterizes insoluble protein aggregates in distinct subtypes of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. TDP-43 mediates many RNA processing steps within distinct protein complexes. Here we identify novel TDP-43 protein interactors found in a yeast two-hybrid screen using an adult human brain cDNA library. We confirmed the TDP-43 interaction of seven hits by co-immunoprecipitation and assessed their co-localization in HEK293E cells. As pathological TDP-43 is ubiquitinated, we focused on the ubiquitin-conjugating enzyme UBE2E3 and the ubiquitin isopeptidase Y (UBPY). When cells were treated with proteasome inhibitor, ubiquitinated and insoluble TDP-43 species accumulated. All three UBE2E family members could enhance the ubiquitination of TDP-43, whereas catalytically inactive UBE2E3(C145S) was much less efficient. Conversely, silencing of UBE2E3 reduced TDP-43 ubiquitination. We examined 15 of the 48 known disease-associated TDP-43 mutants and found that one was excessively ubiquitinated. This strong TDP-43(K263E) ubiquitination was further enhanced by proteasomal inhibition as well as UBE2E3 expression. Conversely, UBE2E3 silencing and expression of UBPY reduced TDP-43(K263E) ubiquitination. Moreover, wild-type but not active site mutant UBPY reduced ubiquitination of TDP-43 C-terminal fragments and of a nuclear import-impaired mutant. In Drosophila melanogaster, UBPY silencing enhanced neurodegenerative TDP-43 phenotypes and the accumulation of insoluble high molecular weight TDP-43 and ubiquitin species. Thus, UBE2E3 and UBPY participate in the regulation of TDP-43 ubiquitination, solubility, and neurodegeneration. PMID:24825905

Hans, Friederike; Fiesel, Fabienne C; Strong, Jennifer C; Jäckel, Sandra; Rasse, Tobias M; Geisler, Sven; Springer, Wolfdieter; Schulz, Jörg B; Voigt, Aaron; Kahle, Philipp J

2014-07-01

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TDP-43 causes differential pathology in neuronal versus glial cells in the mouse brain.  

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Mutations in TAR DNA-binding protein 43 (TDP-43) are associated with familial forms of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Although recent studies have revealed that mutant TDP-43 in neuronal and glial cells is toxic, how mutant TDP-43 causes primarily neuronal degeneration in an age-dependent manner remains unclear. Using adeno-associated virus (AAV) that expresses mutant TDP-43 (M337V) ubiquitously, we found that mutant TDP-43 accumulates preferentially in neuronal cells in the postnatal mouse brain. We then ubiquitously or selectively expressed mutant TDP-43 in neuronal and glial cells in the striatum of adult mouse brains via stereotaxic injection of AAV vectors and found that it also preferentially accumulates in neuronal cells. Expression of mutant TDP-43 in neurons in the striatum causes more severe degeneration, earlier death and more robust symptoms in mice than expression of mutant TDP-43 in glial cells; however, aging increases the expression of mutant TDP-43 in glial cells, and expression of mutant TDP-43 in older mice caused earlier onset of phenotypes and more severe neuropathology than that in younger mice. Although expression of mutant TDP-43 in glial cells via stereotaxic injection does not lead to robust neurological phenotypes, systemic inhibition of the proteasome activity via MG132 in postnatal mice could exacerbate glial TDP-43-mediated toxicity and cause mice to die earlier. Consistently, this inhibition increases the expression of mutant TDP-43 in glial cells in mouse brains. Thus, the differential accumulation of mutant TDP-43 in neuronal versus glial cells contributes to the preferential toxicity of mutant TDP-43 in neuronal cells and age-dependent pathology. PMID:24381309

Yan, Sen; Wang, Chuan-En; Wei, Wenjie; Gaertig, Marta A; Lai, Liangxue; Li, Shihua; Li, Xiao-Jiang

2014-05-15

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Sustained Expression of TDP-43 and FUS in Motor Neurons in Rodent's Lifetime  

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Full Text Available TAR DNA-binding protein (TDP-43 and fused in sarcoma (FUS are two highly conserved ribonucleoproteins. Pathogenic mutations of the TDP-43 or the FUS gene are all linked to amyotrophic lateral sclerosis (ALS that is characterized by progressive degeneration of motor neurons. To better understand the correlation of ALS disease genes with the selectivity of chronic motor neuron degeneration, we examined the longitudinal expression of the TDP-43 and the FUS genes in C57BL6 mice and in Sprague-Dawley rats. TDP-43 and FUS were robustly and ubiquitously expressed in the postnatal mice and rats, but were markedly decreased in the adult rodents. In adulthood, TDP-43 and FUS proteins were even undetectable in peripheral organs including skeletal muscles, liver, and kidney, but were constantly expressed at substantial levels in the central nervous system. Motor neurons expressed the TDP-43 and the FUS genes at robust levels throughout rodent's lifetime. Moreover, TDP-43 and FUS were accumulated in the cytoplasm of motor neurons in aged animals. Our findings suggest that TDP-43 and FUS play an important role in development and that constant and robust expression of the genes in motor neurons may render the neurons vulnerable to pathogenic mutation of the TDP-43 or the FUS gene. To faithfully model the pathology of TDP-43- or FUS gene mutations in rodents, we must replicate the expression patterns of the TDP-43 and the FUS gene in animals.

Cao Huang, Pedro Yuxing Xia, Hongxia Zhou

2010-01-01

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Neuronal-specific overexpression of a mutant valosin-containing protein associated with IBMPFD promotes aberrant ubiquitin and TDP-43 accumulation and cognitive dysfunction in transgenic mice.  

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Mutations in valosin-containing protein (VCP) cause a rare, autosomal dominant disease called inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD). One-third of patients with IBMPFD develop frontotemporal dementia, characterized by an extensive neurodegeneration in the frontal and temporal lobes. Neuropathologic hallmarks include nuclear and cytosolic inclusions positive to ubiquitin and transactive response DNA-binding protein 43 (TDP-43) in neurons and glial activation in affected regions. However, the pathogenic mechanisms by which mutant VCP triggers neurodegeneration remain unknown. Herein, we generated a mouse model selectively overexpressing a human mutant VCP in neurons to study pathogenic mechanisms of mutant VCP-mediated neurodegeneration and cognitive impairment. The overexpression of VCPA232E mutation in forebrain regions produced significant progressive impairments of cognitive function, including deficits in spatial memory, object recognition, and fear conditioning. Although overexpressed or endogenous VCP did not seem to focally aggregate inside neurons, TDP-43 and ubiquitin accumulated with age in transgenic mouse brains. TDP-43 was also found to co-localize with stress granules in the cytosolic compartment. Together with the appearance of high-molecular-weight TDP-43 in cytosolic fractions, these findings demonstrate the mislocalization and accumulation of abnormal TDP-43 in the cytosol of transgenic mice, which likely lead to an increase in cellular stress and cognitive impairment. Taken together, these results highlight an important pathologic link between VCP and cognition. PMID:23747512

Rodriguez-Ortiz, Carlos J; Hoshino, Hitomi; Cheng, David; Liu-Yescevitz, Liqun; Blurton-Jones, Mathew; Wolozin, Benjamin; LaFerla, Frank M; Kitazawa, Masashi

2013-08-01

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Parkin-mediated reduction of nuclear and soluble TDP-43 reverses behavioral decline in symptomatic mice.  

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The transactivation DNA-binding protein (TDP)-43 binds to thousands of mRNAs, but the functional outcomes of this binding remain largely unknown. TDP-43 binds to Park2 mRNA, which expresses the E3 ubiquitin ligase parkin. We previously demonstrated that parkin ubiquitinates TDP-43 and facilitates its translocation from the nucleus to the cytoplasm. Here we used brain penetrant tyrosine kinase inhibitors (TKIs), including nilotinib and bosutinib and showed that they reduce the level of nuclear TDP-43, abrogate its effects on neuronal loss, and reverse cognitive and motor decline. Nilotinib decreased soluble and insoluble TDP-43, while bosutinib did not affect the insoluble level. Parkin knockout mice exhibited high levels of endogenous TDP-43, while nilotinib and bosutinib did not alter TDP-43, underscoring an indispensable role for parkin in TDP-43 sub-cellular localization. These data demonstrate a novel functional relationship between parkin and TDP-43 and provide evidence that TKIs are potential therapeutic candidates for TDP-43 pathologies. PMID:24847002

Wenqiang, Chen; Lonskaya, Irina; Hebron, Michaeline L; Ibrahim, Zainab; Olszewski, Rafal T; Neale, Joseph H; Moussa, Charbel E-H

2014-09-15

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Heteronemin, a marine sponge terpenoid, targets TDP-43, a key factor in several neurodegenerative disorders.  

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Trans-activation response DNA-binding protein of 43 kDa (TDP-43), a key factor in several neurodegenerative conditions, was discovered as a novel target of heteronemin by chemical proteomics. Combining bio-physical orthogonal approaches with biological analysis, heteronemin was found to influence the binding of TDP-43-cognate nucleic acids and to modulate the TDP-43 aggregation state and its cellular localization. PMID:23963116

Cassiano, Chiara; Esposito, Roberta; Tosco, Alessandra; Zampella, Angela; D'Auria, Maria Valeria; Riccio, Raffaele; Casapullo, Agostino; Monti, Maria Chiara

2014-01-14

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Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations.  

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The RNA-binding protein TDP-43 regulates RNA metabolism at multiple levels, including transcription, RNA splicing, and mRNA stability. TDP-43 is a major component of the cytoplasmic inclusions characteristic of amyotrophic lateral sclerosis and some types of frontotemporal lobar degeneration. The importance of TDP-43 in disease is underscored by the fact that dominant missense mutations are sufficient to cause disease, although the role of TDP-43 in pathogenesis is unknown. Here we show that TDP-43 forms cytoplasmic mRNP granules that undergo bidirectional, microtubule-dependent transport in neurons in vitro and in vivo and facilitate delivery of target mRNA to distal neuronal compartments. TDP-43 mutations impair this mRNA transport function in vivo and in vitro, including in stem cell-derived motor neurons from ALS patients bearing any one of three different TDP-43 ALS-causing mutations. Thus, TDP-43 mutations that cause ALS lead to partial loss of a novel cytoplasmic function of TDP-43. PMID:24507191

Alami, Nael H; Smith, Rebecca B; Carrasco, Monica A; Williams, Luis A; Winborn, Christina S; Han, Steve S W; Kiskinis, Evangelos; Winborn, Brett; Freibaum, Brian D; Kanagaraj, Anderson; Clare, Alison J; Badders, Nisha M; Bilican, Bilada; Chaum, Edward; Chandran, Siddharthan; Shaw, Christopher E; Eggan, Kevin C; Maniatis, Tom; Taylor, J Paul

2014-02-01

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TDP-43 Potentiates Alpha-synuclein Toxicity to Dopaminergic Neurons in Transgenic Mice  

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Full Text Available TDP-43 and ?-synuclein are two disease proteins involved in a wide range of neurodegenerative diseases. While TDP-43 proteinopathy is considered a pathologic hallmark of sporadic amyotrophic lateral sclerosis and frontotemporal lobe degeneration, ?-synuclein is a major component of Lewy body characteristic of Parkinson's disease. Intriguingly, TDP-43 proteinopathy also coexists with Lewy body and with synucleinopathy in certain disease conditions. Here we reported the effects of TDP-43 on ?-synuclein neurotoxicity in transgenic mice. Overexpression of mutant TDP-43 (M337V substitution in mice caused early death in transgenic founders, but overexpression of normal TDP-43 only induced a moderate loss of cortical neurons in the transgenic mice at advanced ages. Interestingly, concomitant overexpression of normal TDP-43 and mutant ?-synuclein caused a more severe loss of dopaminergic neurons in the double transgenic mice as compared to single-gene transgenic mice. TDP-43 potentiated ?-synuclein toxicity to dopaminergic neurons in living animals. Our finding provides in vivo evidence suggesting that disease proteins such as TDP-43 and ?-synuclein may play a synergistic role in disease induction in neurodegenerative diseases.

Tian Tian, Cao Huang, Jianbin Tong, Ming Yang, Hongxia Zhou, Xu-Gang Xia

2011-01-01

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Frontotemporal lobar degeneration with TDP-43 proteinopathy and chromosome 9p repeat expansion in C9ORF72: clinicopathologic correlation.  

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Mutations in C9ORF72 resulting in expanded hexanucleotide repeats were recently reported to be the underlying genetic abnormality in chromosome 9p-linked frontotemporal lobar degeneration with TAR DNA-binding protein of 43 kD (TDP-43) proteinopathy (FTLD-TDP), amyotrophic lateral sclerosis (ALS), and frontotemporal lobar degeneration with motor neuron disease (FTLD-MND). Several subsequent publications described the neuropathology as being similar to that of FTLD-TDP and ALS without C9ORF72 mutations, except that cases with mutations have p62 and ubiquitin positive, TDP-43 negative inclusions in cerebellum, hippocampus, neocortex, and basal ganglia. The identity of this protein is as yet unknown, and its significance is unclear. With the goal of potentially uncovering the significance of these inclusions, we compared the clinical, pathologic and genetic characteristics in cases with C9ORF72 mutations to those without. We confirmed the apparent specificity of p62 positive, TDP-43 negative inclusions to cases with C9ORF72 mutations. In hippocampus, these inclusions correlated with hippocampal atrophy. No additional correlations were uncovered. However, this is the first report to show that although most cases with C9ORF72 mutations were TDP type B, some of the pathologic characteristics in these cases were more similar to TDP types A and C than to type B cases. These include greater cortical and hippocampal atrophy, greater ventricular dilatation, more neuronal loss and gliosis in temporal lobe and striatum, and TDP-43 positive fine neuritic profiles in the hippocampus, implying that the C9ORF72 mutation modifies the pathologic phenotype of FTLD-TDP type B. PMID:22702520

Bigio, Eileen H; Weintraub, Sandra; Rademakers, Rosa; Baker, Matt; Ahmadian, Saman S; Rademaker, Alfred; Weitner, Bing Bing; Mao, Qinwen; Lee, Kyung-Hwa; Mishra, Manjari; Ganti, Rakhee A; Mesulam, M-Marsel

2013-04-01

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TDP-43 is a key player in the clinical features associated with Alzheimer's disease.  

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The aim of this study was to determine whether the TAR DNA-binding protein of 43 kDa (TDP-43) has any independent effect on the clinical and neuroimaging features typically ascribed to Alzheimer's disease (AD) pathology, and whether TDP-43 pathology could help shed light on the phenomenon of resilient cognition in AD. Three-hundred and forty-two subjects pathologically diagnosed with AD were screened for the presence, burden and distribution of TDP-43. All had been classified as cognitively impaired or normal, prior to death. Atlas-based parcellation and voxel-based morphometry were used to assess regional atrophy on MRI. Regression models controlling for age at death, apolipoprotein ?4 and other AD-related pathologies were utilized to explore associations between TDP-43 and cognition or brain atrophy, stratified by Braak stage. In addition, we determined whether the effects of TDP-43 were mediated by hippocampal sclerosis. One-hundred and ninety-five (57 %) cases were TDP-positive. After accounting for age, apolipoprotein ?4 and other pathologies, TDP-43 had a strong effect on cognition, memory loss and medial temporal atrophy in AD. These effects were not mediated by hippocampal sclerosis. TDP-positive subjects were 10× more likely to be cognitively impaired at death compared to TDP-negative subjects. Greater cognitive impairment and medial temporal atrophy were associated with greater TDP-43 burden and more extensive TDP-43 distribution. TDP-43 is an important factor in the manifestation of the clinico-imaging features of AD. TDP-43 also appears to be able to overpower what has been termed resilient brain aging. TDP-43 therefore should be considered a potential therapeutic target for the treatment of AD. PMID:24659241

Josephs, Keith A; Whitwell, Jennifer L; Weigand, Stephen D; Murray, Melissa E; Tosakulwong, Nirubol; Liesinger, Amanda M; Petrucelli, Leonard; Senjem, Matthew L; Knopman, David S; Boeve, Bradley F; Ivnik, Robert J; Smith, Glenn E; Jack, Clifford R; Parisi, Joseph E; Petersen, Ronald C; Dickson, Dennis W

2014-12-01

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Tar DNA-binding protein-43 (TDP-43) regulates axon growth in vitro and in vivo.  

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Intracellular inclusions of the TAR-DNA binding protein 43 (TDP-43) have been reported in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD-TDP). Rare mutations in TARDBP have been linked to both ALS and FTD-TDP suggesting that TDP-43 dysfunction is mechanistic in causing disease. TDP-43 is a predominantly nuclear protein with roles in regulating RNA transcription, splicing, stability and transport. In ALS, TDP-43 aberrantly accumulates in the cytoplasm of motor neurons where it forms aggregates. However it has until recently been unclear whether the toxic effects of TDP-43 involve recruitment to motor axons, and what effects this might have on axonal growth and integrity. Here we use chick embryonic motor neurons, in vivo and in vitro, to model the acute effects of TDP-43. We show that wild-type and two TDP-43 mutant proteins cause toxicity in chick embryonic motor neurons in vivo. Moreover, TDP-43 is increasingly mislocalised to axons over time in vivo, axon growth to peripheral targets is truncated, and expression of neurofilament-associated antigen is reduced relative to control motor neurons. In primary spinal motor neurons in vitro, a progressive translocation of TDP-43 to the cytoplasm occurs over time, similar to that observed in vivo. This coincides with the appearance of cytoplasmic aggregates, a reduction in the axonal length, and cellular toxicity, which was most striking for neurons expressing TDP-43 mutant forms. These observations suggest that the capacity of spinal motor neurons to produce and maintain an axon is compromised by dysregulation of TDP-43 and that the disruption of cytoskeletal integrity may play a role in the pathogenesis of ALS and FTD-TDP. PMID:24423647

Tripathi, Vineeta Bhasker; Baskaran, Pranetha; Shaw, Christopher E; Guthrie, Sarah

2014-05-01

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The molecular link between inefficient GluA2 Q/R site-RNA editing and TDP-43 pathology in motor neurons of sporadic amyotrophic lateral sclerosis patients.  

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TAR DNA-binding protein (TDP-43) pathology and reduced expression of adenosine deaminase acting on RNA 2 (ADAR2), which is the RNA editing enzyme responsible for adenosine-to-inosine conversion at the GluA2 glutamine/arginine (Q/R) site, concomitantly occur in the same motor neurons of amyotrophic lateral sclerosis (ALS) patients; this finding suggests a link between these two ALS-specific molecular abnormalities. AMPA receptors containing Q/R site-unedited GluA2 in their subunit assembly are Ca(2+)-permeable, and motor neurons lacking ADAR2 undergo slow death in conditional ADAR2 knockout (AR2) mice, which is a mechanistic ALS model in which the ADAR2 gene is targeted in cholinergic neurons. Moreover, deficient ADAR2 induced mislocalization of TDP-43 similar to TDP-43 pathology seen in the sporadic ALS patients in the motor neurons of AR2 mice. The abnormal mislocalization of TDP-43 specifically resulted from activation of the Ca(2+)-dependent serine protease calpain that specifically cleaved TDP-43 at the C-terminal region, and generated aggregation-prone N-terminal fragments. Notably, the N-terminal fragments of TDP-43 lacking the C-terminus were demonstrated in the brains and spinal cords of ALS patients. Because normalization of either the Ca(2+)-permeability of AMPA receptors or the calpain activity in the motor neurons normalized the subcellular localization of TDP-43 in AR2 mice, it is likely that exaggerated calpain-dependent TDP-43 fragments played a role at least in the initiation of TDP-43 pathology. Elucidation of the molecular cascade of neuronal death induced by ADAR2 downregulation could provide a new specific therapy for sporadic ALS. In this review, we summarized the work from our group on the role of inefficient GluA2 Q/R site-RNA editing and TDP-43 pathology in sporadic ALS, and discussed possible effects of inefficient ADAR2-mediated RNA editing in general. This article is part of a Special Issue entitled RNA Metabolism 2013. PMID:24355598

Yamashita, Takenari; Kwak, Shin

2014-10-10

 
 
 
 
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RNA-Processing Protein TDP-43 Regulates FOXO-Dependent Protein Quality Control in Stress Response  

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Protein homeostasis is critical for cell survival and functions during stress and is regulated at both RNA and protein levels. However, how the cell integrates RNA-processing programs with post-translational protein quality control systems is unknown. Transactive response DNA-binding protein (TARDBP/TDP-43) is an RNA-processing protein that is involved in the pathogenesis of major neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we report a conserved role for TDP-43, from C. elegans to mammals, in the regulation of protein clearance via activation of FOXO transcription factors. In response to proteotoxic insults, TDP-43 redistributes from the nucleus to the cytoplasm, promoting nuclear translocation of FOXOs and relieving an inhibition of FOXO activity in the nucleus. The interaction between TDP-43 and the FOXO pathway in mammalian cells is mediated by their competitive binding to 14-3-3 proteins. Consistent with FOXO-dependent protein quality control, TDP-43 regulates the levels of misfolded proteins. Therefore, TDP-43 mediates stress responses and couples the regulation of RNA metabolism and protein quality control in a FOXO-dependent manner. The results suggest that compromising the function of TDP-43 in regulating protein homeostasis may contribute to the pathogenesis of related neurodegenerative diseases. PMID:25329970

Zhang, Tao; Baldie, Gerard; Periz, Goran; Wang, Jiou

2014-01-01

42

Altered astrocytic expression of TDP-43 does not influence motor neuron survival.  

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The role of glia as a contributing factor to motor neuron (MN) death in amyotrophic lateral sclerosis (ALS) is becoming increasingly appreciated. However, most studies implicating astrocytes have focused solely on models of ALS caused by superoxide dismutase 1 (SOD1) mutations. The goal of our study was to determine whether astrocytes contribute to wild-type MN death in the case of ALS caused by mutations in tar-DNA binding protein 43 (TDP-43). Since it is currently unknown how TDP-43 mutations cause disease, we derived astrocytes for study from both gain and loss of function mouse models of TDP-43. Astrocytes overexpressing mutant TDP-43(A315T) as well as astrocytes lacking TDP-43 were morphologically indistinguishable from wild-type astrocytes in vitro. Furthermore, astrocytes with these TDP-43 alterations did not cause the death of wild-type MNs in co-culture. To investigate the in vivo effects of TDP-43 alterations in astrocytes, glial-restricted precursors were transplanted to the wild-type rat spinal cord where they differentiated into astrocytes and interacted with host MNs. Astrocytes with TDP-43 alterations did not cause host wild-type MN damage although they were capable of engrafting and interacting with host MNs with the same efficiency as wild-type astrocytes. These data indicate that astrocytes do not adopt the same toxic phenotype as mutant SOD1 astrocytes when TDP-43 is mutated or expression levels are modified. Our study reinforces the heterogeneity in ALS disease mechanisms and highlights the potential for future screening subsets of ALS patients prior to treatment with cell type-directed therapies. PMID:24120466

Haidet-Phillips, Amanda M; Gross, Sarah K; Williams, Timothy; Tuteja, Alisha; Sherman, Alex; Ko, Myungsung; Jeong, Yun H; Wong, Philip C; Maragakis, Nicholas J

2013-12-01

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TDP-43 knockdown impairs neurite outgrowth dependent on its target histone deacetylase 6  

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Full Text Available Abstract Background Trans-activation response element (TAR DNA binding protein of 43kDa (TDP-43 is causally related to the neurodegenerative diseases frontotemporal dementia and amyotrophic lateral sclerosis being the hallmark protein in the disease-characteristic neuropathological lesions and via genetic linkage. Histone deacetylase 6 (HDAC6 is an established target of the RNA-binding protein TDP-43. HDAC6 is an unusual cytosolic deacetylase enzyme, central for a variety of pivotal cellular functions including aggregating protein turnover, microtubular dynamics and filopodia formation. All these functions are important in the context of neurodegenerative proteinopathies involving TDP-43. We have previously shown in a human embryonic kidney cell line that TDP-43 knockdown significantly impairs the removal of a toxic, aggregating polyQ ataxin-3 fusion protein in an HDAC6-dependent manner. Here we investigated the influence of TDP-43 and its target HDAC6 on neurite outgrowth. Results Human neuroblastoma SH-SY5Y cells with stably silenced TDP-43 showed a significant reduction of neurite outgrowth induced by retinoic acid and brain-derived neurotrophic factor. Re-transfection with TDP-43 as well as HDAC6 rescued retinoic acid-induced neurite outgrowth. In addition, we show that silencing of HDAC6 alone is sufficient to reduce neurite outgrowth of in vitro differentiated SH-SY5Y cells. Conclusions TDP-43 deficiency leads to impairment of neurite growth in an HDAC6-dependent manner, thereby contributing to neurodegenerative events in TDP-43 diseases.

Weber Stephanie S

2011-08-01

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TDP-43 pathology and neuronal loss in amyotrophic lateral sclerosis spinal cord.  

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We examined the phosphorylated 43-kDa TAR DNA-binding protein (pTDP-43) inclusions as well as neuronal loss in full-length spinal cords and five selected regions of the central nervous system from 36 patients with amyotrophic lateral sclerosis (ALS) and 10 age-matched normal controls. The most severe neuronal loss and pTDP-43 lesions were seen in lamina IX motor nuclei columns 4, 6, and 8 of lower cervical segments and in columns 9-11 of lumbosacral segments. Severity of pTDP-43 pathology and neuronal loss correlated closely with gray and white matter oligodendroglial involvement and was linked to onset of disease, with severe involvement of columns 4, 6, and 8 of upper extremity onset cases and severe involvement of columns of 9, 10, and 11 in cases with lower extremity onset. Severe TDP-43 lesions and neuronal loss were observed in stage 4 cases and sometimes included Onuf's nucleus. Notably, three cases displayed pTDP-43 aggregates in the midbrain oculomotor nucleus, which we had not seen previously even in cases with advanced (i.e., stage 4) pathology. pTDP-43 aggregates were observed in neurons of Clarke's column in 30.6 % of cases but rarely in the intermediolateral nucleus (IML). Gray matter oligodendroglial pTDP-43 inclusions were present in areas devoid of neuronal pTDP-43 aggregates and neuronal loss. Taken together, our findings indicate that (1) the dorsolateral motor nuclei columns of the cervical and lumbosacral anterior horn may be the earliest foci of pTDP-43 pathology in the spinal cord, (2) gray matter oligodendroglial involvement is an early event in the ALS disease process that possibly heralds subsequent involvement of neurons by pTDP-43 pathology, and (3) in some very advanced cases, there is oculomotor nucleus involvement, which may constitute an additional neuropathological stage (designated here as stage 5) of pTDP-43 pathology in ALS. PMID:24916269

Brettschneider, Johannes; Arai, Kimihito; Del Tredici, Kelly; Toledo, Jon B; Robinson, John L; Lee, Edward B; Kuwabara, Satoshi; Shibuya, Kazumoto; Irwin, David J; Fang, Lubin; Van Deerlin, Vivianna M; Elman, Lauren; McCluskey, Leo; Ludolph, Albert C; Lee, Virginia M-Y; Braak, Heiko; Trojanowski, John Q

2014-09-01

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Sequential distribution of pTDP-43 pathology in behavioral variant frontotemporal dementia (bvFTD).  

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We examined regional distribution patterns of phosphorylated 43-kDa TAR DNA-binding protein (pTDP-43) intraneuronal inclusions in frontotemporal lobar degeneration (FTLD). Immunohistochemistry was performed on 70 ?m sections from FTLD-TDP autopsy cases (n = 39) presenting with behavioral variant frontotemporal dementia. Two main types of cortical pTDP-43 pathology emerged, characterized by either predominantly perikaryal pTDP-43 inclusions (cytoplasmic type, cFTLD) or long aggregates in dendrites (neuritic type, nFTLD). Cortical involvement in nFTLD was extensive and frequently reached occipital areas, whereas cases with cFTLD often involved bulbar somatomotor neurons and the spinal cord. We observed four patterns indicative of potentially sequential dissemination of pTDP-43: cases with the lowest burden of pathology (pattern I) were characterized by widespread pTDP-43 lesions in the orbital gyri, gyrus rectus, and amygdala. With increasing burden of pathology (pattern II) pTDP-43 lesions emerged in the middle frontal and anterior cingulate gyrus as well as in anteromedial temporal lobe areas, the superior and medial temporal gyri, striatum, red nucleus, thalamus, and precerebellar nuclei. More advanced cases showed a third pattern (III) with involvement of the motor cortex, bulbar somatomotor neurons, and the spinal cord anterior horn, whereas cases with the highest burden of pathology (pattern IV) were characterized by pTDP-43 lesions in the visual cortex. We interpret the four neuropathological patterns in bvFTD to be consistent with the hypothesis that pTDP-43 pathology can spread sequentially and may propagate along axonal pathways. PMID:24407427

Brettschneider, Johannes; Del Tredici, Kelly; Irwin, David J; Grossman, Murray; Robinson, John L; Toledo, Jon B; Fang, Lubin; Van Deerlin, Vivianna M; Ludolph, Albert C; Lee, Virginia M-Y; Braak, Heiko; Trojanowski, John Q

2014-03-01

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Robust cytoplasmic accumulation of phosphorylated TDP-43 in transgenic models of tauopathy  

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Frontotemporal lobar degeneration (FTLD) has been subdivided based on the main pathology found in the brains of affected individuals. When the primary pathology is aggregated, hyperphosphorylated tau, the pathological diagnosis is FTLD-tau. When the primary pathology is cytoplasmic and/or nuclear aggregates of phosphorylated TAR-DNA-binding protein (TDP-43), the pathological diagnosis is FTLD-TDP. Notably, TDP-43 pathology can also occur in conjunction with a number of neurodegenerative disor...

Clippinger, Amy K.; D’alton, Simon; Lin, Wen-lang; Gendron, Tania F.; Howard, John; Borchelt, David R.; Cannon, Ashley; Carlomagno, Yari; Chakrabarty, Paramita; Cook, Casey; Golde, Todd E.; Levites, Yona; Ranum, Laura; Schultheis, Patrick J.; Xu, Guilian

2013-01-01

47

Different 8-hydroxyquinolines protect models of TDP-43 protein, ?-synuclein, and polyglutamine proteotoxicity through distinct mechanisms.  

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No current therapies target the underlying cellular pathologies of age-related neurodegenerative diseases. Model organisms provide a platform for discovering compounds that protect against the toxic, misfolded proteins that initiate these diseases. One such protein, TDP-43, is implicated in multiple neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. In yeast, TDP-43 expression is toxic, and genetic modifiers first discovered in yeast have proven to modulate TDP-43 toxicity in both neurons and humans. Here, we describe a phenotypic screen for small molecules that reverse TDP-43 toxicity in yeast. One group of hit compounds was 8-hydroxyquinolines (8-OHQ), a class of clinically relevant bioactive metal chelators related to clioquinol. Surprisingly, in otherwise wild-type yeast cells, different 8-OHQs had selectivity for rescuing the distinct toxicities caused by the expression of TDP-43, ?-synuclein, or polyglutamine proteins. In fact, each 8-OHQ synergized with the other, clearly establishing that they function in different ways. Comparative growth and molecular analyses also revealed that 8-OHQs have distinct metal chelation and ionophore activities. The diverse bioactivity of 8-OHQs indicates that altering different aspects of metal homeostasis and/or metalloprotein activity elicits distinct protective mechanisms against several neurotoxic proteins. Indeed, phase II clinical trials of an 8-OHQ has produced encouraging results in modifying Alzheimer disease. Our unbiased identification of 8-OHQs in a yeast TDP-43 toxicity model suggests that tailoring 8-OHQ activity to a particular neurodegenerative disease may be a viable therapeutic strategy. PMID:22147697

Tardiff, Daniel F; Tucci, Michelle L; Caldwell, Kim A; Caldwell, Guy A; Lindquist, Susan

2012-02-01

48

Binding of TDP-43 to the 3'UTR of Its Cognate mRNA Enhances Its Solubility.  

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TAR DNA binding protein of 43 kDa (TDP-43) has been implicated in the pathogenesis of a broad range of neurodegenerative diseases termed TDP-43 proteinopathies, which encompass a spectrum of diseases ranging from amyotrophic lateral sclerosis to frontotemporal dementia. Pathologically misfolded and aggregated forms of TDP-43 are found in cytoplasmic inclusion bodies of affected neurons in these diseases. The mechanism by which TDP-43 misfolding causes disease is not well-understood. Current hypotheses postulate that the TDP-43 aggregation process plays a major role in pathogenesis. We amplify that hypothesis and suggest that binding of cognate ligands to TDP-43 can stabilize the native functional state of the protein and ameliorate aggregation. We expressed recombinant TDP-43 containing an N-terminal Venus yellow fluorescent protein tag in Escherichia coli and induced its aggregation by altering solvent salt concentrations and examined the extent to which various oligonucleotide molecules affect its aggregation in vitro using aggregation-induced turbidity assays. We show that vYFP-TDP-43 binding to its naturally occurring RNA target that comprises a sequence on the 3'UTR region of its mRNA improves its solubility, suggesting interplay among TDP-43 solubility, oligonucleotide binding, and TDP-43 autoregulation. PMID:25171271

Sun, Yulong; Arslan, Pharhad E; Won, Amy; Yip, Christopher M; Chakrabartty, Avi

2014-09-23

49

Hyperphosphorylation as a defense mechanism to reduce TDP-43 aggregation.  

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Several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) are characterized by inclusion bodies formed by TDP-43 (TDP). We established cell and transgenic Drosophila models expressing TDP carboxyl terminal fragment (ND251 and ND207), which developed aggregates recapitulating important features of TDP inclusions in ALS/FTLD-U, including hyperphosphorylation at previously reported serine(403,404,409,410) residues, polyubiquitination and colocalization with optineurin. These models were used to address the pathogenic role of hyperphosphorylation in ALS/FTLD-U. We demonstrated that hyperphosphorylation and ubiquitination occurred temporally later than aggregation in cells. Expression of CK2? which phosphorylated TDP decreased the aggregation propensity of ND251 or ND207; this effect could be blocked by CK2 inhibitor DMAT. Mutation of serines(379,403,404,409,410) to alanines (S5A) to eliminate phosphorylation increased the aggregation propensity and number of aggregates of TDP, but mutation to aspartic acids (S5D) or glutamic acids (S5E) to simulate hyperphosphorylation had the opposite effect. Functionally, ND251 or ND207 aggregates decreased the number of neurites of Neuro2a cells induced by retinoic acid or number of cells by MTT assay. S5A mutation aggravated, but S5E mutation alleviated these cytotoxic effects of aggregates. Finally, ND251 or ND251S5A developed aggregates in neurons, and salivary gland of transgenic Drosophila, but ND251S5E did not. Taken together, our data indicate that hyperphosphorylation may represent a compensatory defense mechanism to stop or prevent pathogenic TDP from aggregation. Therefore, enhancement of phosphorylation may serve as an effective therapeutic strategy against ALS/FTLD-U. PMID:21850253

Li, Huei-Ying; Yeh, Po-An; Chiu, Hsiu-Chiang; Tang, Chiou-Yang; Tu, Benjamin Pang-hsien

2011-01-01

50

Prion-like nuclear aggregation of TDP-43 during heat shock is regulated by HSP40/70 chaperones.  

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TDP-43 aggregation in the cytoplasm or nucleus is a key feature of the pathology of amyotrophic lateral sclerosis and frontotemporal dementia and is observed in numerous other neurodegenerative diseases, including Alzheimer's disease. Despite this fact, the inciting events leading to TDP-43 aggregation remain unclear. We observed that endogenous TDP-43 undergoes reversible aggregation in the nucleus after the heat shock and that this behavior is mediated by the C-terminal prion domain. Substitution of the prion domain from TIA-1 or an authentic yeast prion domain from RNQ1 into TDP-43 can completely recapitulate heat shock-induced aggregation. TDP-43 is constitutively bound to members of the Hsp40/Hsp70 family, and we found that heat shock-induced TDP-43 aggregation is mediated by the availability of these chaperones interacting with the inherently disordered C-terminal prion domain. Finally, we observed that the aggregation of TDP-43 during heat shock led to decreased binding to hnRNPA1, and a change in TDP-43 RNA-binding partners suggesting that TDP-43 aggregation alters its function in response to misfolded protein stress. These findings indicate that TDP-43 shares properties with physiologic prions from yeast, in that self-aggregation is mediated by a Q/N-rich disordered domain, is modulated by chaperone proteins and leads to altered function of the protein. Furthermore, they indicate that TDP-43 aggregation is regulated by chaperone availability, explaining the recurrent observation of TDP-43 aggregates in degenerative diseases of both the brain and muscle where protein homeostasis is disrupted. PMID:23962724

Udan-Johns, Maria; Bengoechea, Rocio; Bell, Shaughn; Shao, Jieya; Diamond, Marc I; True, Heather L; Weihl, Conrad C; Baloh, Robert H

2014-01-01

51

Positive Florbetapir PET Amyloid Imaging in a Subject with Frequent Cortical Neuritic Plaques and Frontotemporal Lobar Degeneration with TDP43-Positive Inclusions.  

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Abnormal neuronal accumulation and modification of TAR DNA binding protein 43 (TDP-43) have recently been discovered to be defining histopathological features of particular subtypes of frontotemporal dementia and amyotrophic lateral sclerosis, and are also common in aging, particularly coexisting with hippocampal sclerosis and Alzheimer's disease pathology. This case report describes a 72 year old Hispanic male with no family history of neurological disease, who presented at age 59 with obsessive behavior, anxiety, agitation, and dysphasia. Positron emission tomography imaging using the amyloid ligand 18F florbetapir (Amyvid) was positive. Postmortem examination revealed frequent diffuse and neuritic amyloid plaques throughout the cerebral cortex, thalamus, and striatum, Braak stage II neurofibrillary degeneration, and frequent frontal and temporal cortex TDP-43-positive neurites with rare nuclear inclusions. The case is unusual and instructive because of the co-existence of frequent cortical and diencephalic amyloid plaques with extensive TDP-43-positive histopathology in the setting of early-onset dementia and because it demonstrates that a positive cortical amyloid imaging signal in a subject with dementia does not necessarily establish that Alzheimer's disease is the sole cause. PMID:24927705

Serrano, Geidy E; Sabbagh, Marwan N; Sue, Lucia I; Hidalgo, Jose A; Schneider, Julie A; Bedell, Barry J; Van Deerlin, Vivianna M; Suh, Eunran; Akiyama, Haruhiko; Joshi, Abhinay D; Pontecorvo, Michael J; Mintun, Mark A; Beach, Thomas G

2014-01-01

52

Scalarane sesterterpenes from Thorectidae sponges as inhibitors of TDP-43 nuclear factor.  

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The analysis of two Thorectidae sponge samples, Hyrtios sp. and Petrosaspongia sp., collected at Fiji Islands, led to the isolation of five new scalarane derivatives along with fifteen known compounds. Their structures were elucidated on the basis of NMR and MS spectroscopic data. The small library of natural scalarane derivatives was investigated for their ability to modulate the activity of trans-activation response DNA-binding protein of 43 kDa (TDP-43), a key factor in several neurodegenerative conditions and the study resulted in the identification of potent inhibitors of TDP-43 protein. PMID:25251727

Festa, Carmen; Cassiano, Chiara; D'Auria, Maria Valeria; Debitus, Cécile; Monti, Maria Chiara; De Marino, Simona

2014-10-15

53

A nonsense mutation in mouse tardbp affects TDP43 alternative splicing activity and causes limb-clasping and body tone defects.  

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Mutations in TARDBP, encoding Tar DNA binding protein-43 (TDP43), cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Attempts to model TDP43 dysfunction in mice have used knockouts or transgenic overexpressors, which have revealed the difficulties of manipulating TDP43, whose level is tightly controlled by auto-regulation. In a complementary approach, to create useful mouse models for the dissection of TDP43 function and pathology, we have identified a nonsense mutat...

Ricketts, T.; Mcgoldrick, P.; Fratta, P.; Oliveira, H. M.; Kent, R.; Phatak, V.; Brandner, S.; Blanco, G.; Greensmith, L.; Acevedo-arozena, A.; Fisher, E. M.

2014-01-01

54

Endogenous TDP-43, but not FUS, contributes to stress granule assembly via G3BP  

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Full Text Available Abstract Amyotrophic lateral sclerosis (ALS is a fatal neurodegenerative disease characterized by the selective loss of upper and lower motor neurons, a cell type that is intrinsically more vulnerable than other cell types to exogenous stress. The interplay between genetic susceptibility and environmental exposures to toxins has long been thought to be relevant to ALS. One cellular mechanism to overcome stress is the formation of small dense cytoplasmic domains called stress granules (SG which contain translationally arrested mRNAs. TDP-43 (encoded by TARDBP is an ALS-causative gene that we have previously implicated in the regulation of the core stress granule proteins G3BP and TIA-1. TIA-1 and G3BP localize to SG under nearly all stress conditions and are considered essential to SG formation. Here, we report that TDP-43 is required for proper SG dynamics, especially SG assembly as marked by the secondary aggregation of TIA-1. We also show that SG assembly, but not initiation, requires G3BP. Furthermore, G3BP can rescue defective SG assembly in cells depleted of endogenous TDP-43. We also demonstrate that endogenous TDP-43 and FUS do not have overlapping functions in this cellular process as SG initiation and assembly occur normally in the absence of FUS. Lastly, we observe that SG assembly is a contributing factor in the survival of neuronal-like cells responding to acute oxidative stress. These data raise the possibility that disruptions of normal stress granule dynamics by loss of nuclear TDP-43 function may contribute to neuronal vulnerability in ALS.

Aulas Anaďs

2012-10-01

55

On the development of markers for pathological TDP-43 in amyotrophic lateral sclerosis with and without dementia.  

Science.gov (United States)

Pathological 43-kDa transactive response sequence DNA-binding protein (TDP-43) has been recognized as the major disease protein in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with ubiquitin positive, tau and ?-synuclein negative inclusions (FTLD-U) and the transitional forms between these multisystem conditions. In order to develop TDP-43 into a successful ALS biomarker, the natural history of TDP-43 pathology needs to be characterized and the underlying pathophysiology established. Here we propose a spatial and temporal "two-axes" model of central nervous system vulnerability for TDP-43 linked degeneration and review recent studies on potential biomarkers related to pathological TDP-43 in the cerebrospinal fluid (CSF), blood, and skeletal muscle. The model includes the following two arms: Firstly, a "motor neuron disease" or "spinal cord/brainstem to motor cortex" axis (with degeneration possibly ascending from the lower motor neurons to the upper motor neurons); and secondly, a "dementia" or "corticoid/allocortex to neocortex" axis (with a probable spread of TDP-43 linked degeneration from the mediotemporal lobe to wider mesocortical and neocortical brain areas). At the cellular level, there is a gradual disappearance of normal TDP-43 in the nucleus in combination with the formation of pathological aggregates in the cell body and cellular processes, which can also be used to identify the stage of the disease process. Moreover, TDP-43 lesions in subpial/subependymal or perivascular localizations have been noted, and this might account for increased CSF and blood TDP-43 levels through mechanisms that remain to be elucidated. PMID:21911035

Geser, F; Prvulovic, D; O'Dwyer, L; Hardiman, O; Bede, P; Bokde, A L W; Trojanowski, J Q; Hampel, H

2011-12-01

56

On the development of markers for pathological TDP-43 in amyotrophic lateral sclerosis with and without dementia.  

LENUS (Irish Health Repository)

Pathological 43-kDa transactive response sequence DNA-binding protein (TDP-43) has been recognized as the major disease protein in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with ubiquitin positive, tau and ?-synuclein negative inclusions (FTLD-U) and the transitional forms between these multisystem conditions. In order to develop TDP-43 into a successful ALS biomarker, the natural history of TDP-43 pathology needs to be characterized and the underlying pathophysiology established. Here we propose a spatial and temporal "two-axes" model of central nervous system vulnerability for TDP-43 linked degeneration and review recent studies on potential biomarkers related to pathological TDP-43 in the cerebrospinal fluid (CSF), blood, and skeletal muscle. The model includes the following two arms: Firstly, a "motor neuron disease" or "spinal cord\\/brainstem to motor cortex" axis (with degeneration possibly ascending from the lower motor neurons to the upper motor neurons); and secondly, a "dementia" or "corticoid\\/allocortex to neocortex" axis (with a probable spread of TDP-43 linked degeneration from the mediotemporal lobe to wider mesocortical and neocortical brain areas). At the cellular level, there is a gradual disappearance of normal TDP-43 in the nucleus in combination with the formation of pathological aggregates in the cell body and cellular processes, which can also be used to identify the stage of the disease process. Moreover, TDP-43 lesions in subpial\\/subependymal or perivascular localizations have been noted, and this might account for increased CSF and blood TDP-43 levels through mechanisms that remain to be elucidated.

Geser, F

2011-12-01

57

Corticospinal tract degeneration associated with TDP-43 type C pathology and semantic dementia.  

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Four subtypes of frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions have been described (types A-D). Of these four subtypes, motor neuron disease is more commonly associated with type B pathology, but has also been reported with type A pathology. We have noted, however, the unusual occurrence of cases of type C pathology having corticospinal tract degeneration. We aimed to assess the severity of corticospinal tract degeneration in a large cohort of cases with type C (n = 31). Pathological analysis included semi-quantitation of myelin loss of fibres of the corticospinal tract and associated macrophage burden, as well as axonal loss, at the level of the medullary pyramids. We also assessed for motor cortex degeneration and fibre loss of the medial lemniscus/olivocerebellar tract. All cases were subdivided into three groups based on the degree of corticospinal tract degeneration: (i) no corticospinal tract degeneration; (ii) equivocal corticospinal tract degeneration; and (iii) moderate to very severe corticospinal tract degeneration. Clinical, genetic, pathological and imaging comparisons were performed across groups. Eight cases had no corticospinal tract degeneration, and 14 cases had equivocal to mild corticospinal tract degeneration. Nine cases, however, had moderate to very severe corticospinal tract degeneration with myelin and axonal loss. In these nine cases, there was degeneration of the motor cortex without lower motor neuron degeneration or involvement of other brainstem tracts. These cases most commonly presented as semantic dementia, and they had longer disease duration (mean: 15.3 years) compared with the other two groups (10.8 and 9.9 years; P = 0.03). After adjusting for disease duration, severity of corticospinal tract degeneration remained significantly different across groups. Only one case, without corticospinal tract degeneration, was found to have a hexanucleotide repeat expansion in the C9ORF72 gene. All three groups were associated with anterior temporal lobe atrophy on MRI; however, the cases with moderate to severe corticospinal tract degeneration showed right-sided temporal lobe asymmetry and greater involvement of the right temporal lobe and superior motor cortices than the other groups. In contrast, the cases with no or equivocal corticospinal tract degeneration were more likely to show left-sided temporal lobe asymmetry. For comparison, the corticospinal tract was assessed in 86 type A and B cases, and only two cases showed evidence of corticospinal tract degeneration without lower motor neuron degeneration. These findings confirm that there exists a unique association between frontotemporal lobar degeneration with type C pathology and corticospinal tract degeneration, with this entity showing a predilection to involve the right temporal lobe. PMID:23358603

Josephs, Keith A; Whitwell, Jennifer L; Murray, Melissa E; Parisi, Joseph E; Graff-Radford, Neill R; Knopman, David S; Boeve, Bradley F; Senjem, Matthew L; Rademakers, Rosa; Jack, Clifford R; Petersen, Ronald C; Dickson, Dennis W

2013-02-01

58

Wild Type TDP-43 Induces Neuro-Inflammation and Alters APP Metabolism in Lentiviral Gene Transfer Models  

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The transactivation DNA-binding protein (TDP-43) pathology is associated with Fronto-Temporal Lobar Dementia (FTLD) with ubiquitinated inclusions and some cases of Alzheimer's disease (AD). Proteolytic fragments of ?-amyloid precursor protein (?APP) are detected in AD as well as the cerebrospinal fluid (CSF) from FTLD and Amyotrophic Lateral Sclerosis (ALS) patients, suggesting alteration in APP processing. Because of the overlap in TDP-43 pathology between FTLD and AD, we sought to determi...

Herman, Alexander M.; Khandelwal, Preeti J.; Rebeck, G. William; Moussa, Charbel E-h

2012-01-01

59

TDP-43 suppresses CGG repeat-induced neurotoxicity through interactions with HnRNP A2/B1.  

Science.gov (United States)

Nucleotide repeat expansions can elicit neurodegeneration as RNA by sequestering specific RNA-binding proteins, preventing them from performing their normal functions. Conversely, mutations in RNA-binding proteins can trigger neurodegeneration at least partly by altering RNA metabolism. In Fragile X-associated tremor/ataxia syndrome (FXTAS), a CGG repeat expansion in the 5'UTR of the fragile X gene (FMR1) leads to progressive neurodegeneration in patients and CGG repeats in isolation elicit toxicity in Drosophila and other animal models. Here, we identify the amyotrophic lateral sclerosis (ALS)-associated RNA-binding protein TAR DNA-binding protein (TDP-43) as a suppressor of CGG repeat-induced toxicity in a Drosophila model of FXTAS. The rescue appears specific to TDP-43, as co-expression of another ALS-associated RNA-binding protein, FUS, exacerbates the toxic effects of CGG repeats. Suppression of CGG RNA toxicity was abrogated by disease-associated mutations in TDP-43. TDP-43 does not co-localize with CGG RNA foci and its ability to bind RNA is not required for rescue. TDP-43-dependent rescue does, however, require fly hnRNP A2/B1 homologues Hrb87F and Hrb98DE. Deletions in the C-terminal domain of TDP-43 that preclude interactions with hnRNP A2/B1 abolish TDP-43-dependent rescue of CGG repeat toxicity. In contrast, suppression of CGG repeat toxicity by hnRNP A2/B1 is not affected by RNAi-mediated knockdown of the fly TDP-43 orthologue, TBPH. Lastly, TDP-43 suppresses CGG repeat-triggered mis-splicing of an hnRNP A2/B1-targeted transcript. These data support a model in which TDP-43 suppresses CGG-mediated toxicity through interactions with hnRNP A2/B1 and suggest a convergence of pathogenic cascades between repeat expansion disorders and RNA-binding proteins implicated in neurodegenerative disease. PMID:24920338

He, Fang; Krans, Amy; Freibaum, Brian D; Taylor, J Paul; Todd, Peter K

2014-10-01

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Neurotoxic 43-kDa TAR DNA-binding Protein (TDP-43) Triggers Mitochondrion-dependent Programmed Cell Death in Yeast*  

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Pathological neuronal inclusions of the 43-kDa TAR DNA-binding protein (TDP-43) are implicated in dementia and motor neuron disorders; however, the molecular mechanisms of the underlying cell loss remain poorly understood. Here we used a yeast model to elucidate cell death mechanisms upon expression of human TDP-43. TDP-43-expressing cells displayed markedly increased markers of oxidative stress, apoptosis, and necrosis. Cytotoxicity was dose- and age-dependent and was potentiated upon expres...

Braun, Ralf J.; Sommer, Cornelia; Carmona-gutierrez, Didac; Khoury, Chamel M.; Ring, Julia; Bu?ttner, Sabrina; Madeo, Frank

2011-01-01

 
 
 
 
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TAR DNA-binding protein 43 (TDP-43) regulates stress granule dynamics via differential regulation of G3BP and TIA-1.  

Science.gov (United States)

TAR deoxyribonucleic acid-binding protein 43 (TDP-43) is a multifunctional protein with roles in transcription, pre-messenger ribonucleic acid (mRNA) splicing, mRNA stability and transport. TDP-43 interacts with other heterogeneous nuclear ribonucleoproteins (hnRNPs), including hnRNP A2, via its C-terminus and several hnRNP family members are involved in the cellular stress response. This relationship led us to investigate the role of TDP-43 in cellular stress. Our results demonstrate that TDP-43 and hnRNP A2 are localized to stress granules (SGs), following oxidative stress, heat shock and exposure to thapsigargin. TDP-43 contributes to both the assembly and maintenance of SGs in response to oxidative stress and differentially regulates key SGs components, including TIA-1 and G3BP. The controlled aggregation of TIA-1 is disrupted in the absence of TDP-43 resulting in slowed SG formation. In addition, TDP-43 regulates the levels of G3BP mRNA, a SG nucleating factor. The disease-associated mutation TDP-43(R361S) is a loss-of-function mutation with regards to SG formation and confers alterations in levels of G3BP and TIA-1. In contrast, a second mutation TDP-43(D169G) does not impact this pathway. Thus, mutations in TDP-43 are mechanistically divergent. Finally, the cellular function of TDP-43 extends beyond splicing and places TDP-43 as a participant of the central cellular response to stress and an active player in RNA storage. PMID:21257637

McDonald, Karli K; Aulas, Anaďs; Destroismaisons, Laurie; Pickles, Sarah; Beleac, Evghenia; Camu, William; Rouleau, Guy A; Vande Velde, Christine

2011-04-01

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Neurotoxic 43-kDa TAR DNA-binding protein (TDP-43) triggers mitochondrion-dependent programmed cell death in yeast.  

Science.gov (United States)

Pathological neuronal inclusions of the 43-kDa TAR DNA-binding protein (TDP-43) are implicated in dementia and motor neuron disorders; however, the molecular mechanisms of the underlying cell loss remain poorly understood. Here we used a yeast model to elucidate cell death mechanisms upon expression of human TDP-43. TDP-43-expressing cells displayed markedly increased markers of oxidative stress, apoptosis, and necrosis. Cytotoxicity was dose- and age-dependent and was potentiated upon expression of disease-associated variants. TDP-43 was localized in perimitochondrial aggregate-like foci, which correlated with cytotoxicity. Although the deleterious effects of TDP-43 were significantly decreased in cells lacking functional mitochondria, cell death depended neither on the mitochondrial cell death proteins apoptosis-inducing factor, endonuclease G, and cytochrome c nor on the activity of cell death proteases like the yeast caspase 1. In contrast, impairment of the respiratory chain attenuated the lethality upon TDP-43 expression with a stringent correlation between cytotoxicity and the degree of respiratory capacity or mitochondrial DNA stability. Consistently, an increase in the respiratory capacity of yeast resulted in enhanced TDP-43-triggered cytotoxicity, oxidative stress, and cell death markers. These data demonstrate that mitochondria and oxidative stress are important to TDP-43-triggered cell death in yeast and may suggest a similar role in human TDP-43 pathologies. PMID:21471218

Braun, Ralf J; Sommer, Cornelia; Carmona-Gutierrez, Didac; Khoury, Chamel M; Ring, Julia; Büttner, Sabrina; Madeo, Frank

2011-06-01

63

Neurotoxic 43-kDa TAR DNA-binding Protein (TDP-43) Triggers Mitochondrion-dependent Programmed Cell Death in Yeast*  

Science.gov (United States)

Pathological neuronal inclusions of the 43-kDa TAR DNA-binding protein (TDP-43) are implicated in dementia and motor neuron disorders; however, the molecular mechanisms of the underlying cell loss remain poorly understood. Here we used a yeast model to elucidate cell death mechanisms upon expression of human TDP-43. TDP-43-expressing cells displayed markedly increased markers of oxidative stress, apoptosis, and necrosis. Cytotoxicity was dose- and age-dependent and was potentiated upon expression of disease-associated variants. TDP-43 was localized in perimitochondrial aggregate-like foci, which correlated with cytotoxicity. Although the deleterious effects of TDP-43 were significantly decreased in cells lacking functional mitochondria, cell death depended neither on the mitochondrial cell death proteins apoptosis-inducing factor, endonuclease G, and cytochrome c nor on the activity of cell death proteases like the yeast caspase 1. In contrast, impairment of the respiratory chain attenuated the lethality upon TDP-43 expression with a stringent correlation between cytotoxicity and the degree of respiratory capacity or mitochondrial DNA stability. Consistently, an increase in the respiratory capacity of yeast resulted in enhanced TDP-43-triggered cytotoxicity, oxidative stress, and cell death markers. These data demonstrate that mitochondria and oxidative stress are important to TDP-43-triggered cell death in yeast and may suggest a similar role in human TDP-43 pathologies. PMID:21471218

Braun, Ralf J.; Sommer, Cornelia; Carmona-Gutierrez, Didac; Khoury, Chamel M.; Ring, Julia; Buttner, Sabrina; Madeo, Frank

2011-01-01

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TDP-43 loss-of-function causes neuronal loss due to defective steroid receptor-mediated gene program switching in Drosophila.  

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TDP-43 proteinopathy is strongly implicated in the pathogenesis of amyotrophic lateral sclerosis and related neurodegenerative disorders. Whether TDP-43 neurotoxicity is caused by a novel toxic gain-of-function mechanism of the aggregates or by a loss of its normal function is unknown. We increased and decreased expression of TDP-43 (dTDP-43) in Drosophila. Although upregulation of dTDP-43 induced neuronal ubiquitin and dTDP-43-positive inclusions, both up- and downregulated dTDP-43 resulted in selective apoptosis of bursicon neurons and highly similar transcriptome alterations at the pupal-adult transition. Gene network analysis and genetic validation showed that both up- and downregulated dTDP-43 directly and dramatically increased the expression of the neuronal microtubule-associated protein Map205, resulting in cytoplasmic accumulations of the ecdysteroid receptor (EcR) and a failure to switch EcR-dependent gene programs from a pupal to adult pattern. We propose that dTDP-43 neurotoxicity is caused by a loss of its normal function. PMID:23333275

Vanden Broeck, Lies; Naval-Sánchez, Marina; Adachi, Yoshitsugu; Diaper, Danielle; Dourlen, Pierre; Chapuis, Julien; Kleinberger, Gernot; Gistelinck, Marc; Van Broeckhoven, Christine; Lambert, Jean-Charles; Hirth, Frank; Aerts, Stein; Callaerts, Patrick; Dermaut, Bart

2013-01-31

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Allele-Specific Knockdown of ALS-Associated Mutant TDP-43 in Neural Stem Cells Derived from Induced Pluripotent Stem Cells  

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TDP-43 is found in cytoplasmic inclusions in 95% of amyotrophic lateral sclerosis (ALS) and 60% of frontotemporal lobar degeneration (FTLD). Approximately 4% of familial ALS is caused by mutations in TDP-43. The majority of these mutations are found in the glycine-rich domain, including the variant M337V, which is one of the most common mutations in TDP-43. In order to investigate the use of allele-specific RNA interference (RNAi) as a potential therapeutic tool, we designed and screened a set of siRNAs that specifically target TDP-43M337V mutation. Two siRNA specifically silenced the M337V mutation in HEK293T cells transfected with GFP-TDP-43wt or GFP-TDP-43M337V or TDP-43 C-terminal fragments counterparts. C-terminal TDP-43 transfected cells show an increase of cytosolic inclusions, which are decreased after allele-specific siRNA in M337V cells. We then investigated the effects of one of these allele-specific siRNAs in induced pluripotent stem cells (iPSCs) derived from an ALS patient carrying the M337V mutation. These lines showed a two-fold increase in cytosolic TDP-43 compared to the control. Following transfection with the allele-specific siRNA, cytosolic TDP-43 was reduced by 30% compared to cells transfected with a scrambled siRNA. We conclude that RNA interference can be used to selectively target the TDP-43M337V allele in mammalian and patient cells, thus demonstrating the potential for using RNA interference as a therapeutic tool for ALS. PMID:24651281

Nishimura, Agnes L.; Shum, Carole; Scotter, Emma L.; Abdelgany, Amr; Sardone, Valentina; Wright, Jamie; Lee, Youn-Bok; Chen, Han-Jou; Bilican, Bilada; Carrasco, Monica; Maniatis, Tom; Chandran, Siddharthan; Rogelj, Boris; Gallo, Jean-Marc; Shaw, Christopher E.

2014-01-01

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Coaggregation of RNA-Binding Proteins in a Model of TDP-43 Proteinopathy with Selective RGG Motif Methylation and a Role for RRM1 Ubiquitination  

Science.gov (United States)

TAR DNA-binding protein 43 (TDP-43) is a major component within ubiquitin-positive inclusions of a number of neurodegenerative diseases that increasingly are considered as TDP-43 proteinopathies. Identities of other inclusion proteins associated with TDP-43 aggregation remain poorly defined. In this study, we identify and quantitate 35 co-aggregating proteins in the detergent-resistant fraction of HEK-293 cells in which TDP-43 or a particularly aggregate prone variant, TDP-S6, were enriched following overexpression, using stable isotope-labeled (SILAC) internal standards and liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). We also searched for differential post-translational modification (PTM) sites of ubiquitination. Four sites of ubiquitin conjugation to TDP-43 or TDP-S6 were confirmed by dialkylated GST-TDP-43 external reference peptides, occurring on or near RNA binding motif (RRM) 1. RRM-containing proteins co-enriched in cytoplasmic granular structures in HEK-293 cells and primary motor neurons with insoluble TDP-S6, including cytoplasmic stress granule associated proteins G3BP, PABPC1, and eIF4A1. Proteomic evidence for TDP-43 co-aggregation with paraspeckle markers RBM14, PSF and NonO was also validated by western blot and by immunocytochemistry in HEK-293 cells. An increase in peptides from methylated arginine-glycine-glycine (RGG) RNA-binding motifs of FUS/TLS and hnRNPs was found in the detergent-insoluble fraction of TDP-overexpressing cells. Finally, TDP-43 and TDP-S6 detergent-insoluble species were reduced by mutagenesis of the identified ubiquitination sites, even following oxidative or proteolytic stress. Together, these findings define some of the aggregation partners of TDP-43, and suggest that TDP-43 ubiquitination influences TDP-43 oligomerization. PMID:22761693

Dammer, Eric B.; Fallini, Claudia; Gozal, Yair M.; Duong, Duc M.; Rossoll, Wilfried; Xu, Ping; Lah, James J.; Levey, Allan I.; Peng, Junmin; Bassell, Gary J.; Seyfried, Nicholas T.

2012-01-01

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Chronological requirements of TDP-43 function in synaptic organization and locomotive control.  

Science.gov (United States)

Alterations in TDP-43 are commonly found in patients suffering from amyotrophic lateral sclerosis (ALS) and the genetic suppression of the conserved homologue in Drosophila (TBPH) provokes alterations in the functional organization of motoneuron synaptic terminals, resulting in locomotive defects and reduced life span. To gain more insight into this pathological process, it is of fundamental importance to establish when during the fly life cycle the lack of TBPH affects motoneuron activity and whether this is a reversible phenomenon. To achieve this, we conditionally expressed the endogenous protein in TBPH minus Drosophila neurons and found that TBPH is a short lived protein permanently required for Drosophila motility and synaptic assembly through the direct modulation of vesicular proteins, such as Syntaxin 1A, indicating that synaptic transmission defects are early pathological consequences of TBPH dysfunction in vivo. Importantly, TBPH late induction is able to recover synaptogenesis and locomotion in adult flies revealing an unexpected late-stage functional and structural neuronal plasticity. These observations suggest that late therapeutic approaches based on TDP-43 functionality may also be successful for the human pathology. PMID:25088713

Romano, Giulia; Klima, Raffaella; Buratti, Emanuele; Verstreken, Patrik; Baralle, Francisco E; Feiguin, Fabian

2014-11-01

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Motor neuron expression of the voltage-gated calcium channel cacophony restores locomotion defects in a Drosophila, TDP-43 loss of function model of ALS.  

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Dysfunction of the RNA-binding protein, TDP-43, is strongly implicated as a causative event in many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). TDP-43 is normally found in the nucleus and pathological hallmarks of ALS include the presence of cytoplasmic protein aggregates containing TDP-43 and an associated loss of TDP-43 from the nucleus. Loss of nuclear TDP-43 likely contributes to neurodegeneration. Using Drosophila melanogaster to model TDP-43 loss of function, we show that reduced levels of the voltage-gated calcium channel, cacophony, mediate some of the physiological effects of TDP-43 loss. Null mutations in the Drosophila orthologue of TDP-43, named TBPH, resulted in defective larval locomotion and reduced levels of cacophony protein in whole animals and at the neuromuscular junction. Restoring the levels of cacophony in all neurons or selectively in motor neurons rescued these locomotion defects. Using TBPH immunoprecipitation, we showed that TBPH associates with cacophony transcript, indicating that it is likely to be a direct target for TBPH. Loss of TBPH leads to reduced levels of cacophony transcript, possibly due to increased degradation. In addition, TBPH also appears to regulate the inclusion of some alternatively spliced exons of cacophony. If similar effects of cacophony or related calcium channels are found in human ALS patients, these could be targets for the development of pharmacological therapies for ALS. This article is part of a Special Issue entitled RNA Metabolism 2013. PMID:24275199

Chang, Jer-Cherng; Hazelett, Dennis J; Stewart, Judith A; Morton, David B

2014-10-10

69

Selective forelimb impairment in rats expressing a pathological TDP-43 25?kDa C-terminal fragment to mimic amyotrophic lateral sclerosis.  

Science.gov (United States)

Pathological inclusions containing transactive response DNA-binding protein 43?kDa (TDP-43) are common in several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). TDP-43 normally localizes predominantly to the nucleus, but during disease progression, it mislocalizes to the cytoplasm. We expressed TDP-43 in rats by an adeno-associated virus (AAV9) gene transfer method that transduces neurons throughout the central nervous system (CNS). To mimic the aberrant cytoplasmic TDP-43 found in disease, we expressed a form of TDP-43 with mutations in the nuclear localization signal sequence (TDP-NLS). The TDP-NLS was detected in both the cytoplasm and the nucleus of transduced neurons. Unlike wild-type TDP-43, expression of TDP-NLS did not induce mortality. However, the TDP-NLS induced disease-relevant motor impairments over 24 weeks. We compared the TDP-NLS to a 25?kDa C-terminal proaggregatory fragment of TDP-43 (TDP-25). The clinical phenotype of forelimb impairment was pronounced with the TDP-25 form, supporting a role of this C-terminal fragment in pathogenesis. The results advance previous rodent models by inducing cytoplasmic expression of TDP-43 in the spinal cord, and the non-lethal phenotype enabled long-term study. Approaching a more relevant disease state in an animal model that more closely mimics underlying mechanisms in human disease could unlock our ability to develop therapeutics. PMID:23689600

Dayton, Robert D; Gitcho, Michael A; Orchard, Elysse A; Wilson, Jon D; Wang, David B; Cain, Cooper D; Johnson, Jeffrey A; Zhang, Yong-Jie; Petrucelli, Leonard; Mathis, J Michael; Klein, Ronald L

2013-07-01

70

Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43  

Science.gov (United States)

Cross-linking and immunoprecipitation coupled with high-throughput sequencing was used to identify binding sites within 6,304 genes as the brain RNA targets for TDP-43, an RNA binding protein which when mutated causes Amyotrophic Lateral Sclerosis (ALS). Use of massively parallel sequencing and splicing-sensitive junction arrays revealed that levels of 601 mRNAs are changed (including Fus/Tls, progranulin, and other transcripts encoding neurodegenerative disease-associated proteins) and 965 altered splicing events are detected (including in sortilin, the receptor for progranulin), following depletion of TDP-43 from mouse adult brain with antisense oligonucleotides. RNAs whose levels are most depleted by reduction in TDP-43 are derived from genes with very long introns and which encode proteins involved in synaptic activity. Lastly, TDP-43 was found to auto-regulate its synthesis, in part by directly binding and enhancing splicing of an intron within the 3? untranslated region of its own transcript, thereby triggering nonsense mediated RNA degradation. (147 words) PMID:21358643

Polymenidou, Magdalini; Lagier-Tourenne, Clotilde; Hutt, Kasey R.; Huelga, Stephanie C.; Moran, Jacqueline; Liang, Tiffany Y.; Ling, Shuo-Chien; Sun, Eveline; Wancewicz, Edward; Mazur, Curt; Kordasiewicz, Holly; Sedaghat, Yalda; Donohue, John Paul; Shiue, Lily; Bennett, C. Frank; Yeo, Gene W.; Cleveland, Don W.

2011-01-01

71

Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Cross-linking and immunoprecipitation coupled with high-throughput sequencing was used to identify binding sites within 6,304 genes as the brain RNA targets for TDP-43, an RNA binding protein which when mutated causes Amyotrophic Lateral Sclerosis (ALS). Use of massively parallel sequencing and splicing-sensitive junction arrays revealed that levels of 601 mRNAs are changed (including Fus/Tls, progranulin, and other transcripts encoding neurodegenerative disease-associated proteins) and 965 a...

Polymenidou, Magdalini; Lagier-tourenne, Clotilde; Hutt, Kasey R.; Huelga, Stephanie C.; Moran, Jacqueline; Liang, Tiffany Y.; Ling, Shuo-chien; Sun, Eveline; Wancewicz, Edward; Mazur, Curt; Kordasiewicz, Holly; Sedaghat, Yalda; Donohue, John Paul; Shiue, Lily; Bennett, C. Frank

2011-01-01

72

Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs.  

Science.gov (United States)

FUS/TLS (fused in sarcoma/translocated in liposarcoma) and TDP-43 are integrally involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We found that FUS/TLS binds to RNAs from >5,500 genes in mouse and human brain, primarily through a GUGGU-binding motif. We identified a sawtooth-like binding pattern, consistent with co-transcriptional deposition of FUS/TLS. Depletion of FUS/TLS from the adult nervous system altered the levels or splicing of >950 mRNAs, most of which are distinct from RNAs dependent on TDP-43. Abundance of only 45 RNAs was reduced after depletion of either TDP-43 or FUS/TLS from mouse brain, but among these were mRNAs that were transcribed from genes with exceptionally long introns and that encode proteins that are essential for neuronal integrity. Expression levels of a subset of these were lowered after TDP-43 or FUS/TLS depletion in stem cell-derived human neurons and in TDP-43 aggregate-containing motor neurons in sporadic ALS, supporting a common loss-of-function pathway as one component underlying motor neuron death from misregulation of TDP-43 or FUS/TLS. PMID:23023293

Lagier-Tourenne, Clotilde; Polymenidou, Magdalini; Hutt, Kasey R; Vu, Anthony Q; Baughn, Michael; Huelga, Stephanie C; Clutario, Kevin M; Ling, Shuo-Chien; Liang, Tiffany Y; Mazur, Curt; Wancewicz, Edward; Kim, Aneeza S; Watt, Andy; Freier, Sue; Hicks, Geoffrey G; Donohue, John Paul; Shiue, Lily; Bennett, C Frank; Ravits, John; Cleveland, Don W; Yeo, Gene W

2012-11-01

73

Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs  

Science.gov (United States)

FUS/TLS (fused in sarcoma/translocated in liposarcoma) and TDP-43 are integrally involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We found that FUS/TLS binds to RNAs from >5,500 genes in mouse and human brain, primarily through a GUGGU-binding motif. We identified a sawtooth-like binding pattern, consistent with co-transcriptional deposition of FUS/TLS. Depletion of FUS/TLS from the adult nervous system altered the levels or splicing of >950 mRNAs, most of which are distinct from RNAs dependent on TDP-43. Abundance of only 45 RNAs was reduced after depletion of either TDP-43 or FUS/TLS from mouse brain, but among these were mRNAs that were transcribed from genes with exceptionally long introns and that encode proteins that are essential for neuronal integrity. Expression levels of a subset of these were lowered after TDP-43 or FUS/TLS depletion in stem cell-derived human neurons and in TDP-43 aggregate–containing motor neurons in sporadic ALS, supporting a common loss-of-function pathway as one component underlying motor neuron death from misregulation of TDP-43 or FUS/TLS. PMID:23023293

Lagier-Tourenne, Clotilde; Polymenidou, Magdalini; Hutt, Kasey R; Vu, Anthony Q; Baughn, Michael; Huelga, Stephanie C; Clutario, Kevin M; Ling, Shuo-Chien; Liang, Tiffany Y; Mazur, Curt; Wancewicz, Edward; Kim, Aneeza S; Watt, Andy; Freier, Sue; Hicks, Geoffrey G; Donohue, John Paul; Shiue, Lily; Bennett, C Frank; Ravits, John; Cleveland, Don W; Yeo, Gene W

2013-01-01

74

Increased metal content in the TDP-43(A315T) transgenic mouse model of frontotemporal lobar degeneration and amyotrophic lateral sclerosis.  

Science.gov (United States)

Disrupted metal homeostasis is a consistent feature of neurodegenerative disease in humans and is recapitulated in mouse models of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) and neuronal ceriod lipofuscinosis. While the definitive pathogenesis of neurodegenerative disease in humans remains to be fully elucidated, disease-like symptoms in the mouse models are all driven by the presence or over-expression of a putative pathogenic protein, indicating an in vivo relationship between expression of these proteins, disrupted metal homeostasis and the symptoms of neuronal failure. Recently it was established that mutant TAR DNA binding protein-43 (TDP-43) is associated with the development of frontotemporal lobar degeneration and ALS. Subsequent development of transgenic mice that express human TDP-43 carrying the disease-causing A315T mutation has provided new opportunity to study the underlying mechanisms of TDP-43-related neurodegenerative disease. We assessed the cognitive and locomotive phenotype of TDP-43 (A315T) mice and their wild-type littermates and also assessed bulk metal content of brain and spinal cord tissues. Metal levels in the brain were not affected by the expression of mutant TDP-43, but zinc, copper, and manganese levels were all increased in the spinal cords of TDP-43 (A315T) mice when compared to wild-type littermates. Performance of the TDP-43 (A315T) mice in the Y-maze test for cognitive function was not significantly different to wild-type mice. By contrast, performance of the TDP-43 (A315T) in the rotarod test for locomotive function was consistently worse than wild-type mice. These preliminary in vivo data are the first to show that expression of a disease-causing form of TDP-43 is sufficient to disrupt metal ion homeostasis in the central nervous system. Disrupted metal ion homeostasis in the spinal cord but not the brain may explain why the TDP-43 (A315T) mice show symptoms of locomotive decline and not cognitive decline. PMID:24575040

Dang, Theresa N T; Lim, Nastasia K H; Grubman, Alexandra; Li, Qiao-Xin; Volitakis, Irene; White, Anthony R; Crouch, Peter J

2014-01-01

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Increased metal content in the TDP-43A315T transgenic mouse model of frontotemporal lobar degeneration and amyotrophic lateral sclerosis  

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Full Text Available Disrupted metal homeostasis is a consistent feature of neurodegenerative disease in humans and is recapitulated in mouse models of Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS and neuronal ceriod lipofuscinosis. While the definitive pathogenesis of neurodegenerative disease in humans remains to be fully elucidated, disease-like symptoms in the mouse models are all driven by the presence or over-expression of a putative pathogenic protein, indicating an in vivo relationship between expression of these proteins, disrupted metal homeostasis and the symptoms of neuronal failure. Recently it was established that mutant TAR DNA binding protein-43 (TDP-43 is associated with the development of frontotemporal lobar degeneration (FTLD and ALS. Subsequent development of transgenic mice that express human TDP-43 carrying the disease-causing A315T mutation has provided new opportunity to study the underlying mechanisms of TDP-43-related neurodegenerative disease. We assessed the cognitive and locomotive phenotype of TDP-43A315T mice and their wild-type littermates and also assessed bulk metal content of brain and spinal cord tissues. Metal levels in the brain were not affected by the expression of mutant TDP-43, but Zn, Cu and Mn levels were all increased in the spinal cords of TDP-43A315T mice when compared to wild-type littermates. Performance of the TDP-43A315T mice in the Y-maze test for cognitive function was not significantly different to wild-type mice. By contrast, performance of the TDP-43A315T in the rotarod test for locomotive function was consistently worse than wild-type mice. These preliminary in vivo data are the first to show that expression of a disease-causing form of TDP-43 is sufficient to disrupt metal ion homeostasis in the central nervous system. Disrupted metal ion homeostasis in the spinal cord but not the brain may explain why the TDP-43A315T mice show symptoms of locomotive decline and not cognitive decline.

PeterCrouch

2014-02-01

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TDP-43 high throughput screening analyses in neurodegeneration: advantages and pitfalls.  

Science.gov (United States)

Dysfunctions in RNA processing and in particular the aberrant regulation of RNA binding proteins (RBPs) have recently been shown to play a fundamental role in the pathogenesis of neurodegenerative diseases. Understanding the pathogenic mechanisms involved will require the elucidation of the role(s) played by these RBPs in the general cell metabolism and neuronal survival in particular. In the past, the preferred approach has been to determine first of all the functional properties of the factor(s) of interest and then use this knowledge to determine targets in biologically relevant events. More recently, novel experimental approaches such as microarrays, RNA-seq and CLIP-seq have also become very popular to study RBPs. The advantage of these approaches, collectively known as high throughput screening (HTS), is their ability to determine gene expression changes or RNA/protein targets at a global cellular level. In theory, HTS strategies should be ideal for uncovering novel functional roles/targets of any RBP inside the cell. In practice, however, there are still difficulties in getting a coherent picture from all the huge amount of data they generate, frequently not validated experimentally and thus of unknown value. They may even act unfavorably towards a specific increase of knowledge of RBP functions, as the incomplete results are taken as solid data. In this work we will illustrate as an example the use of the HTS methodologies to characterize the interactions of a specific RBP: TDP-43. The multiple functions of this protein in RNA processing and its involvement in the pathogenesis of several forms of amyotrophic lateral sclerosis, frontotemporal lobar degeneration and other neurodegenerative diseases make it an excellent substrate for our analysis of the various advantages and limitations of different HTS experimental approaches. PMID:23500590

Buratti, Emanuele; Romano, Maurizio; Baralle, Francisco E

2013-09-01

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Hu Antigen R (HuR) Is a Positive Regulator of the RNA-binding Proteins TDP-43 and FUS/TLS: IMPLICATIONS FOR AMYOTROPHIC LATERAL SCLEROSIS.  

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Posttranscriptional gene regulation is governed by a network of RNA-binding proteins (RBPs) that interact with regulatory elements in the mRNA to modulate multiple molecular processes, including splicing, RNA transport, RNA stability, and translation. Mounting evidence indicates that there is a hierarchy within this network whereby certain RBPs cross-regulate other RBPs to coordinate gene expression. HuR, an RNA-binding protein we linked previously to aberrant VEGF mRNA metabolism in models of SOD1-associated amyotrophic lateral sclerosis, has been identified as being high up in this hierarchy, serving as a regulator of RNA regulators. Here we investigated the role of HuR in regulating two RBPs, TDP-43 and FUS/TLS, that have been linked genetically to amyotrophic lateral sclerosis. We found that HuR promotes the expression of both RBPs in primary astrocytes and U251 cells under normal and stressed (hypoxic) conditions. For TDP-43, we found that HuR binds to the 3' untranslated region (UTR) and regulates its expression through translational efficiency rather than RNA stability. With HuR knockdown, there was a shift of TDP-43 and FUS mRNAs away from polysomes, consistent with translational silencing. The TDP-43 splicing function was attenuated upon HuR knockdown and could be rescued by ectopic TDP-43 lacking the 3' UTR regulatory elements. Finally, conditioned medium from astrocytes in which HuR or TDP-43 was knocked down produced significant motor neuron and cortical neuron toxicity in vitro. These findings indicate that HuR regulates TDP-43 and FUS/TLS expression and that loss of HuR-mediated RNA processing in astrocytes can alter the molecular and cellular landscape to produce a toxic phenotype. PMID:25239623

Lu, Liang; Zheng, Lei; Si, Ying; Luo, Wenyi; Dujardin, Gwendal; Kwan, Thaddaeus; Potochick, Nicholas R; Thompson, Sunnie R; Schneider, David A; King, Peter H

2014-11-14

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Transcriptome-wide analysis of TDP-43 binding small RNAs identifies miR-NID1 (miR-8485), a novel miRNA that represses NRXN1 expression.  

Science.gov (United States)

The Tar DNA-binding protein 43 (TARDBP, TDP-43) regulates RNA processing and miRNA biogenesis and is known to be involved in neurodegeneration. Messenger RNA (mRNA) targets of TDP-43 have recently been systematically identified, but small RNAs (sRNAs) bound by TDP-43 have not been studied in details. Here, we reexamine cross-linking, immunoprecipitation and sequencing (CLIP-seq) data, and identify pre-miRNAs, miRNAs and piRNAs bound by TDP-43 in human and mouse brains. Subsequent analysis of TDP-43 binding miRNAs suggests that target genes are enriched in functions involving synaptic activities. We further identify a novel miRNA (miR-NID1) processed from the intron 5 of human neurexin 1, NRXN1, and show that miR-NID1 represses NRXN1 expression by binding to TDP-43. Our results are in accordance with previously published data indicating TDP-43 through binding of specific miRNAs to play roles in neurodevelopmental activities and neurological disorders and further our understanding of TDP-43 function. PMID:23827811

Fan, Zhen; Chen, Xiaowei; Chen, Runsheng

2014-01-01

79

TDP-43 pathology in a patient carrying G2019S LRRK2 mutation and a novel p.Q124E MAPT.  

Science.gov (United States)

Leucine-rich repeat kinase 2 (LRRK2) mutation is the most common cause of genetic-related parkinsonism and is usually associated with Lewy body pathology; however, tau, ?-synuclein, and ubiquitin pathologies have also been reported. We report the case of a patient carrying the LRRK2 G2019S mutation and a novel heterozygous variant c.370C>G, p.Q124E in exon 4 of the microtubule-associated protein tau (MAPT). The patient developed parkinsonism with good levodopa response in her 70s. Neuropathological analysis revealed nigral degeneration and Alzheimer-type tau pathology without Lewy bodies. Immunohistochemical staining using phospho-TDP-43 antibodies identified occasional TDP-43 pathology in the hippocampus, temporal neocortex, striatum, and substantia nigra. However, TDP-43 pathology was not identified in another 4 archival LRRK2 G2019S cases with Lewy body pathology available in the Queen Square Brain Bank. Among other published cases of patients carrying LRRK2 G2019S mutation, only 3 were reportedly evaluated for TDP-43 pathology, and the results were negative. The role of the MAPT variant in the clinical and pathological manifestation in LRRK2 cases remains to be determined. PMID:23664753

Ling, Helen; Kara, Eleanna; Bandopadhyay, Rina; Hardy, John; Holton, Janice; Xiromerisiou, Georgia; Lees, Andrew; Houlden, Henry; Revesz, Tamas

2013-12-01

80

CGG repeats in RNA modulate expression of TDP-43 in mouse and fly models of fragile X tremor ataxia syndrome.  

Science.gov (United States)

Determining the molecular mechanism(s) leading to Purkinje neuron loss in the neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS) is limited by the complex morphology of this cell type. Purkinje neurons are notoriously difficult to isolate and maintain in culture presenting considerable difficultly to identify molecular changes in response to expanded CGG repeat (rCGG)-containing mRNA that induces neurotoxicity in FXTAS. Several studies have uncovered a number of RNA-binding proteins involved in translation that aberrantly interact with the CGG-containing RNA; however, whether these interactions alter the translational profile of cells has not been investigated. Here we employ bacTRAP translational profiling to demonstrate that Purkinje neurons ectopically expressing 90 CGG repeats exhibit a dramatic change in their translational profile even prior to the onset of rCGG-induced phenotypes. This approach identified ?500 transcripts that are differentially associated with ribosomes in r(CGG)90-expressing mice. Functional annotation cluster analysis revealed broad ontologies enriched in the r(CGG)90 list, including RNA binding and response to stress. Intriguingly, a transcript for the Tardbp gene, implicated in a number of other neurodegenerative disorders, exhibits altered association with ribosomes in the presence of r(CGG)90 repeats. We therefore tested and showed that reduced association of Tardbp mRNA with the ribosomes results in a loss of TDP-43 protein expression in r(CGG)90-expressing Purkinje neurons. Furthermore, we showed that TDP-43 could modulate the rCGG repeat-mediated toxicity in a Drosophila model that we developed previously. These findings together suggest that translational dysregulation may be an underlying mechanism of rCGG-induced neurotoxicity in FXTAS. PMID:24986919

Galloway, Jocelyn N; Shaw, Chad; Yu, Peng; Parghi, Deena; Poidevin, Mickael; Jin, Peng; Nelson, David L

2014-11-15

 
 
 
 
81

ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43  

Science.gov (United States)

Mitochondria and the endoplasmic reticulum (ER) form tight structural associations and these facilitate a number of cellular functions. However, the mechanisms by which regions of the ER become tethered to mitochondria are not properly known. Understanding these mechanisms is not just important for comprehending fundamental physiological processes but also for understanding pathogenic processes in some disease states. In particular, disruption to ER–mitochondria associations is linked to some neurodegenerative diseases. Here we show that the ER-resident protein VAPB interacts with the mitochondrial protein tyrosine phosphatase-interacting protein-51 (PTPIP51) to regulate ER–mitochondria associations. Moreover, we demonstrate that TDP-43, a protein pathologically linked to amyotrophic lateral sclerosis and fronto-temporal dementia perturbs ER–mitochondria interactions and that this is associated with disruption to the VAPB–PTPIP51 interaction and cellular Ca2+ homeostasis. Finally, we show that overexpression of TDP-43 leads to activation of glycogen synthase kinase-3? (GSK-3?) and that GSK-3? regulates the VAPB–PTPIP51 interaction. Our results describe a new pathogenic mechanism for TDP-43. PMID:24893131

Stoica, Radu; De Vos, Kurt J.; Paillusson, Sebastien; Mueller, Sarah; Sancho, Rosa M.; Lau, Kwok-Fai; Vizcay-Barrena, Gema; Lin, Wen-Lang; Xu, Ya-Fei; Lewis, Jada; Dickson, Dennis W.; Petrucelli, Leonard; Mitchell, Jacqueline C.; Shaw, Christopher E.; Miller, Christopher C. J.

2014-01-01

82

ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43  

Science.gov (United States)

Mitochondria and the endoplasmic reticulum (ER) form tight structural associations and these facilitate a number of cellular functions. However, the mechanisms by which regions of the ER become tethered to mitochondria are not properly known. Understanding these mechanisms is not just important for comprehending fundamental physiological processes but also for understanding pathogenic processes in some disease states. In particular, disruption to ER-mitochondria associations is linked to some neurodegenerative diseases. Here we show that the ER-resident protein VAPB interacts with the mitochondrial protein tyrosine phosphatase-interacting protein-51 (PTPIP51) to regulate ER-mitochondria associations. Moreover, we demonstrate that TDP-43, a protein pathologically linked to amyotrophic lateral sclerosis and fronto-temporal dementia perturbs ER-mitochondria interactions and that this is associated with disruption to the VAPB-PTPIP51 interaction and cellular Ca2+ homeostasis. Finally, we show that overexpression of TDP-43 leads to activation of glycogen synthase kinase-3? (GSK-3?) and that GSK-3? regulates the VAPB-PTPIP51 interaction. Our results describe a new pathogenic mechanism for TDP-43.

Stoica, Radu; de Vos, Kurt J.; Paillusson, Sébastien; Mueller, Sarah; Sancho, Rosa M.; Lau, Kwok-Fai; Vizcay-Barrena, Gema; Lin, Wen-Lang; Xu, Ya-Fei; Lewis, Jada; Dickson, Dennis W.; Petrucelli, Leonard; Mitchell, Jacqueline C.; Shaw, Christopher E.; Miller, Christopher C. J.

2014-06-01

83

Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs  

Digital Repository Infrastructure Vision for European Research (DRIVER)

FUS/TLS (fused in sarcoma/translocated in liposarcoma) and TDP-43 are integrally involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We found that FUS/TLS binds to RNAs from >5,500 genes in mouse and human brain, primarily through a GUGGU-binding motif. We identified a sawtooth-like binding pattern, consistent with co-transcriptional deposition of FUS/TLS. Depletion of FUS/TLS from the adult nervous system altered the levels or splicing of >950 mRNAs, most of which ar...

Lagier-tourenne, Clotilde; Polymenidou, Magdalini; Hutt, Kasey R.; Vu, Anthony Q.; Baughn, Michael; Huelga, Stephanie C.; Clutario, Kevin M.; Ling, Shuo-chien; Liang, Tiffany Y.; Mazur, Curt; Wancewicz, Edward; Kim, Aneeza S.; Watt, Andy; Freier, Sue; Hicks, Geoffrey G.

2012-01-01

84

The voltage-gated calcium channel blocker lomerizine is neuroprotective in motor neurons expressing mutant SOD1, but not TDP-43.  

Science.gov (United States)

Excitotoxicity and disruption of Ca(2+) homeostasis have been implicated in amyotrophic lateral sclerosis (ALS) and limiting Ca(2+) entry is protective in models of ALS caused by mutation of SOD1. Lomerizine, an antagonist of L- and T-type voltage-gated calcium channels and transient receptor potential channel 5 transient receptor potential channels, is well tolerated clinically, making it a potential therapeutic candidate. Lomerizine reduced glutamate excitotoxicity in cultured motor neurons by reducing the accumulation of cytoplasmic Ca(2+) and protected motor neurons against multiple measures of mutant SOD1 toxicity: Ca(2+) overload, impaired mitochondrial trafficking, mitochondrial fragmentation, formation of mutant SOD1 inclusions, and loss of viability. To assess the utility of lomerizine in other forms of ALS, calcium homeostasis was evaluated in culture models of disease because of mutations in the RNA-binding proteins transactive response DNA-binding protein 43 (TDP-43) and Fused in Sarcoma (FUS). Calcium did not play the same role in the toxicity of these mutant proteins as with mutant SOD1 and lomerizine failed to prevent cytoplasmic accumulation of mutant TDP-43, a hallmark of its pathology. These experiments point to differences in the pathogenic pathways between types of ALS and show the utility of primary culture models in comparing those mechanisms and effectiveness of therapeutic strategies. PMID:24716897

Tran, Luan T; Gentil, Benoit J; Sullivan, Kathleen E; Durham, Heather D

2014-08-01

85

C57BL/6J congenic Prp-TDP43A315T mice develop progressive neurodegeneration in the myenteric plexus of the colon without exhibiting key features of ALS.  

Science.gov (United States)

ALS therapy development has been hindered by the lack of rodent animal models. The discovery of TDP-43, a transcription factor that accumulates in the cytoplasm of motor neurons (MNs) in most cases of ALS, prompted attempts to develop TDP-43-based models of the disease. The current study sought to examine, in extensive detail, the emerging disease phenotype of a transgenic mouse model that overexpresses a mutant human TDP-43 (hTDP-43) gene under mouse prion promoter control. Careful attention was given to ALS-like characteristics to determine the appropriateness of this model for testing therapies for ALS. In light of previous reports that gastrointestinal (GI) dysfunction is responsible for early death in these mice, gut immunohistochemistry (IHC) and longitudinal gut motility assays were used to identify the onset and the progression of these defects. IHC studies revealed that site-specific overexpression of the hTDP-43 transgene in colonic myenteric plexes resulted in progressive neurodegeneration in this region. This change was associated with progressively reduced GI motility, culminating in frank stasis that was primarily responsible for decreasing longevity in these mice. The disease phenotype was gender- and genetic background-dependent, with congenic C57BL/6J male mice exhibiting the most aggressive form of the disease. Spinal cord IHC revealed ubiquitin-positive inclusions, but not TDP-43 aggregates, in the cytoplasm of MNs. Neither gender exhibited compelling ALS-like neuromuscular deficits, irrespective of age. While this model may be useful for studying GI tract neurodegeneration, in its present state it does not display a phenotype suitable for testing ALS therapeutics. This article is part of a Special Issue entitled RNA Metabolism 2013. PMID:24141148

Hatzipetros, Theo; Bogdanik, Laurent P; Tassinari, Valerie R; Kidd, Joshua D; Moreno, Andy J; Davis, Crystal; Osborne, Melissa; Austin, Andrew; Vieira, Fernando G; Lutz, Cathleen; Perrin, Steve

2014-10-10

86

Poly-A binding protein-1 localization to a subset of TDP-43 inclusions in amyotrophic lateral sclerosis occurs more frequently in patients harboring an expansion in C9orf72.  

Science.gov (United States)

Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease in which the loss of spinal cord motor neurons leads to paralysis and death within a few years of clinical disease onset. In almost all cases of ALS, transactive response DNA binding protein of 43 kDa (TDP-43) forms cytoplasmic neuronal inclusions. A second causative gene for a subset of ALS is fused in sarcoma, an RNA binding protein that also forms cytoplasmic inclusions in spinal cord motor neurons. Poly-A binding protein-1 (PABP-1) is a marker of stress granules (i.e. accumulations of proteins and RNA indicative of translational arrest in cells under stress). We report on the colocalization of PABP-1 to both TDP-43 and fused-in-sarcoma inclusions in 4 patient cohorts: ALS without a mutation, ALS with an intermediate polyglutamine repeat expansion in ATXN2, ALS with a GGGGCC hexanucleotide repeat expansion in C9orf72, and ALS with basophilic inclusion body disease. Notably, PABP-1 colocalization to TDP-43 was twice as frequent in ALS with C9orf72 expansions compared to ALS with no mutation. This study highlights PABP-1 as a protein that is important to the pathology of ALS and indicates that the proteomic profile of TDP-43 inclusions in ALS may differ depending on the causative genetic mutation. PMID:25111021

McGurk, Leeanne; Lee, Virginia M; Trojanowksi, John Q; Van Deerlin, Vivianna M; Lee, Edward B; Bonini, Nancy M

2014-09-01

87

A novel GRN mutation (GRN c.708+6_+9delTGAG) in frontotemporal lobar degeneration with TDP-43-positive inclusions: clinicopathologic report of 6 cases.  

Science.gov (United States)

Understanding of frontotemporal lobar degeneration, the underlying pathology most often linked to the clinical diagnosis of frontotemporal dementia, is rapidly increasing. Mutations in 7 known genes (MAPT, GRN, C9orf72, VCP, CHMP2B, and, rarely, TARDBP and FUS) are associated with frontotemporal dementia, and the pathologic classification of frontotemporal lobar degeneration has recently been modified to reflect these discoveries. Mutations in one of these genes (GRN), which encodes progranulin, have been implicated in up to a quarter of cases of frontotemporal lobar degeneration with TDP-43 (TAR DNA-binding protein 43)-positive inclusions; currently, there are more than 60 known pathogenic mutations of the gene. We present the clinical, pathologic, and genetic findings on 6 cases from 4 families, 5 of which were shown to have a novel GRN c.708+6_+9delTGAG mutation. PMID:24709683

Bit-Ivan, Esther N; Suh, Eunran; Shim, Hyung-Sub; Weintraub, Sandra; Hyman, Bradley T; Arnold, Steven E; McCarty-Wood, Elisabeth; Van Deerlin, Viviana M; Schneider, Julie A; Trojanowski, John Q; Frosch, Matthew P; Baker, Matt C; Rademakers, Rosa; Mesulam, Marsel; Bigio, Eileen H

2014-05-01

88

Pathological hallmarks of amyotrophic lateral sclerosis/frontotemporal lobar degeneration in transgenic mice produced with TDP-43 genomic fragments.  

Science.gov (United States)

Transactive response DNA-binding protein 43 ubiquitinated inclusions are a hallmark of amyotrophic lateral sclerosis and of frontotemporal lobar degeneration with ubiquitin-positive inclusions. Yet, mutations in TARDBP, the gene encoding these inclusions are associated with only 3% of sporadic and familial amyotrophic lateral sclerosis. Recent transgenic mouse studies have revealed a high degree of toxicity due to transactive response DNA-binding protein 43 proteins when overexpressed under the control of strong neuronal gene promoters, resulting in early paralysis and death, but without the presence of amyotrophic lateral sclerosis-like ubiquitinated transactive response DNA-binding protein 43-positive inclusions. To better mimic human amyotrophic lateral sclerosis, we generated transgenic mice that exhibit moderate and ubiquitous expression of transactive response DNA-binding protein 43 species using genomic fragments that encode wild-type human transactive response DNA-binding protein 43 or familial amyotrophic lateral sclerosis-linked mutant transactive response DNA-binding protein 43 (G348C) and (A315T). These novel transgenic mice develop many age-related pathological and biochemical changes reminiscent of human amyotrophic lateral sclerosis including ubiquitinated transactive response DNA-binding protein 43-positive inclusions, transactive response DNA-binding protein 43 cleavage fragments, intermediate filament abnormalities, axonopathy and neuroinflammation. All three transgenic mouse models (wild-type, G348C and A315T) exhibited impaired learning and memory capabilities during ageing, as well as motor dysfunction. Real-time imaging with the use of biophotonic transactive response DNA-binding protein 43 transgenic mice carrying a glial fibrillary acidic protein-luciferase reporter revealed that the behavioural defects were preceded by induction of astrogliosis, a finding consistent with a role for reactive astrocytes in amyotrophic lateral sclerosis pathogenesis. These novel transactive response DNA-binding protein 43 transgenic mice mimic several characteristics of human amyotrophic lateral sclerosis-frontotemporal lobar degeneration and they should provide valuable animal models for testing therapeutic approaches. PMID:21752789

Swarup, Vivek; Phaneuf, Daniel; Bareil, Christine; Robertson, Janice; Rouleau, Guy A; Kriz, Jasna; Julien, Jean-Pierre

2011-09-01

89

Abnormal distribution of heterogeneous nuclear ribonucleoproteins in sporadic inclusion body myositis.  

Science.gov (United States)

Previous histopathologic studies of sporadic inclusion body myositis (sIBM) identified sarcoplasmic aggregation and myonuclear depletion of the predominantly nuclear heterogeneous nuclear ribonucleoprotein (hnRNP) TDP-43 in sIBM myofibers. Here, we examined sIBM muscle for abnormalities in two other hnRNPs hnRNPA1 and hnRNPA2B1, mutations in which cause multisystem proteinopathy associated with rimmed-vacuolar myopathies. Muscle biopsy specimens from 13 patients with sIBM and 13 patients without sIBM (dermatomyositis N=3, polymyositis N=3, muscular dystrophy N=3, motor neuron disease N=2, non-neuromuscular disease N=2) underwent immunohistochemistry for hnRNPA1, hnRNPA2B1, and TDP-43. Muscle transcriptional microarray data from 27 patients with sIBM and 12 patients without neuromuscular disease was analyzed. Depletion of hnRNPA1 and hnRNPA2B1 was present in 15% and 7% of sIBM myonuclei, respectively, compared with 1% and 0% of myonuclei in non-sIBM muscle. Sarcoplasmic aggregates of hnRNPA1 and hnRNPA2B1 distinct from TDP-43 aggregates were also found in sIBM. hnRNPA1 and hnRNPA2B1, as well as other hnRNPs, gene expression was unaltered in sIBM compared to normal muscle. Along with TDP-43, other hnRNPs, including hnRNPA1 and hnRNPA2B1, are depleted from sIBM myonuclei at the protein but not transcript level. The depletion of multiple hnRNPs from sIBM myonuclei together with their sarcoplasmic aggregation suggests that one aspect of sIBM pathophysiology may involve abnormal RNA metabolism that includes hyperassembly of ribonucleoprotein granules mediated by prion-like domains in hnRNPs, evolving into pathological aggregates. PMID:24857366

Pinkus, Jack L; Amato, Anthony A; Taylor, J Paul; Greenberg, Steven A

2014-07-01

90

Abnormal serine phosphorylation of insulin receptor substrate 1 is associated with tau pathology in Alzheimer's disease and tauopathies.  

Science.gov (United States)

Neuronal insulin signaling abnormalities have been associated with Alzheimer's disease (AD). However, the specificity of this association and its underlying mechanisms have been unclear. This study investigated the expression of abnormal serine phosphorylation of insulin receptor substrate 1 (IRS1) in 157 human brain autopsy cases that included AD, tauopathies, ?-synucleinopathies, TDP-43 proteinopathies, and normal aging. IRS1-pS(616), IRS1-pS(312) and downstream target Akt-pS(473) measures were most elevated in AD but were also significantly increased in the tauopathies: Pick's disease, corticobasal degeneration and progressive supranuclear palsy. Double immunofluorescence labeling showed frequent co-expression of IRS1-pS(616) with pathologic tau in neurons and dystrophic neurites. To further investigate an association between tau and abnormal serine phosphorylation of IRS1, we examined the presence of abnormal IRS1-pS(616) expression in pathological tau-expressing transgenic mice and demonstrated that abnormal IRS1-pS(616) frequently co-localizes in tangle-bearing neurons. Conversely, we observed increased levels of hyperphosphorylated tau in the high-fat diet-fed mouse, a model of insulin resistance. These results provide confirmation and specificity that abnormal phosphorylation of IRS1 is a pathological feature of AD and other tauopathies, and provide support for an association between insulin resistance and abnormal tau as well as amyloid-?. PMID:25107476

Yarchoan, Mark; Toledo, Jon B; Lee, Edward B; Arvanitakis, Zoe; Kazi, Hala; Han, Li-Ying; Louneva, Natalia; Lee, Virginia M-Y; Kim, Sangwon F; Trojanowski, John Q; Arnold, Steven E

2014-11-01

91

Congenital Abnormalities  

Science.gov (United States)

... to the next. Twenty-three come from the father; twenty-three come from the mother. The genes ... develop serious health problems (e.g. Down syndrome ). Single-Gene Abnormalities Sometimes the chromosomes are normal in ...

92

Endogenous TDP-43, but not FUS, contributes to stress granule assembly via G3BP  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective loss of upper and lower motor neurons, a cell type that is intrinsically more vulnerable than other cell types to exogenous stress. The interplay between genetic susceptibility and environmental exposures to toxins has long been thought to be relevant to ALS. One cellular mechanism to overcome stress is the formation of small dense cytoplasmic domains called stress granul...

Aulas Anaďs; Stabile Stéphanie; Vande Velde Christine

2012-01-01

93

Nuclear TAR DNA-binding protein 43: A new target for amyotrophic lateral sclerosis treatment.  

Science.gov (United States)

Abnormal TAR DNA-binding protein 43 (TDP-43) inclusion bodies can be detected in the degenerative neurons of amyotrophic lateral sclerosis. In this study, we induced chronic oxidative stress injury by applying malonate to cultured mouse cortical motor neurons. In the later stages of the malonate insult, TDP-43 expression reduced in the nuclei and transferred to the cytoplasm. This was accompanied by neuronal death, mimicking the pathological changes in TDP-43 that are seen in patients with amyotrophic lateral sclerosis. Interestingly, in the early stages of the response to malonate treatment, nuclear TDP-43 expression increased, and neurons remained relatively intact, without inclusion bodies or fragmentation. Therefore, we hypothesized that the increase of nuclear TDP-43 expression might be a pro-survival factor against oxidative stress injury. This hypothesis was confirmed by an in vitro transgenic experiment, in which overexpression of wild type mouse TDP-43 in cultured cortical motor neurons significantly reduced malonate-induced neuronal death. Our findings suggest that the loss of function of TDP-43 is an important cause of neuronal degeneration, and upregulation of nuclear TDP-43 expression might be neuroprotective in amyotrophic lateral sclerosis. PMID:25206650

Zheng, Mei; Shi, Yujie; Fan, Dongsheng

2013-12-15

94

Polyamine-like immunoreactivity in rat neurons.  

Science.gov (United States)

The localization of polyamine (PA) pools in motor, sensory, and autonomic neurons and in the nerve cells of the hypothalamo-hypophysial system of rats was examined by immunocytochemical method using the monoclonal antibody ASPM-29 specific to spermine (Spm) and spermidine (Spd) fixed in situ. Strong PA immunoreactivity was found in the cytoplasm and dendrites of the large perikaryon of motor neurons in the anterior spinal column, in the Purkinje cells of the cerebellum, in the pyramidal cells of the cerebrum, in the nerve cells of the paraventricular and supraoptic nuclei in the hypothalamus, and in the nerve cells of the spinal and autonomic ganglions. No PA immunoreactivity was seen in the nucleus and nerve terminals of the neurons. The PA immunoreactivities in the motor and sensory neurons were characterized by clustered masses and blocks of immunoreactive cells. Irrespective of location, small and medium-sized neurons were weakly PA-positive. The glia cells, some stellite cells, and Schwann cells were almost completely PA-negative. These results may suggest that in neurons PAs are not transported axonally, but are located in conjunction with Nissl bodies (the rough endoplasmic reticulum), specified as sites for protein synthesis within cells. PMID:9365032

Fujiwara, K; Bai, G; Kitagawa, T

1997-08-29

95

Effects of Static Magnetic Field on Growth of Leptospire, Leptospira interrogans serovar canicola: Immunoreactivity and Cell Division  

CERN Document Server

The effects of the exposure of the bacterium, Leptospira interrogans serovar canicola to a constant magnetic field with magnetic flux density from a permanent ferrite magnet = 140 mT were studied. Changes in Leptospira cells after their exposure to the field were determined on the basis of changes in their growth behavior and agglutination immunoreactivity with a homologous antiserum using darkfield microscopy together with visual imaging. The data showed that the exposed Leptospira cells have lower densities and lower agglutination immunoreactivity than the unexposed control group. Interestingly, some of the exposed Leptospira cells showed abnormal morphologies such as large lengths. We discussed some of the possible reasons for these observations.

Triampo, W; Triampo, D; Wong-Ekkabut, J; Tang, I M; Triampo, Wannapong; Doungchawee, Galayanee; Triampo, Darapond; Wong-Ekkabut, Jirasak

2004-01-01

96

21 CFR 862.1405 - Immunoreactive insulin test system.  

Science.gov (United States)

...serum and plasma. Immunoreactive insulin measurements are used in the diagnosis and treatment of various carbohydrate metabolism disorders, including diabetes mellitus, and hypoglycemia. (b) Classification. Class I (general...

2010-04-01

97

Wobbler mice modeling motor neuron disease display elevated transactive response DNA binding protein.  

Science.gov (United States)

Wobbler mice model motor neuron disease with a substantial decline in motor neurons. TDP-43 is a nucleic acid binding protein that accumulates, along with ubiquitin, in the cytoplasm of amyotrophic lateral sclerosis (ALS) motor neurons. Recently, it was reported that Cu/Zn superoxide dismutase type 1 (SOD1) familial amyotrophic lateral sclerosis (fALS) model mice do not mimic the TDP-43 changes seen in sporadic ALS, although they share a large number of other properties with the human disorder. We examined ubiquitin inclusions and TDP-43 expression in wobbler mice. TDP-43 mRNA, measured by quantitative reverse transcription-coupled PCR, was elevated in the wobbler spinal cord. Immunohistochemistry revealed intracellular ubiquitin inclusions and abnormal distribution of TDP-43 into the cytoplasm in wobblers similar to the staining reported in ALS. Finally, nuclear and cytoplasmic fractions, examined by Western immunoblotting, confirmed a delocalization of TDP-43 in the neurodegenerative wobbler. These observations indicate that wobbler mice, which suffer motor neuron loss at 21 days, undergo TDP-43 and ubiquitin changes characteristic of sporadic ALS. PMID:19013502

Dennis, J S; Citron, B A

2009-01-23

98

Immunoreactive trypsin and neonatalscreening for cystic fibrosis  

Energy Technology Data Exchange (ETDEWEB)

Immunoreactive trypsin (IRT) was measured in dried blood spots from 160.822 five-day-old babies as a part of a regionwide neonatal screening program for cystic fibrosis. A second test was performed for 492 babies in whom blood IRT levels were found greater than 900 ..mu..g/l; retesting revealed persistent elevation in 55. Sweat testing confirmed cystic fibrosis in 43 babies, but results were normal in 12. During the course of this study, a total of 51 cystic fibrosis babies were identified: 43 by newborn screening, 6 because they had meconium ileus; so, early diagnosis was achieved in 49 cases out of 51. Two newborn babies did not have elevated IRT and they were missed by the screening test. Our results confirm that elevated blood IRT is characteristic of newborn babies with cystic fibrosis and show that this test has an excellent specificity (99.7%) and a good sensitivity (95%) when used as a neonatal screening test.

Travert, G.; Laroche, D.; Blandin, C.; Pasquet, C.

1988-01-01

99

Immunoreactive trypsin and neonatalscreening for cystic fibrosis  

International Nuclear Information System (INIS)

Immunoreactive trypsin (IRT) was measured in dried blood spots from 160.822 five-day-old babies as a part of a regionwide neonatal screening program for cystic fibrosis. A second test was performed for 492 babies in whom blood IRT levels were found greater than 900 ?g/l; retesting revealed persistent elevation in 55. Sweat testing confirmed cystic fibrosis in 43 babies, but results were normal in 12. During the course of this study, a total of 51 cystic fibrosis babies were identified: 43 by newborn screening, 6 because they had meconium ileus; so, early diagnosis was achieved in 49 cases out of 51. Two newborn babies did not have elevated IRT and they were missed by the screening test. Our results confirm that elevated blood IRT is characteristic of newborn babies with cystic fibrosis and show that this test has an excellent specificity (99.7%) and a good sensitivity (95%) when used as a neonatal screening test

100

Determination of immunoreactive proteins of Babesia ovis.  

Science.gov (United States)

Babesia ovis, an intraerythrocytic protozoan parasite transmitted by ticks, causes severe infections in sheep in tropical and subtropical regions of the world. Parasite-specific immunoreactive proteins have been used as antigen in the serological diagnosis of babesiosis. There is no study about determination of B. ovis-specific proteins in sheep. This study was planned to determine the immunoreactive proteins of B. ovis. In this study, two splenectomized lambs, and twelve seropositive sheep and five seronegative lambs for anti-B. ovis antibodies were used as materials. Infected blood samples at 5% of parasitemia from the two splenectomized lambs experimentally infected with a virulent B. ovis field strain were analyzed for B. ovis-specific proteins by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting (WB). B. ovis-specific five major proteins were recognized by anti-B. ovis serum but not by healthy sheep serum. They were of approximate molecular weights 154, 109, 77, 58, and 38 kDa. As the control samples, protein profiles of the blood extracts of two lambs before splenectomy operation were also blotted with the immune sera, but none of the five proteins was detected. These proteins were also immunoblotted with heterologous positive and negative sheep sera. All of twelve positive sera recognized the 109 kDa protein with 100 percent sensitivity. The 77 kDa protein reacted in 11 of 12 sera (91.6%). The sensitivities of the other 3 proteins ranged between 83.3% and 25%. The five protein bands immunoblotted with sera of the 5 negative lambs did not give any positive reaction. The results of this study revealed the presence of proteins recognized by the serum antibodies of experimentally and naturally infected sheep with B. ovis. Additional studies on the purification of these proteins and on subsequently their utilization in a serodiagnostic method are required to improve the serological diagnosis of ovine babesiosis. PMID:24209710

Sevinc, Ferda; Guler, Leyla; Sevinc, Mutlu; Ekici, Ozlem Derinbay; Isik, Nermin

2013-12-01

 
 
 
 
101

FMRFamide-like immunoreactivity in the nervous system of Hydra  

DEFF Research Database (Denmark)

FMRFamide-like immunoreactivity has been localized in different parts of the hydra nervous system. Immunoreactivity occurs in nerve perikarya and processes in the ectoderm of the lower peduncle region near the basal disk, in the ectoderm of the hypostome and in the ectoderm of the tentacles. The immunoreactive nerve perikarya in the lower peduncle region form ganglion-like structures. Radioimmunoassays of extracts of hydra gave displacement curves parallel to standard FMRFamide and values of at least 8 pmol/gram wet weight of FMRFamide-like immunoreactivity. The immunoreactive material eluted from Sephadex G-50 in several components emerging shortly before or after position of authentic FMRFamide. The presence of FMRFamide-like material in coelenterates shows that this family of peptides is of great antiquity.

Grimmelikhuijzen, C J; Dockray, G J

1982-01-01

102

Immunoreactivity assay for {alpha}-particle emitting monoclonal antibody constructs  

Energy Technology Data Exchange (ETDEWEB)

Clinical trials using {alpha}-particle radiolabeled antibodies require a rapid and reproducible assay of the immunoreactivity of drugs. While live cell assays are typically used to determine the immunoreactive drug fraction, a fixed cell assay may replace the traditional live cell assay and offer the advantages of rapidity, easy availability and consistency for qualifying drugs for preclinical or clinical studies. We have identified optimal cell fixation and immunoreactivity assay conditions and have validated them by performing the fixed-cell assay in clinical trials.

Bonavia, Anthony S. [Molecular Pharmacology and Chemistry Department, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021 (United States)]. E-mail: asb2592@yahoo.com; McDevitt, Michael R. [Molecular Pharmacology and Chemistry Department, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021 (United States); Curcio, Michael J. [Molecular Pharmacology and Chemistry Department, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021 (United States); Scheinberg, David A. [Molecular Pharmacology and Chemistry Department, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021 (United States)]. E-mail: d-scheinberg@ski.mskcc.org

2006-04-15

103

Bombesin-like immunoreactivity in the nervous system of hydra  

DEFF Research Database (Denmark)

With immunocytochemical methods, nerve cells have been detected in Hydra attenuata containing bombesin-like immunoreactivity. These nerve cells are located in ectoderm of all body regions of the animal and are especially abundant in basal disk and tentacles. Radioimmunoassay of extracts of hydra demonstrated at least 0.2 pmol/g wet weight of bombesin-like immunoreactivity. The immunoreactive material elutes from Sephadex G-50 in a similar position to synthetic bombesin. The data show that bombesin-like peptides are among the phylogenetically oldest neuropeptides found so far.

Grimmelikhuijzen, C J; Dockray, G J

1981-01-01

104

Aspartate immunoreactivity in the telencephalon of the adult sea lamprey: comparison with GABA immunoreactivity.  

Science.gov (United States)

The excitatory amino acid l-aspartate (Asp) plays a number of roles in neuronal function. We studied the distribution of Asp-immunoreactive (ir) cells in the telencephalon of young and upstream migrating adult sea lamprey, Petromyzon marinus, and compared it with the distribution of gamma-aminobutyric acid (GABA) immunoreactivity, by using double immunofluorescence methods. Our results reveal for the first time the existence of Asp-ir neuronal populations in the lamprey forebrain. In the olfactory bulbs, Asp-ir neurons were observed in the mitral cell layer and in the inner cellular layer. Many granule-like cells were both Asp-ir and GABA-ir. In the pallium, Asp-ir cells were abundant in the lateral pallium and most of them were also GABA-ir. In the septum/terminal lamina nucleus, some cerebrospinal fluid-contacting type (CSF-c) cells were either Asp-ir or GABA-ir, and a few were double-labeled. Some non-CSF-c septal cells were both Asp-ir and GABA-ir. In the striatum, Asp-ir and/or GABA-ir cells were either subependymal or located in the characteristic arched cell row. In the lateral preoptic region, a few small Asp-ir/GABA-ir neurons were observed. In the caudal preoptic recess nucleus, numerous CSF-c cells were Asp-ir and/or GABA-ir. This study also reveals that colocalization of GABA and Asp immunoreactivities in telencephalic neurons is partial. Further investigation is required to establish whether Asp is a neurotransmitter and/or an intermediate in GABA synthesis in lamprey telencephalon. PMID:18331879

Villar-Cervińo, Verona; Barreiro-Iglesias, Antón; Anadón, Ramón; Rodicio, María Celina

2008-03-18

105

Developmental analysis of GFAP immunoreactivity in the cerebellum of the meander tail mutant mouse.  

Science.gov (United States)

It is thought that Bergmann glial fibers assist in the inward migration of granule cells. Model systems in which there is a perturbation of either the migrating cells or the glial cell population have been useful in understanding the migratory process. In the meander tail mutant mouse, the anterior cerebellar region is agranular, whereas the posterior cerebellum is relatively unaffected by the mutation. This study presents a qualitative analysis of the development of cerebellar radial glia in mea/mea and +/mea mice aged from postnatal day 0 to adult, using an antibody against the glia specific antigen, glial fibrillary acidic protein. The results indicate a slight delay in the onset of immunoreactivity in the mea/mea cerebellum and abnormal glial formation in the anterior and posterior regions by postnatal day 5. At postnatal day 11, the full complement of labeled fibers appears to be present and although they appear abnormal in formation, they eventually reach the surface and terminate in oddly shaped and irregularly spaced endfeet. In adult mea/mea and +/mea mice, as compared to the early postnatal stages, there is a significant reduction in GFAP immunoreactive fibers. Cresyl violet stained adult mea/mea sections revealed the presence of ectopic granule cells in radial columns and small clumps at the surface of and within the molecular layer of the caudal cerebellum. Quantitative analyses revealed a 4- to 5-fold increase in the number of ectopic granule cells in lobule VIII of the mea/mea when compared with the +/mea cerebellum. These results suggest that the radial glia in the mea/mea cerebellum exhibit some uncharacteristic morphologies, but that these abnormalities are most likely the consequence of environmental alterations produced by the mutant gene. PMID:8827322

Grishkat, H L; Schwartz, E; Jain, G; Eisenman, L M

1996-08-01

106

Effects of static magnetic field on growth of leptospire, Leptospira interrogans serovar canicola: immunoreactivity and cell division.  

Science.gov (United States)

The effects of the exposure of the bacterium, Leptospira interrogans serovar canicola to a constant magnetic field with magnetic flux density from a permanent ferrite magnet=140+/-5 mT were studied. Changes in Leptospira cells after their exposure to the field were determined on the basis of changes in their growth behavior and agglutination immunoreactivity with a homologous antiserum using dark-field microscopy together with visual imaging. The data showed that the exposed Leptospira cells have lower densities and lower agglutination immunoreactivity than the unexposed control group. Interestingly, some of the exposed Leptospira cells showed abnormal morphologies such as large lengths. We discussed some of the possible reasons for these observations. PMID:16233687

Triampo, Wannapong; Doungchawee, Galayanee; Triampo, Darapond; Wong-Ekkabut, Jirasak; Tang, I-Ming

2004-01-01

107

Effect of electroconvulsive therapy on serum myelin basic protein immunoreactivity.  

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A sensitive radioimmunoassay that can detect brain damage in cases of head injury and stroke was applied to blood samples from 13 patients before and after they received multiple treatments with electroconvulsive therapy for psychiatric disorder. None of the patients showed a significant increase in serum myelin basic protein immunoreactivity. As increased serum myelin basic protein immunoreactivity may reflect myelin damage it is apparent that in these patients electroconvulsive therapy did ...

Hoyle, N. R.; Pratt, R. T.; Thomas, D. G.

1984-01-01

108

DCLK1 immunoreactivity in colorectal neoplasia  

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Full Text Available Giuseppe Gagliardi1, Monica Goswami1, Roberto Passera2, Charles F Bellows11Department of Surgery and Pathology, Tulane University, New Orleans, LA, USA; 2Division of Nuclear Medicine Azienda Ospedaliero-Universitaria San Giovanni Battista, Turin, ItalyIntroduction: Microtubule-associated doublecortin and CaM kinase-like-1 (DCLK1 is a novel candidate marker for intestinal stem cells. The aim of our study was to assess DCLK1 immunoreactivity in colorectal carcinogenesis and its correlation with prognosis.Methods: DCLK1 immunostaining was performed in colorectal tissue from 71 patients, including 18 adenomatous polyps, 40 primary adenocarcinomas, and 14 metastatic lesions. Each case was evaluated by a combined scoring method based on the intensity of staining (score 0–3 and the percentage of tissue staining positive (score 0–3. Immunoexpression for DCLK1 was considered as positive when the combined score was 2–6 and negative with a score of 0–1.Results: Overall, 14/18 (78% of polyps, 30/40 (75% of primary adenocarcinomas, and 7/14 (50% of distant metastases were positive for DCLK1. In adenomatous polyps and primary cancer there was no association between DCLK1 staining score and tumor pathology. However, after curative colorectal cancer resection, patients whose tumor had a high (?5 combined staining score had increased cancer-specific mortality compared to patients with low (0–4 staining score (hazard ratio 5.89; 95% confidence interval: 1.22–28.47; P = 0.027.Conclusion: We found that DCLK1 is frequently expressed in colorectal neoplasia and may be associated with poor prognosis. Further studies are necessary to validate the use of DCLK1 as a prognostic marker.Keywords: DCLK1, DCAMKL-1, gastrointestinal stem cell, cancer stem cell, adenomatous polyps, liver metastasis, immunohistochemistry

Bellows CF

2012-04-01

109

Rapid renal clearance of immunoreactive canine plasma myoglobin  

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Rates and mechanisms of myoglobin removal from plasma were examined in closed-chest dogs, using disappearance patterns of immunoreactivity and radioactivity after i.v. canine myoglobin radiolabeled with 125I. Arterial immunoreactive myoglobin concentration decreased monoexponentially over a 2-decade range, with rate constants of disappearance averaging -0.080 +/- 0.014 min-1 (+/- SD). Renal arteriovenous difference in immunoreactive myoglobin concentration documented extraction of the parent molecule, with extraction ratios averaging 0.36 +/- 0.06. Renal venous specific activity increased a few minutes after myoglobin administration, consistent with discharge from the kidney of nonimmunoreactive radiolabeled peptides of the parent molecule. Arterial disappearance of 125I was subsequently delayed in relation to immunoreactive myoglobin. Urinary recoveries of immunoreactive parent molecule and radiolabeled constituents were limited, averaging 2.5 +/- 1.1% and 12 +/- 1.1% over a 6-hour period. Arterial rate, constants of disappearance of immunoreactive myoglobin decreased markedly with decreases in renal perfusion produced by obstruction of renal arterial inflow. Researchers conclude that myoglobin entering the vascular space is normally cleared rapidly by renal catabolism. Seven myoglobin concentration-time patterns during acute myocardial infarction directly reflect patterns of protein entry into the vascular space after release from injured tissue.

Klocke, F.J.; Copley, D.P.; Krawczyk, J.A.; Reichlin, M.

1982-06-01

110

Rapid renal clearance of immunoreactive canine plasma myoglobin  

International Nuclear Information System (INIS)

Rates and mechanisms of myoglobin removal from plasma were examined in closed-chest dogs, using disappearance patterns of immunoreactivity and radioactivity after i.v. canine myoglobin radiolabeled with 125I. Arterial immunoreactive myoglobin concentration decreased monoexponentially over a 2-decade range, with rate constants of disappearance averaging -0.080 +/- 0.014 min-1 (+/- SD). Renal arteriovenous difference in immunoreactive myoglobin concentration documented extraction of the parent molecule, with extraction ratios averaging 0.36 +/- 0.06. Renal venous specific activity increased a few minutes after myoglobin administration, consistent with discharge from the kidney of nonimmunoreactive radiolabeled peptides of the parent molecule. Arterial disappearance of 125I was subsequently delayed in relation to immunoreactive myoglobin. Urinary recoveries of immunoreactive parent molecule and radiolabeled constituents were limited, averaging 2.5 +/- 1.1% and 12 +/- 1.1% over a 6-hour period. Arterial rate, constants of disappearance of immunoreactive myoglobin decreased markedly with decreases in renal perfusion produced by obstruction of renal arterial inflow. Researchers conclude that myoglobin entering the vascular space is normally cleared rapidly by renal catabolism. Seven myoglobin concentration-time patterns during acute myocardial infarction directly reflect patterns of protein entry into the vascular space after release from injured tissue

111

Alveolar capillary dysplasia: absence of CD117 immunoreactivity of putative hemangioblast precursor cells.  

Science.gov (United States)

Alveolar capillary dysplasia is a rare cause of irreversible persistent pulmonary hypertension in newborns resulting from failure of formation of peripheral capillary loops with consequent reduction in the blood-gas barrier. The basic defect in morphogenesis is unknown, although it is postulated that there is a structural abnormality of the hemangioblast precursors of the primitive lung mesenchyme in the septal regions of the developing lung leading to abnormal vasculogenesis. Two cases of alveolar capillary dysplasia evaluated immunohistochemically showed uniform CD117 negativity in the septal interstitial cells forming the pulmonary capillaries. A series of 12 control cases showed positive immunoreactivity for CD117 in a subset of septal interstitial cells forming the putative hemangioblast precursor cells. This novel finding is a useful adjunctive diagnostic tool and may support the hypothesis that absence of putative CD117-positive hemangioblast precursor cells is a key structural defect. This defect results in abnormal vasculogenesis and consequent failure of formation of an adequate blood-gas barrier. PMID:18633766

Chang, Kenneth Tou En; Rajadurai, Victor Samuel; Walford, Norman Q; Hwang, Wei-Sek

2008-01-01

112

Expression of neuron-specific enolase immunoreactivity by cutaneous and extracutaneous Langerhans-cell histiocytoses ("X").  

Science.gov (United States)

The immunohistochemical expression of Neuron-Specific Enolase (NSE) and of S100 protein was studied in 10 cases of cutaneous and 19 cases of extracutaneous Langerhans cell histiocytoses (LCH), including acute/proliferative forms (cutaneous Letterer-Siwe disease) and chronic/granulomatous forms (eosinophilic granuloma, Hand-Schüller-Christian disease). Of the LCH cases, 18 (62%) exhibited detectable NSE-immunoreactivity as compared to 82.8% for S100. NSE expression was found more frequently and intensely within acute (as compared to chronic) forms of LCH. This result lends further support to the cellular unicity of LCH, but also suggests some degree of heterogeneity among LCH cells. It can be speculated that NSE-expression is correlated with the proliferation/activation state of (abnormal) Langerhans cells. PMID:1293186

Roca-Miralles, M; Kanitakis, J; Béjui-Thivolet, F; Schmitt, D; Castels-Rodellas, A; Thivolet, J

1992-12-01

113

Mechanism of action of cysteamine in depleting prolactin immunoreactivity  

International Nuclear Information System (INIS)

The thiol reagent cysteamine (CSH) depletes anterior pituitary cells of immunoreactive PRL both in vivo and in vitro. The authors examined the hypothesis that CSH affects either the solubility or immunoreactivity of PRL through a mechanism involving thiol-disulfide exchange. Adult female rats were treated with either CSH (300 mg/kg, sc) or an equimolar dose of ethanolamine as a control. Anterior pituitary glands were extracted in 0.1 M sodium borate buffer, pH 9.0. Treatment of pituitary extracts with beta-mercaptoethanol (BME) destroys the immunoreactivity of PRL. However, extraction in the presence of reduced glutathione or CSH of pituitaries of rats treated with CSH restores immunoreactive PRL to control levels. Extracts were also subjected to polyacrylamide gel electrophoresis (PAGE). On gels of pituitary extracts of CSH-treated rats, the band that comigrates with purified PRL is diminished compared to that in ethanolamine-treated controls. However, extraction of the pituitaries in sodium dodecyl sulfate-containing buffer followed by chemical reduction with BME restores the PRL band. Therefore, CSH acts on PRL through a thiol-related mechanism to yield a product that is poorly soluble in aqueous buffer at pH 9 and is poorly immunoreactive. Dispersed anterior pituitary cells in tissue culture were incubated with L-[35S]methionine to radiolabel newly synthesized peptides. PAGE followed by autoradiography confirmed the above results obtained in vivo the above results obtained in vivo

114

Novel neuritic clusters with accumulations of amyloid precursor protein and amyloid precursor-like protein 2 immunoreactivity in brain regions damaged by thiamine deficiency.  

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Experimental thiamine deficiency (TD) is a classical model of a nutritional deficit associated with a generalized impairment of oxidative metabolism and selective cell loss in the brain. In rats, TD-induced cell degeneration is accompanied by an accumulation of amyloid precursor protein (APP)/amyloid precursor-like protein 2 (APLP2) immunoreactivity in abnormal neurites and perikarya along the periphery of, or scattered within, the lesion. Prompted by these data and our previous findings of a...

Calingasan, N. Y.; Gandy, S. E.; Baker, H.; Sheu, K. F.; Smith, J. D.; Lamb, B. T.; Gearhart, J. D.; Buxbaum, J. D.; Harper, C.; Selkoe, D. J.; Price, D. L.; Sisodia, S. S.; Gibson, G. E.

1996-01-01

115

Substance P-like immunoreactivity in sympathetic ganglion from toad.  

Science.gov (United States)

Substance P-like immunoreactivity cellular in toad sympathetic ganglia was studied in normal and capsaicin-treated ganglia. In the eighth sympathetic ganglion substance P-like immunoreactive are found in mast cells and SIF cells. The effect of substance P (0.001-0.003 mM) caused increase of compound action potential during tetanical stimulation (50 Hz by 40 sec.) and post-tetanic potentiation (0.1 Hz). Our results show that substance P facilitates synaptic transmission in the sympathetic ganglia from Caudiverbera caudiverbera. PMID:2476215

Montoya, G A; Villena, F; Jofre, A; Pezo, A A

1989-01-01

116

Urine - abnormal color  

Science.gov (United States)

The usual color of urine is straw-yellow. Abnormally colored urine may be cloudy, dark, or blood-colored. ... Abnormal urine color may be caused by infection, disease, medicines, or food you eat. Cloudy or milky urine is a sign ...

117

Somatostatin-like immunoreactive cells in the ground squirrel retina.  

Science.gov (United States)

Immunocytochemical techniques were employed to locate somatostatin (SS)-containing cells in the retina of the 13-lined ground squirrel (Spermophilus tridecemlineatus). In normal retinas immunostain was limited to neuronal processes, yet distinctly labeled somata were detected in retinas of animals pretreated with colchicine. Labeled cell bodies were located in the outermost and innermost portions of the inner nuclear layer (INL) and in the ganglion cell layer (GCL). The largest population of SS-like immunoreactive neurons was found in the innermost INL. These cells were identified as small and medium sized amacrine cells whose soma diameters ranged from 4 to 14 microns. A smaller population of immunoreactive cells was observed in the outermost region of the INL. These cells, presumptive horizontal cells, were found mainly in peripheral regions of the retina. Immunoreactive cells in the GCL were of two types: displaced amacrines, and retinal ganglion cells. SS-positive axons in the optic fiber layer suggest that some of the immunoreactive GCL neurons were ganglion cells, and it is our opinion that these cells belong to a class of associational ganglion cells previously identified in other species. PMID:9313344

Lugo, N; Blanco, R E

1997-07-01

118

A novel TARDBP insertion/deletion mutation in the flail arm variant of amyotrophic lateral sclerosis.  

Science.gov (United States)

Phenotypic variation in amyotrophic lateral sclerosis (ALS) is common, and one atypical form is the flail arm variant (FAV). Some classic ALS patients carry TARDBP mutations, and so we sought to establish whether TARDBP mutations are also present in the FAV of ALS. Mutation analysis of TARDBP, the gene encoding TDP-43, was performed in cohorts of classic and FAV ALS patients. An analysis of mutation effects was performed in patient fibroblasts. Results showed that a novel heterozygous in-frame insertion/deletion (indel), c.1158_1159delAT; c.1158_1159insCACCAACC, was identified in a highly conserved region encoding the glycine-rich area of TDP-43 in a patient with FAV. This indel was confirmed in the proband's mother, an obligate carrier, and was absent from 480 ethnically-matched control individuals. Transcription of the mutant allele was confirmed. Under induced stress, indel-mutant fibroblasts showed a loss of normal nuclear TDP-43 immunoreactivity and formation of cytoplasmic inclusions of TDP-43, consistent with features seen in affected neurons. In conclusion, TARDBP missense mutations have previously been reported in classic ALS and frontotemporal lobar degeneration. The identification of a TARDBP indel mutation in a patient with FAV extends the spectrum of mutations and further supports the role of TDP-43 in a range of neurodegenerative phenotypes. PMID:22424122

Solski, Jennifer A; Yang, Shu; Nicholson, Garth A; Luquin, Natasha; Williams, Kelly L; Fernando, Ruvini; Pamphlett, Roger; Blair, Ian P

2012-09-01

119

Immunoreactive atrial natriuretic factor (IR-ANF) in human plasma.  

Science.gov (United States)

A direct radioimmunoassay for ANF in human plasma was developed. A synthetic alpha-human atrial peptide (Ser 99-Tyr 126) was used for preparation of the iodinated tracer and the standards. The sensitivity of the method is 1.9 pg/ml. Concentration of immunoreactive ANF (IR-ANF) in plasma of 59 clinically normal subjects was 65.3 +/- 2.5 pg/ml (mean +/- SE). In two patients who underwent atrial pacing an increase of about 100 percent in circulating IR-ANF was observed. IR-ANF was extracted from human plasma by Vycor glass and purified by HPLC. The main immunoreactive isolated peak contained a low molecular weight peptide. PMID:3159387

Gutkowska, J; Bourassa, M; Roy, D; Thibault, G; Garcia, R; Cantin, M; Genest, J

1985-05-16

120

Catestatin-like immunoreactivity in the rat eye.  

Science.gov (United States)

The aim of the study was to investigate the presence and distribution of the chromogranin A-derived peptide catestatin in the rat eye and trigeminal ganglion by immunofluorescence using an antibody which recognizes not only free catestatin but also larger fragments containing the sequence of catestatin. Western blots were performed in an attempt to characterize the immunoreactivities detected by the catestatin antiserum. Sparse immunoreactive nerve fibers were visualized in the corneal stroma, in the chamber angle, in the sphincter muscle but also in association with the dilator muscle, in the stroma of the ciliary body and processes, but dense in the irideal stroma, around blood vessels at the limbus and in the choroid and in cells of the innermost retina representing amacrine cells as identified by colocalization with substance P. Furthermore, catestatin-immunoreactivity was detected in the trigeminal ganglion in small to medium-sized cells and there were abundant catestatin-positive nerve fibers stained throughout the stroma of the ganglion. Double immunofluorescence of catestatin with substance P revealed colocalization both in cells of the trigeminal ganglion as well as in nerve fibers in the choroid. The immunoreactivities are present obviously as free catestatin and/or small-sized catestatin-containing fragments in the retina and ocular nerves but as large processed fragments as well, weak in the retina and more prominent in remaining ocular tissues, possibly in endothelial cells. This indicates that this peptide is a constituent of sensory neurons innervating the rat eye and the presence in amacrine cells in the retina is typical for neuropeptides. Catestatin is biologically highly active and might be of significance in the pathophysiology of the eye. PMID:24331778

Gramlich, Oliver W; Lorenz, Katrin; Grus, Franz H; Kriechbaum, Maren; Ehrlich, Daniela; Humpel, Christian; Fischer-Colbrie, Reiner; Bechrakis, Nikolaos E; Troger, Josef

2014-02-01

 
 
 
 
121

Biomolecular immunoreactivity factor in antibody labelling design for potent radiopharmaceutical  

International Nuclear Information System (INIS)

Biomolecular factors' importance in optimum immunoconjugate design when high specific labelling is attempted is discussed. High specific labelling allows a small dose to be administered avoiding saturating antigen binding sites and to compensate for loss of bivalency etc. upon fragmentation. Clinical therapeutic and diagnostic applications result in adverse toxicity and poor scintigraphic resolution from the corrupted distribution upon labelling. DTPA is a strong chelator and forms a tight sequestering cryptate structure of small dimensions with the radioactive metals Tc-99m and In-111. Size severely affects permeability with reticuloendothelial accumulation. Compact scaled radiolabels are advantageous as potent payload moieties for radiotherapy as well as imaging. The antibody binding site requires close surface contact with its epitope to effect the specificity of immunoreaction. Binding site exposure to coupling chemistry can be directed via affinity purification methodology. The globular antibody with an amphiphilic structure presents conformed surface chemistry and is relatively inert requiring excess reaction stoichiometry. Radiolabelled antibodies to calcitonin (a 32 aminoacid polypeptide ectopic lung tumor antigen) in a solid phase immunoreactivity assay demonstrate 48 hours for 90% uptake. Site directed radiolabelling is of interest in preservation of immunoreactivity in protein engineering. 19 refs., 8 figs

122

Consanguinity and chromosomal abnormality  

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Full Text Available BACKGROUND : Consanguinity is defined as the marriage between close relatives. The deleterious effects associated with consanguinity may be caused by the expression of rare recessive genes inherited from common ancestors. AIMS AND OBJECTIVES : The present study was undertaken to analyze the effect of consanguinity on chromosomal abnormality (CA. METHODS AND MATERIALS : During last 6 years period, a total of 1465 cases with suspected genetic etiology like bad obstetric history, mental retardation, multiple congenital anomalies, Down syndrome, primary amenorrhea and primary infertility was referred to Division of Human Genetics for karyotyping and genetic counseling. The information regarding consanguinity was obtained through pedigree analyzes up to three generations from all the patients. Chi-square test was applied to test the significance. RESULTS : Consanguinity was seen in 427 cases (29.14%, 305 cases were confirmed to have CA, among them 240 (78.7% had numerical abnormality and 65 (21.3% had structural abnormality. The presence of consanguinity in CA was seen in 53 cases (17%, including 43 (81.1% with numerical and 10 (18.9% with structural abnormality. CONCLUSION : The effect of consanguinity on CA was almost significant ( P < 0.001, whereas the effect was not significant for the type of CA. It may be because of the pooled types of consanguinity as well as the CA. Further information is needed to state categorically that there could be the effect of consanguinity on CA.

Amudha S

2005-01-01

123

CT of pleural abnormalities  

International Nuclear Information System (INIS)

Briefly discussed were CT diagnosis of pleural thickening, CT technique for examining the pleura or pleuro-pulmonary disease, diagnosis of pleural collections, diagnosis of pleural fluid abnormalities in patients with pneumonia, pleural neoplasms, malignant (diffuse) mesothelioma, metastases, local fibrous tumor of the pleura (benign mesothelioma) (21 refs.)

124

Immunoreactivity examination of patients with testicular tumours treated with radiotherapy  

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Results of the immunoreactivity study of 72 patients receiving radiotherapy are presented. Tuberculin and DNCB (2,4 dinitrochlorobenzol) reactivity tests were performed before, during and 3 years after the radiation therapy and at the time when metastases appeared. The number of positive reactions decreased slightly in both tuberculin and DNCB groups, though not significantly. Metastatic patients showed a significant decrease of reactivity against DNCB as compared with the results obtained before the treatment. In 5,6% of patients herpes zoster was registered. No other infections occured. It was found that immunosuppression caused by the radiation treatment does not influence the later fate of patients with testicular tumours. 41 refs.

Stefanits, K.; Kuhn, E.; Csere, T.

1985-02-01

125

Immunoreactivity examination of patients with testicular tumours treated with radiotherapy  

International Nuclear Information System (INIS)

Results of the immunoreactivity study of 72 patients receiving radiotherapy are presented. Tuberculin and DNCB (2,4 dinitrochlorobenzol) reactivity tests were performed before, during and 3 years after the radiation therapy and at the time when metastases appeared. The number of positive reactions decreased slightly in both tuberculin and DNCB groups, though not significantly. Metastatic patients showed a significant decrease of reactivity against DNCB as compared with the results obtained before the treatment. In 5,6% of patients herpes zoster was registered. No other infections occured. It was found that immunosuppression caused by the radiation treatment does not influence the later fate of patients with testicular tumours. (author)

126

Prognostic importance of proliferating cell nuclear antigen immunoreactivity and mitotic index in malignant mesothelioma  

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Full Text Available Aim: In this study, proliferating nuclear cell antigen (PCNA immunoreactivity and the mitotix index were searched in human malignant mesothelioma to assess their prognostic value.Material and Methods: PCNA immunoreactivity was investigated in 19 cases. The authors also compared this with mitosis counts.Results: There was no correlation between the percentage of PCNA immunoreactive cells and their mitotic counts. However, the median survival was 16.4 months for patients with less than 25% PCNA immunoreactive cells, 17.8 months for patients with less than 4 mitotic figures 10 high power fields of tumoral tissue, 10.8 months for patients with more than 25 per cent PCNA immunoreactive cells, and 14.2 months for patients with more than 4 mitotic figures in 10 high power fields of tumoral tissue.Conclusion: Our results suggest that PCNA immunoreactivity and mitotic count may have prognostic values in malignant mesothelioma.

I??n SOYUER

2002-09-01

127

Interleukin-8 receptor B immunoreactivity in brain and neuritic plaques of Alzheimer's disease.  

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Cytokines mediate inflammatory responses through their receptors in the hematopoietic system. In a search for potential mediators of inflammatory responses in Alzheimer's disease, we examined brain for cytokine receptors. Herein we describe interleukin-8 receptor B (IL-8RB, also termed CXCR2) immunoreactivity in the central nervous system. Strong IL-8RB immunoreactivity is present in both Alzheimer's disease and control brains. Neurons, dendrites, and axons are clearly immunoreactive. In Alzh...

Xia, M.; Qin, S.; Mcnamara, M.; Mackay, C.; Hyman, B. T.

1997-01-01

128

A single allatostatin-immunoreactive neuron innervates skeletal muscles of several segments in the locust  

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In the nervous system of embryos and adult Locusta migratoria, somata, neurites within the ganglia, and axons leaving the thoracic ganglia show allatostatin immunoreactivity. The immunoreactive efferent axons divide to follow different nerve branches and form varicose terminals on skeletal muscles. In the adult locust, one pair of motor neurons is particularly prominent among the allatostatin-immunoreactive neurons. The somata are located symmetrically in a lateral position in the first abdom...

Kreißl, Sabine; Schulte, Claudia C.; Agricola, Hans-ju?rgen; Rathmayer, Werner

1999-01-01

129

Abnormal corpus callosum  

International Nuclear Information System (INIS)

Earlier observations have led the authors to investigate abnormal corpus callosum (CC) as an indicator of multiple sclerosis (MS). They have evaluated 42 patients with MS and 127 patients with other forms of periventricular white matter disease (PWMD). All underwent long TR/short TE and lone TR/long TE axial and sagittal imaging. Thirty nine (93%) of 42 MS patients demonstrated lesions of the CC; these were best demonstrated on sagittal imaging. In one of the three false-negative studies, the patient had severe callosal strophy, which made evaluation of the CC difficult. Only two (1.5%) of 127 non-MS patients with PWMD had an abnormal CC. The authors conclude that the mid-sagittal lone TR/short TE image is highly sensitive and specific for MS, callosal involvement in MS is far more common than previously reported, and such lesions are rarely seen in patients without MS

130

Menin immunoreactivity in secretory granules of human pancreatic islet cells.  

Science.gov (United States)

The protein product of the Multiple Endocrine Neoplasia Type I (MEN1) gene is thought to be involved in predominantly nuclear functions; however, immunohistochemical (IHC) analysis data on cellular localization are conflicting. To further investigate menin expression, we analyzed human pancreas (an MEN1 target organ) using IHC analyses and 6 antibodies raised against full-length menin or its peptides. In 10 normal pancreas specimens, 2 independently raised antibodies showed unexpected cytoplasmic immunoreactivity in peripheral cells in each islet examined (over 100 total across all 10 patients). The staining exhibited a distinct punctate pattern and subsequent immunoelectron microscopy indicated the target antigen was in secretory granules. Exocrine pancreas and pancreatic stroma were not immunoreactive. In MEN1 patients, unaffected islets stained similar to those in normal samples but with a more peripheral location of positive cells, whereas hyperplastic islets and tumorlets showed increased and diffuse cytoplasmic staining, respectively. Endocrine tumors from MEN1 patients were negative for menin, consistent with a 2-hit loss of a tumor suppressor gene. Secretory granule localization of menin in a subset of islet cells suggests a function of the protein unique to a target organ of familial endocrine neoplasia, although the IHC data must be interpreted with some caution because of the possibility of antibody cross-reaction. The identity, cellular trafficking, and role of this putative secretory granule-form of menin warrant additional investigation. PMID:25153502

Debelenko, Larisa V; Agarwal, Sunita; Du, Qiang; Yan, Wusheng; Erickson, Heidi S; Abu-Asab, Mones; Raffeld, Mark A; Libutti, Steven K; Marx, Stephen J; Emmert-Buck, Michael R

2014-01-01

131

ALS-associated protein FIG4 is localized in Pick and Lewy bodies, and also neuronal nuclear inclusions, in polyglutamine and intranuclear inclusion body diseases.  

Science.gov (United States)

FIG4 is a phosphatase that regulates intracellular vesicle trafficking along the endosomal-lysosomal pathway. Mutations of FIG4 lead to the development of Charcot-Marie-Tooth disease type 4J and amyotrophic lateral sclerosis (ALS). Moreover, ALS-associated proteins (transactivation response DNA protein 43 (TDP-43), fused in sarcoma (FUS), optineurin, ubiquilin-2, charged mutivesicular body protein 2b (CHMP2B) and valosin-containing protein) are involved in inclusion body formation in several neurodegenerative diseases. Using immunohistochemistry, we examined the brains and spinal cords of patients with various neurodegenerative diseases, including sporadic TDP-43 proteinopathy (ALS and frontotemporal lobar degeneration). TDP-43 proteinopathy demonstrated no FIG4 immunoreactivity in neuronal inclusions. However, FIG4 immunoreactivity was present in Pick bodies in Pick's disease, Lewy bodies in Parkinson's disease and dementia with Lewy bodies, neuronal nuclear inclusions in polyglutamine and intranuclear inclusion body diseases, and Marinesco and Hirano bodies in aged control subjects. These findings suggest that FIG4 is not incorporated in TDP-43 inclusions and that it may have a common role in the formation or degradation of neuronal cytoplasmic and nuclear inclusions in several neurodegenerative diseases. PMID:23888880

Kon, Tomoya; Mori, Fumiaki; Tanji, Kunikazu; Miki, Yasuo; Toyoshima, Yasuko; Yoshida, Mari; Sasaki, Hidenao; Kakita, Akiyoshi; Takahashi, Hitoshi; Wakabayashi, Koichi

2014-02-01

132

[Developmental abnormalities in humans].  

Science.gov (United States)

Recently, tremendous advances have been made in our understanding of pre- and perinatal death and congenital anomaly, but many aspects of the field remain unknown and require the continued collaboration of workers in many clinical and basic science disciplines. Most of mankind dies before, not after birth, mostly due to chromosome abnormalities arising during pregenesis. A few trisomy 13 and 18 cases survive till birth by virtue of placental mosaicism; even trisomy 21 is an 80% prenatally lethal and a postnatally sublethal syndrome. Most aneuploid individuals surviving postnatally have sex chromosomes abnormalities (47,XXY, 47,XYY, 47,XXX). Until recently the term "monsters" was applied to many abnormalities of blastogenesis--i.e. the disruptions and malformations arising during the first 4 weeks of embyronic development (till the end of mesoderm formation). This includes not only acardia/acephaly, but also holoprosencephaly, sirenomelia, gross defects of cord, body wall and -stalk formation and conjoined twins, but also non-conjoined monozygotic twins with apparent high prenatal mortality and a high incidence of midline anomalies. One of the most important recent insights has been that associations, e.g. the VACTERAL association, and the relatively characteristic combination of anomalies seen in infants of diabetic mothers, represent disruptions of blastogenesis. The latter represent a particularly satisfying development in the field since it has been shown that control of the woman's blood sugar levels before, during and after conception helps to reduce the high incidence of defects of blastogenesis in infants of diabetic mothers. Most malformations arise during organogenesis in secondary or epimorphic fields and mostly represent anomalies of incomplete, less commonly of abnormal differentiation. An important distinction must be made between mild malformations (all-or-none defects of organogenesis) which are relatively innocuous and common in the population but never normal, and minor anomalies which are graded defects of phenogenogenesis (i.e. of the developmental processes during the fetal period (weeks 8-10 p.c.), and the most frequent anomalies in aneuploidy syndromes with resulting loss of family resemblance.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:1870596

Opitz, J M

1991-05-01

133

Epilepsy and chromosomal abnormalities  

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Full Text Available Abstract Background Many chromosomal abnormalities are associated with Central Nervous System (CNS malformations and other neurological alterations, among which seizures and epilepsy. Some of these show a peculiar epileptic and EEG pattern. We describe some epileptic syndromes frequently reported in chromosomal disorders. Methods Detailed clinical assessment, electrophysiological studies, survey of the literature. Results In some of these congenital syndromes the clinical presentation and EEG anomalies seems to be quite typical, in others the manifestations appear aspecific and no strictly linked with the chromosomal imbalance. The onset of seizures is often during the neonatal period of the infancy. Conclusions A better characterization of the electro clinical patterns associated with specific chromosomal aberrations could give us a valuable key in the identification of epilepsy susceptibility of some chromosomal loci, using the new advances in molecular cytogenetics techniques - such as fluorescent in situ hybridization (FISH, subtelomeric analysis and CGH (comparative genomic hybridization microarray. However further studies are needed to understand the mechanism of epilepsy associated with chromosomal abnormalities.

Sorge Giovanni

2010-05-01

134

Immunoreactive atrial natriuretic peptide in the guinea pig spleen  

International Nuclear Information System (INIS)

The presence of immunoreative ANP precursor-like material in the guinea pig spleen is suggested. This is based on the following experimental evidence: An acidic extract of guinea pig spleen analyzed by Sephadex G-50 gel filtration contained 4.6 pmol/g wet tissue immunoreactive atrial natriuretic peptide (IR-ANP), IR-ANP coeluting with 15 kDa synthetic ANP (2-126). Gel filtrated IR-ANP material was further submitted to reverse phase high performance liquid chromatography and monitored by radioimmunoassay employing two antisera. One antiserum recognizes the C-terminal of ANP (1-126), the second is directed against the N-terminal sequence. Both antisera revealed material eluting with synthetic ANP (2-126). Furthermore, immunohistochemical analysis suggests this ANP-like material to be localized mainly at the periphery of the white pulp of the spleen. These findings link ANP with the immune system

135

Digoxin-like immunoreactivity in human body fluids  

International Nuclear Information System (INIS)

The clinical and chemical characteristics of a solid-phase radioimmunoassay (RIA) for routine digoxin determination has been studied with the aim to confirm our previous observation of the presence of digoxin-like immunoreactive substance (DLIS) in serum (plasma) and urine of normal subjects not under digoxin treatment. The sensitivity of the assay was 2.1±0.6 pg/tube and the reproducibility, tested with two different urine pools in terms of digoxin-equivalents (d.e.), was 12.5% (285.6±35.7 pg/ml d.e., n=19) and 20.6% (123.8±25.5 pg/ml d.e., n=19), respectively. The mean DLIS concentration in the blood of 32 normal subjects was 15.6±8.0 pg/ml d.e. (range 0-60 pg/ml d.e.). The mean DLIS concentration in urine of 37 normal subjects (overnight collection) was 160.0±52.3 pg/ml d.e. (range 70-350 pg/ml d.e.), while the mean 24-hour DLIS excretion of 10 normal subjects was 97.3±39.7 ng d.e. Two urine pools were extracted with organic solvents. Good recoveries (80-100%) were obtained with methanol, while poor recoveries were obtained with methylene chloride, hexane and petroleum ether. The present study indicates that DLIS is not a large charged molecule, neither salt, nor fatty acid, which are considered the most frequent non-specific interferences in RIA systems. Urine samples may be more useful for pathophysiological studies on digoxin-like immunoreactivity in human body fluids, because of their higher DLIS concentrations (4-10 times the concetration in blood)

136

Abnormal Occupation REvisited  

CERN Document Server

It is demonstrated the Fermi surface of dense neutron matter may experience a rearrangement near the onset of pion condensation, due to strong momentum dependence of the effective interaction induced by spin-isospin fluctuations. In particular, the Fermi surface may take the form of a partially hollow sphere having a spherical hole in its center (a ``Lifschitz bubble''). Thus, a second (inner) Fermi surface may form as high-momentum single-particle states are filled and low-momentum states are vacated. The influence of this phenomenon on the superfluid transition temperature of the Fermi system is characterized with the help of a separation transformation of the BCS gap equation. This work may be viewed as a revival of the search for physical realizations of abnormal occupation in infinite, homogeneous Fermi systems -- plausible instances in which the quasiparticle distribution differs from that of an ideal Fermi gas and Fermi liquid theory breaks down.

Clark, J W; Zverev, M V

2001-01-01

137

Chronic 835-MHz radiofrequency exposure to mice hippocampus alters the distribution of calbindin and GFAP immunoreactivity.  

Science.gov (United States)

Exponential interindividual handling in wireless communication system has raised possible doubts in the biological aspects of radiofrequency (RF) exposure on human brain owing to its close proximity to the mobile phone. In the nervous system, calcium (Ca(2+)) plays a critical role in releasing neurotransmitters, generating action potential and membrane integrity. Alterations in intracellular Ca(2+) concentration trigger aberrant synaptic action or cause neuronal apoptosis, which may exert an influence on the cellular pathology for learning and memory in the hippocampus. Calcium binding proteins like calbindin D28-K (CB) is responsible for the maintaining and controlling Ca(2+) homeostasis. Therefore, in the present study, we investigated the effect of RF exposure on rat hippocampus at 835 MHz with low energy (specific absorption rate: SAR=1.6 W/kg) for 3 months by using both CB and glial fibrillary acidic protein (GFAP) specific antibodies by immunohistochemical method. Decrease in CB immunoreactivity (IR) was noted in exposed (E1.6) group with loss of interneurons and pyramidal cells in CA1 area and loss of granule cells. Also, an overall increase in GFAP IR was observed in the hippocampus of E1.6. By TUNEL assay, apoptotic cells were detected in the CA1, CA3 areas and dentate gyrus of hippocampus, which reflects that chronic RF exposure may affect the cell viability. In addition, the increase of GFAP IR due to RF exposure could be well suited with the feature of reactive astrocytosis, which is an abnormal increase in the number of astrocytes due to the loss of nearby neurons. Chronic RF exposure to the rat brain suggested that the decrease of CB IR accompanying apoptosis and increase of GFAP IR might be morphological parameters in the hippocampus damages. PMID:20546709

Maskey, Dhiraj; Pradhan, Jonu; Aryal, Bijay; Lee, Chang-Min; Choi, In-Young; Park, Ki-Sup; Kim, Seok Bae; Kim, Hyung Gun; Kim, Myeung Ju

2010-07-30

138

FMRF-amide-like immunoreactivity in brain and pituitary of the hagfish Eptatretus burgeri (Cyclostomata)  

DEFF Research Database (Denmark)

Paraffin sections of brain and pituitary of the hagfish Eptatretus burgeri were immunostained with an antiserum to FMRF-amide. Immunoreactivity was visible in a large number of neurons in the posterior part of the ventromedial hypothalamus and in long neuronal processes extending cranially from the hypothalamus to the olfactory system and caudally to the medulla oblongata. FMRF-amide-like immunoreactivity was also found in cells of the adenohypophysis. These observations suggest that the hagfish possesses a brain FMRF-amide-like transmitter system and pituitary cells containing FMRF-amide-like material. Antisera to ACTH, alpha-MSH and pancreatic polypeptide gave no immunoreaction in hagfish brain or pituitary.

Jirikowski, G; Erhart, G

1984-01-01

139

[Extracellular immunoreactive nucleoprotein of Influenza virus not related to the virion].  

Science.gov (United States)

Extracellular immunoreactive virus NP is accumulated in virus-containing fluid in the course of A/Duck/Ukraine/1/63(H3N8) influenza virus infection. The major part of this extracellular NP is included in viral RNP and characterized by relatively low molecular weight: 53 kD vs. 56 kD of virion NP. Extracellular immunoreactive NP is oligomerized. Presumably, there is partially intracellular cleavage of NP with loss of hydrophobic determinants. Such truncated NP in RNP is highly hydrophilic and passes through cell membranes. These data prompt the diagnosis of influenza infection by detection of free immunoreactive NP in analyzed fluids. PMID:11450139

Prokudina, E N; Semenova, N P; Chumakov, V M; Rudneva, I A

2001-01-01

140

Deposition of immunoreactants in a cutaneous allergic drug reaction  

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Full Text Available Context: The analysis of allergic drug reaction pathology may be difficult, especially if multiple histological reaction patterns are detected on review of hematoxylin and eosin (H&E stained sections. In this case, we emphasize the value of adding immunohistochemistry (IHC and multicolor direct immunofluorescence (DIF as tools to improve the diagnosis of these complex disorders. Patient and Methods: Our patient is a twenty-year-old Caucasian female, who presented with a sudden onset of erythematous macules on the skin following administration of amoxicillin. Lesional tissue was examined by H & E and IHC, and perilesional tissue by DIF and IHC. Results: The H&E findings revealed diffuse dermal edema, and a mild, superficial, perivascular dermatitis with a mixed inflammatory infiltrate, consistent with an allergic drug eruption. The IHC and DIF studies revealed autoreactivity to sweat glands, nerves and dermal blood vessels, as well as dermal deposits of immune reactants such as fibrinogen and complement around the inflamed areas. Conclusions: Fibrin-fibrinogen degradation products have been shown in some cases of allergic disorders; thus, we encourage the effect further testing for these immunoreactants in biopsies from patients with possible allergic drug reactions.

Ana Maria Abreu Velez

2009-09-01

 
 
 
 
141

Clinical applications of measurement of serum immunoreactive levels of erythropoietin  

International Nuclear Information System (INIS)

The purification of erythropoietin (Ep) in 1977 enabled investigators to more clearly define the role of this hormone in erythropoiesis in man. Radioimmunoassays were rapidly developed. Undoubtedly differences between levels of immunoreactive and biologically active Ep will be found but the resolution of these discrepancies will expand our understanding of the erythron. Recently others described a monoclonal antibody against Ep. Because of this breakthrough, large quantities of pure hormone should soon be available to a larger number of investigators than currently have access to it. The major clinical use of this hormone will probably be in the treatment of the anemia of chronic renal disease. In the relatively few years since the radioimmunoassay (RIA) was developed, measurements of the levels of this hormone have been made in several disease states as well as in normal man. Most of the findings to date confirm the predictions that have been made over the years based on studies done using the rather crude bioassay for Ep. In the present study the authors shall review and expand on what is known about subjects with chronic lung and renal disease

142

Serum immunoreactive erythropoietin in HIV-infected patients  

International Nuclear Information System (INIS)

Serum immunoreactive erythropoietin (SIE) and hemoglobin levels were measured in 152 patients infected with the human immunodeficiency virus. Anemia was present in 18% of asymptomatic patients who tested positive for the human immunodeficiency virus, 50% of patients with a condition related to the acquired immunodeficiency syndrome (AIDS), and 75% of patients with AIDS. The mean SIE level for untreated AIDS patients was greater than for patients who tested positive for human immunodeficiency virus or patients with an AIDS-related condition but not outside the normal range for SIE, and the incremental increase in SIE level for a given decline in hemoglobin level was much less in AIDS patients than in patients with uncomplicated iron deficiency anemia. Forty-two patients were treated with zidovudine, and the hemoglobin level fell 10 g/L or more in 48%. The data indicate that SIE level is inappropriately low in anemic AIDS patients. The ability of these patients to produce erythropoietin is intact and can be expressed with zidovudine therapy. However, even very high levels of SIE fail to stimulate erythropoiesis adequately

143

Inducible nitric oxide synthase immunoreactivity in healthy rat pancreas.  

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Full Text Available Nitric oxide (NO is produced by NO synthase (NOS isoforms: neuronal NOS (nNOS, endothelial NOS (eNOS and inducible NOS (iNOS. It is believed that, while nNOS and eNOS are effective in regulation of normal physiological processes, iNOS is expressed at an increasing rate especially in inflammatory process. The aim of this study was to determine the presence of iNOS immunoreactivity (iNOS-IR and, to compare the iNOS-IR in islet of Langerhans cells (LC, acinar cells (AC, centroacinar cells (CC and ductal cells (DC by immunohistochemical (IHC method in healthy rat pancreata. This study revealed the presence of iNOS-IR in all cell types except AC. Statistical analysis revealed a highly significant difference (p<0.001 with respect to iNOS-IR in comparison of all cell types. However, binary comparison of cell types revealed no significant differences between LC and DC (p=0.136, significant differences LC and CC, CC and DC (p=0.001 and 0.022, respectively and a highly significant differences LC and AC, AC and DC (P<0.001. The results of this study indicate that iNOS-IR is present in almost all LC. Thus, especially in reseach related to diabetes, it should not be disregarded that iNOS may be constitutively present in pancreatic islets.

Nurullah Keklikoglu

2008-06-01

144

Neurotensin-like immunoreactivity in the nervous system of hydra  

DEFF Research Database (Denmark)

Neurotensin-like immunoreactivity is found in nerve fibers present in all body regions of hydra. The nerve fibers are especially numerous in the ectoderm at the bases of the tentacles and in the ectoderm at a site just above the foot. Radioimmunoassays of acetic-acid extracts of hydra, using various region-specific antisera towards mammalian neurotensin, show the presence of multiple neurotensin-related peptides. The amounts of these peptides vary between 1 and 350 pmol per gram wet weight. Gel filtration on Sephadex G-25 reveals a fraction of neurotensin-like peptides that crossreact equally well with an antiserum directed against sequence 1-8 and an antiserum directed against sequence 6-13 of neurotensin. This fraction elutes also at the position of neurotensin and might closely resemble the mammalian peptide. A fraction eluting with the void volume crossreacts preferentially with antisera directed against sequences 1-8 and 10-13 of neurotensin. Several components of apparent lower molecular weight than neurotensin crossreact preferentially with an antiserum against sequence 10-13. These last peptides represent the major portion of the neurotensin-like peptides in hydra.

Grimmelikhuijzen, C J; Carraway, R E

1981-01-01

145

Influence of feeding on serum canine pancreatic lipase immunoreactivity concentrations  

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Full Text Available Jörg M Steiner, Craig G Ruaux, David A Williams Gastrointestinal Laboratory, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA Abstract: Measurement of serum concentration of pancreatic lipase immunoreactivity (PLI has been shown to be highly specific for exocrine pancreatic function and sensitive for the diagnosis of canine pancreatitis. Currently, it is recommended that food be withheld for at least 12 hours before collecting a blood sample for analysis from dogs. However, it is unknown whether feeding has any influence on serum canine PLI concentration. Thus, the goal of this study was to evaluate the influence of feeding on serum canine PLI concentrations in healthy dogs. Food was withheld from eight healthy adult Beagle dogs for at least 17 hours and a baseline serum sample (0 minutes was collected. Dogs were fed and serum samples were collected at 15, 30, 45, 60, 75, 90, 105, 150, 180, 210, 240, 300, 360, 420, and 480 minutes. There was no significant difference in serum canine PLI concentrations at any time after feeding (P=0.131. We conclude that feeding has no significant influence on serum canine PLI concentrations. Keywords: dog, pancreatic function, pancreatitis, biomarker, diagnostic test

Steiner JM

2014-10-01

146

Immunoreactive inhibin concentration in blood tested under variable sampling conditions  

DEFF Research Database (Denmark)

The stability of immunoreactive (i.r.) inhibin in blood samples drawn and handled under different conditions and at different time intervals were studied. Ten serum and plasma samples drawn in 1994 from healthy volunteers were compared to samples collected in 1986 from 10 healthy women admitted for laparoscopic sterilization and analysed 6 years later. All samples were drawn on the twelfth day of the menstrual cycle and handled under identical clinical conditions (22 degrees C). The concentrations in the 1986 samples were similar to the Se-i.r. inhibin levels from 1994. Different clotting temperatures, repetitive freezing and thawing or hemolysis had no effects on the i.r. inhibin values, whereas non-hemolysed samples left at room temperature (22 degrees C) for 3 days were significantly lower, which might be due to a statistical type 2 error. No differences in concentration between serum and plasma i.r. inhibin were demonstrated. In conclusion, i.r. inhibin is a very stable peptide hormone in both serum and plasma if drawn and handled under normal conditions.

Blaakćr, Jan; Micic, S

1996-01-01

147

Abnormal pressure in hydrocarbon environments  

Science.gov (United States)

Abnormal pressures, pressures above or below hydrostatic pressures, occur on all continents in a wide range of geological conditions. According to a survey of published literature on abnormal pressures, compaction disequilibrium and hydrocarbon generation are the two most commonly cited causes of abnormally high pressure in petroleum provinces. In young (Tertiary) deltaic sequences, compaction disequilibrium is the dominant cause of abnormal pressure. In older (pre-Tertiary) lithified rocks, hydrocarbon generation, aquathermal expansion, and tectonics are most often cited as the causes of abnormal pressure. The association of abnormal pressures with hydrocarbon accumulations is statistically significant. Within abnormally pressured reservoirs, empirical evidence indicates that the bulk of economically recoverable oil and gas occurs in reservoirs with pressure gradients less than 0.75 psi/ft (17.4 kPa/m) and there is very little production potential from reservoirs that exceed 0.85 psi/ft (19.6 kPa/m). Abnormally pressured rocks are also commonly associated with unconventional gas accumulations where the pressuring phase is gas of either a thermal or microbial origin. In underpressured, thermally mature rocks, the affected reservoirs have most often experienced a significant cooling history and probably evolved from an originally overpressured system.

Law, B.E.; Spencer, C.W.

1998-01-01

148

Chromosomal abnormalities in indolent lymphoma.  

Science.gov (United States)

Cytogenetic studies were performed on lymph node biopsies from 60 patients with indolent (low grade) non-Hodgkin's lymphoma. Thirty-two of the 39 successfully cultured biopsies had abnormal clones. The 32 abnormal clones represented the following histologies: seven small lymphocytic lymphoma (SL), eight follicular small cleaved cell lymphoma (FSC), 14 follicular mixed, small cleaved, and large cell lymphoma (FM), and three composite lymphomas. One of the composite lymphomas had FSC/DSC (diffuse small cleaved cell) and the other two FM/DM (diffuse mixed, small cleaved and large cell). Twenty-seven of the 32 biopsies were immunologically typed, and all were B cell. The clones all exhibited more structural than numerical abnormalities, and there was no difference in the modal chromosome number of the abnormal clones found in each histology. Biopsies with no normal cells were more frequently found in the SL histology (71%) than in the two follicular lymphoma groups (54%-55%). A translocation of the 14q32 segment was the most common abnormality found in all three histologies. In the follicular lymphomas a t(14;18)(q32;q21) was seen in 52% (13 of 25) of these patients, this translocation was not observed in the SL patients. Overall 84% (21 of 25) of the follicular lymphoma patients had abnormalities of 14q32 and/or 18q21. Other specific abnormalities included anomalies of chromosome #3 in FM, an abnormal 10q in FSC and FM lymphoma, and a high incidence of +18 and chromosome #1 abnormalities in patients with t(14;18). The presence of specific chromosome abnormalities in the indolent lymphoma patients suggests a relationship between certain karyotypic features and histology. PMID:3297304

Speaks, S L; Sanger, W G; Linder, J; Johnson, D R; Armitage, J O; Weisenburger, D; Purtilo, D

1987-08-01

149

Decreased serotonin transporter immunoreactivity in the human hypothalamic infundibular nucleus of overweight subjects  

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Full Text Available Context: That serotonin plays a role in the regulation of feeding behavior and energy metabolism has been known for a long time. Serotonin transporters (SERT play a crucial role in serotonin signalling by regulating its availability in the synaptic cleft. The neuroanatomy underlying serotonergic signalling in humans is largely unknown, and until now, SERT immunoreactivity in relation to body weight has not been investigated.Objective: To clarify the distribution of SERT immunoreactivity throughout the human hypothalamus and to compare SERT immunoreactivity in the infundibular nucleus (IFN, the human equivalent of the arcuate nucleus, in lean and overweight subjects. Design: First, we investigated the distribution of serotonin transporters (SERT over the rostro-caudal axis of six postmortem hypothalami by means of immunohistochemistry. Second, we estimated SERT immunoreactivity in the IFN of lean and overweight subjects. Lastly, double-labelling of SERT with Neuropeptide Y (NPY and melanocortin cell populations was performed to further identify cells showing basket-like SERT staining. Results: SERT-immunoreactivity was ubiquitously expressed in fibers throughout the hypothalamus and was the strongest in the IFN. Immunoreactivity in the IFN was lower in overweight subjects (p=0.036. Basket-like staining in the IFN was highly suggestive of synaptic innervation. A very small minority of cells showed SERT double labelling with NPY, agouti-related protein and ??melanocyte stimulating hormone. Conclusions: SERT is ubiquitously expressed in the human hypothalamus. Strong SERT immunoreactivity, was observed in the IFN a region important for appetite regulation, in combination with lower SERT immunoreactivity in the IFN of overweight and obese subjects, may point towards a role for hypothalamic SERT in human obesity.

AnnekeAlkemade

2014-05-01

150

Neonatal screening strategy for cystic fibrosis using immunoreactive trypsinogen and direct gene analysis.  

Digital Repository Infrastructure Vision for European Research (DRIVER)

OBJECTIVE--To assess the effectiveness of a two tier neonatal screening strategy for cystic fibrosis, which combines estimation of immunoreactive trypsinogen followed by direct gene analysis in dried blood spot samples collected at age 5 days. DESIGN--Prospective study of two tier screening strategy. The first tier of testing immunoreactive trypsinogen concentration was measured in dried blood spot samples from neonates aged 4-5 days. In the second tier direct gene analysis to detect cystic f...

Ranieri, E.; Ryall, R. G.; Morris, C. P.; Nelson, P. V.; Carey, W. F.; Pollard, A. C.; Robertson, E. F.

1991-01-01

151

Immunoreactivity of ICAM-1 in Human Tumors, Metastases and Normal Tissues  

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Intercellular adhesion molecule-1 (ICAM-1) is implicated to play a role in cancer metastasis, and may serve as a diagnostic tool for tumor prognosis and progression as well as a target for therapeutic intervention. The aim of this study was to carry out a comprehensive survey of ICAM-1 immunoreactivity in normal, malignant and metastatic tissues. We assessed immunoreactivity of ICAM-1 in a total of 300 tissue cores from multiple tissue arrays of normal, malignant, and metastatic tissues by im...

Hayes, Sarah H.; Seigel, Gail M.

2009-01-01

152

Diurnal variation of ?-endorphin like immunoreactivity in rat brain, pituitary gland, and plasma  

International Nuclear Information System (INIS)

?-endorphin like immunoreactivity was measured in the brain, pituitary gland and plasma of rats at 2 A.M, 8 A.M, 2 P.M and 8 P.M. Values were higher in the brain and pituitary gland at 8 P.M and in the plasma at 8 A.M and 2 P.M. The findings suggest a circadian rhythm in the production and release of ?-endorphin immunoreactive material. (Author)

153

A simple method to determine the immunoreactivity of radiolabelled monoclonal antibodies to the TAG-72 antigen  

International Nuclear Information System (INIS)

A simple method has been developed for determining the immunoreactivity of radiolabelled monoclonal antibodies to the TAG-72 antigen. The method involves binding of a constant small amount of the antibody to increasing concentrations of bovine submaxillary mucin. The immunoreactive fraction (IRF) is then determined by linear extrapolation of binding to infinite antigen excess. Using this assay, the IRF of radioiodinated anti-TAG-72 antibodies ranged from 0.22-0.48. (author)

154

Induction of Fos protein immunoreactivity by spinal cord contusion  

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Full Text Available The objective of the present study was to identify neurons in the central nervous system that respond to spinal contusion injury in the rat by monitoring the expression of the nuclear protein encoded by the c-fos gene, an activity-dependent gene, in spinal cord and brainstem regions. Rats were anesthetized with urethane and the injury was produced by dropping a 5-g weight from 20.0 cm onto the exposed dura at the T10-L1 vertebral level (contusion group. The spinal cord was exposed but not lesioned in anesthetized control animals (laminectomy group; intact animals were also subjected to anesthesia (intact control. Behavioral alterations were analyzed by Tarlov/Bohlman scores, 2 h after the procedures and the animals were then perfused for immunocytochemistry. The patterns of Fos-like immunoreactivity (FLI which were site-specific, reproducible and correlated with spinal laminae that respond predominantly to noxious stimulation or injury: laminae I-II (outer substantia gelatinosa and X and the nucleus of the intermediolateral cell column. At the brain stem level FLI was detected in the reticular formation, area postrema and solitary tract nucleus of lesioned animals. No Fos staining was detected by immunocytochemistry in the intact control group. However, detection of FLI in the group submitted to anesthesia and surgical procedures, although less intense than in the lesion group, indicated that microtraumas may occur which are not detected by the Tarlov/Bohlman scores. There is both a local and remote effect of a distal contusion on the spinal cord of rats, implicating sensory neurons and centers related to autonomic control in the reaction to this kind of injury.

E.A. Del-Bel

2000-05-01

155

Induction of Fos protein immunoreactivity by spinal cord contusion  

Scientific Electronic Library Online (English)

Full Text Available SciELO Brazil | Language: English Abstract in english The objective of the present study was to identify neurons in the central nervous system that respond to spinal contusion injury in the rat by monitoring the expression of the nuclear protein encoded by the c-fos gene, an activity-dependent gene, in spinal cord and brainstem regions. Rats were anest [...] hetized with urethane and the injury was produced by dropping a 5-g weight from 20.0 cm onto the exposed dura at the T10-L1 vertebral level (contusion group). The spinal cord was exposed but not lesioned in anesthetized control animals (laminectomy group); intact animals were also subjected to anesthesia (intact control). Behavioral alterations were analyzed by Tarlov/Bohlman scores, 2 h after the procedures and the animals were then perfused for immunocytochemistry. The patterns of Fos-like immunoreactivity (FLI) which were site-specific, reproducible and correlated with spinal laminae that respond predominantly to noxious stimulation or injury: laminae I-II (outer substantia gelatinosa) and X and the nucleus of the intermediolateral cell column. At the brain stem level FLI was detected in the reticular formation, area postrema and solitary tract nucleus of lesioned animals. No Fos staining was detected by immunocytochemistry in the intact control group. However, detection of FLI in the group submitted to anesthesia and surgical procedures, although less intense than in the lesion group, indicated that microtraumas may occur which are not detected by the Tarlov/Bohlman scores. There is both a local and remote effect of a distal contusion on the spinal cord of rats, implicating sensory neurons and centers related to autonomic control in the reaction to this kind of injury.

E.A., Del-Bel; C.A.G., Borges; H.L.A., Defino; F.S., Guimarăes.

156

Immunoreactive LH in long-term frozen human urine samples.  

Science.gov (United States)

Urine provides a convenient non-invasive alternative to blood sampling for measurement of certain hormones. Urinary luteinizing hormone (LH) measurements have been used for endocrinology research and anti-doping testing. However, the commercially available LH immunoassays are developed and validated for human blood samples but not urine so that LH assays intended for use with urine samples need thorough validation. Therefore, the present study evaluated the measurement of urinary LH immunoreactivity using previously validated immunofluorometric (IF) and immunochemiluminometric (ICL) LH assays after prolonged frozen storage. LH was measured in serial urine samples following administration of a single injection of one of two doses of recombinant human chorionic hormone (rhCG) with assays run at the end of study (2008) and again after four years of frozen (-20?°C) storage where samples were stored without adding preservatives. The ICL assay showed quantitatively reproducible LH measurements after prolonged -20?°C storage. However, the IF immunoassay gave consistently lower LH levels relative to ICL (2008) with a further proportionate reduction after four years of sample storage (2012). Yet, both the assays displayed similar patterns of the time-course of urine LH measurement both before and after four years of frozen storage. In conclusion, we found that both immunoassays are suitable for urinary LH measurements with ICL assay being more robust for quantitative urinary LH measurement such as for anti-doping purposes, whereas the IF could be applicable for research studies where urine LH levels are compared within-study but not in absolute terms. PMID:23606665

Singh, Gurmeet Kaur Surindar; Jimenez, Mark; Newman, Ron; Handelsman, David J

2014-04-01

157

Comparison of immunoreactive serum trypsinogen and lipase in Cystic Fibrosis  

International Nuclear Information System (INIS)

The incidence of Cystic Fibrosis (CF) is 1 in 2,000. Early detection and treatment of CF may necessitate newborn screening with a reliable and cost-effective test. Serum immunoreactive trypsinogen (IRT) an enzyme produced by the pancreas, is detectable by radioimmunoassay (RIA) techniques. Recently, it has been shown that IRT is elevated in CF infants for the first few months of life and levels become subnormal as pancreatic insufficiency progresses. Other enzymes produced by the pancreas, such as lipase, are also elevated during this time. The author's earlier work confirmed previous reports of elevated IRT levels in CF infants. The development of a new RIA for lipase (nuclipase) has enabled comparison of these 2 pancreatic enzymes in C.F. Serum IRT and lipase determinations were performed on 2 groups of CF patients; infants under 1 year of age, and children between 1 and 18 years of age. Control populations of the same age groups were included. The results showed that both trypsin (161 +- 92 ng/ml, range 20 to 400) and lipase (167 +- 151 ng/ml, range 29 to 500) are elevated in CF in the majority of infants. Control infants had values of IRT ranging from 20 to 29.5 ng/ml and lipase values ranging from 23 to 34 ng/ml. IRT becomes subnormal in most CF patients by 8 years of age as pancreatic function insufficiency increases. Lipase levels and IRT levels correlate well in infancy, but IRT is a more sensitive indicator of pancreatic insufficiency in older patients with CF

158

Biochemical analysis of CTLA-4 immunoreactive material from human blood  

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Full Text Available Abstract Background CTLA-4 was initially described as a membrane-bound molecule that inhibited lymphocyte activation by interacting with B7.1 and B7.2 molecules on antigen presenting cells. Alternative splicing of mRNA encoding the CTLA-4 receptor leads to the production of a molecule (sCTLA-4 that lacks a membrane anchor and is therefore secreted into the extracellular space. Despite studies finding that people with autoimmune disease more frequently express high levels of sCTLA-4 in their blood than apparently healthy people, the significance of these findings is unclear. Methods Molecules isolated from blood using CTLA-4 specific antibodies were analyzed with ligand binding assays, mass spectroscopy, and biochemical fractionation in an effort to increase our understanding of CTLA-4 immunoreactive material. Results Mass spectroscopy analysis of the molecules recognized by multiple CTLA-4-specific antibodies failed to identify any CTLA-4 protein. Even though these molecules bind to the CTLA-4 receptors B7.1 and B7.2, they also exhibit properties common to immunoglobulins. Conclusion We have identified molecules in blood that are recognized by CTLA-4 specific antibodies but also exhibit properties of immunoglobulins. Our data indicates that what has been called sCTLA-4 is not a direct product of the CTLA-4 gene, and that the CTLA-4 protein is not part of this molecule. These results may explain why the relationship of sCTLA-4 to immune system activity has been difficult to elucidate.

Dennert Kate

2009-09-01

159

Induction of Fos protein immunoreactivity by spinal cord contusion  

Scientific Electronic Library Online (English)

Full Text Available SciELO Brazil | Language: English Abstract in english The objective of the present study was to identify neurons in the central nervous system that respond to spinal contusion injury in the rat by monitoring the expression of the nuclear protein encoded by the c-fos gene, an activity-dependent gene, in spinal cord and brainstem regions. Rats were anest [...] hetized with urethane and the injury was produced by dropping a 5-g weight from 20.0 cm onto the exposed dura at the T10-L1 vertebral level (contusion group). The spinal cord was exposed but not lesioned in anesthetized control animals (laminectomy group); intact animals were also subjected to anesthesia (intact control). Behavioral alterations were analyzed by Tarlov/Bohlman scores, 2 h after the procedures and the animals were then perfused for immunocytochemistry. The patterns of Fos-like immunoreactivity (FLI) which were site-specific, reproducible and correlated with spinal laminae that respond predominantly to noxious stimulation or injury: laminae I-II (outer substantia gelatinosa) and X and the nucleus of the intermediolateral cell column. At the brain stem level FLI was detected in the reticular formation, area postrema and solitary tract nucleus of lesioned animals. No Fos staining was detected by immunocytochemistry in the intact control group. However, detection of FLI in the group submitted to anesthesia and surgical procedures, although less intense than in the lesion group, indicated that microtraumas may occur which are not detected by the Tarlov/Bohlman scores. There is both a local and remote effect of a distal contusion on the spinal cord of rats, implicating sensory neurons and centers related to autonomic control in the reaction to this kind of injury.

E.A., Del-Bel; C.A.G., Borges; H.L.A., Defino; F.S., Guimarăes.

2000-05-01

160

Similar fine structural localization of immunoreactive glutamate in the frog pineal complex and retina.  

Science.gov (United States)

The distribution of immunoreactive glutamate was compared in the pineal complex (pineal and frontal organs) and retina of frogs (Rana esculenta, R. arvalis, R. ridibunda, R. catesbeiana, Bufo viridis, Bombinator igneus) by postembedding immuno-electron microscopy. Similar to retinal photoreceptors (rods and cones), bipolars and ganglion cells, the rod- and cone-like photoreceptors and the neurons of the pineal and frontal organs exhibited glutamate immunoreactivity. Synaptic terminals of photoreceptor cells on secondary neurons of the pineal complex and retina were strongly immunoreactive. The pineal tract and the fibers of the frontal nerve also displayed glutamate immunoreactivity. There was no essential difference in the immunoreactivity of the retinal and pineal elements among the species studied. The similar histology of the pineal complex and retina of the frog and the high correlation of their binding sites of antiglutamate immunosera allow us to assume that glutamate performs a similar role in the pineal complex as is already known for the retina. The high immunoreactivity of the presynaptic region of pinealocytic processes and axons of secondary neurons suggests the role of a neurotransmitter for this excitatory amino acid in the efferent pathways of the pineal complex. PMID:7612360

Vigh, B; Vigh-Teichmann, I; Debreceni, K; Takács, J

1995-03-01

 
 
 
 
161

Echocardiographic abnormalities following cardiac radiation  

International Nuclear Information System (INIS)

Five years or more after receiving cardiac radiation, 41 patients with Hodgkin's disease and seminoma in remission were subjected to echocardiography. The abnormalities detected included pericardial thickening in 70%, thickening of the aortic and/or mitral valves in 28%, right ventricular dilatation or hypokinesis in 39%, and left ventricular dysfunction in 39%. In the 23 patients treated by an upper mantle technique with shielding, the incidence of right ventricular abnormalities and valvular thickening was significantly lower than in patients treated with modified techniques. Although no symptoms were attributable to the observed abnormalities, longer follow-up time may reveal important functional implications

162

Postnatal changes in tryptophan hydroxylase and serotonin transporter immunoreactivity in multiple brainstem nuclei of the rat: implications for a sensitive period.  

Science.gov (United States)

Previously, we found that the brainstem neuronal network in normal rats undergoes abrupt neurochemical, metabolic, and physiological changes around postnatal days (P) 12-13, a critical period when the animal's response to hypoxia is also the weakest. This has special implications for sudden infant death syndrome (SIDS), insofar as seemingly normal infants succumb to SIDS when exposed to respiratory stressors (e.g., hypoxia) during a narrow postnatal window. Because an abnormal serotonergic system has recently been implicated in SIDS, we conducted a large-scale investigation of the 5-HT-synthesizing enzyme tryptophan hydroxylase (TPH) and serotonin transporter (SERT) with semiquantitative immunohistochemistry in multiple brainstem nuclei of normal rats aged P2-21. We found that 1) TPH and SERT immunoreactivity in neurons of raphé magnus, obscurus, and pallidus and SERT in the neuropil of the pre-Bötzinger complex, nucleus ambiguus, and retrotrapezoid nucleus were high at P2-11 but decreased markedly at P12 and plateaued thereafter until P21; 2) SERT labeling in neurons of the lateral paragigantocellular nucleus (LPGi) and parapyramidal region (pPy) was high at P2-9 but fell significantly at P10, followed by a gradual decline until P21; 3) TPH labeling in neurons of the ventrolateral medullary surface was stable except for a significant fall at P12; and 4) TPH and SERT immunoreactivity in a number of other nuclei was relatively stable from P2 to P21. Thus, multiple brainstem nuclei exhibited a significant decline in TPH and SERT immunoreactivity during the critical period, suggesting that such normal development can contribute to a narrow window of vulnerability in postnatal animals. PMID:20127812

Liu, Qiuli; Wong-Riley, Margaret T T

2010-04-01

163

GFAP immunoreactivity within the rat nucleus ambiguus after laryngeal nerve injury.  

Science.gov (United States)

Changes that occur in astroglial populations of the nucleus ambiguus after recurrent (RLN) or superior (SLN) laryngeal nerve injury have hitherto not been fully characterised. In the present study, rat RLN and SLN were lesioned. After 3, 7, 14, 28 or 56 days of survival, the nucleus ambiguus was investigated by means of glial fibrillary acidic protein (GFAP) immunofluorescence or a combination of GFAP immunofluorescence and the application of retrograde tracers. GFAP immunoreactivity was significantly increased 3 days after RLN resection and it remained significantly elevated until after 28 days post injury (dpi). By 56 dpi it had returned to basal levels. In contrast, following RLN transection with repair, GFAP immunoreactivity was significantly elevated at 7 dpi and remained significantly elevated until 14 dpi. It had returned to basal levels by 28 dpi. Topographical analysis of the distribution of GFAP immunoreactivity revealed that after RLN injury, GFAP immunoreactivity was increased beyond the area of the nucleus ambiguus within which RLN motor neuron somata were located. GFAP immunoreactivity was also observed in the vicinity of neuronal somata that project into the uninjured SLN. Similarly, lesion of the SLN resulted in increased GFAP immunoreactivity around the neuronal somata projecting into it and also in the vicinity of the motor neuron somata projecting into the RLN. The increase in GFAP immunoreactivity outside of the region containing the motor neurons projecting into the injured nerve, may reflect the onset of a regenerative process attempting to compensate for impairment of one of the laryngeal nerves and may occur because of the dual innervation of the posterior cricoarytenoid muscle. This dual innervation of a very specialised muscle could provide a useful model system for studying the molecular mechanisms underlying axonal regeneration process and the results of the current study could provide the basis for studies into functional regeneration following laryngeal nerve injury, with subsequent application to humans. PMID:25181319

Berdugo-Vega, G; Arias-Gil, G; Rodriguez-Niedenführ, M; Davies, D C; Vázquez, T; Pascual-Font, A

2014-11-01

164

Distinct patterns of C4d immunoreactivity in placentas with villitis of unknown etiology, cytomegaloviral placentitis, and infarct.  

Science.gov (United States)

C4d deposition is considered to be evidence of antibody-mediated rejection. This study was conducted to compare C4d immunoreactivity between villitis of unknown etiology (VUE) and cytomegaloviral placentitis. C4d immunohistochemistry was performed in cases with VUE (n = 16) and cytomegaloviral placentitis (n = 5). Distinct, linear C4d immunoreactivity along the syncytiotrophoblast was found in all VUE cases. In cytomegaloviral placentitis, the intensity of C4d immunoreactivity along the syncytiotrophoblast was not prominent, but cytoplasmic C4d immunoreactivity of villous cytotrophoblasts was frequently observed. Further screening of the cases with placental infarcts (n = 5) demonstrated prominent C4d immunoreactivity in the chorionic villi adjacent to the infarct. We report the characteristic co-localization of VUE and C4d immunoreactivity. The overall findings in this study strongly suggest that the complement activation is a common mechanism of diverse placental injuries associated with rejection, infection, and ischemia. PMID:23481222

A Lee, K; Kim, Y W; Shim, J Y; Won, H S; Lee, P R; Kim, A; Kim, C J

2013-05-01

165

FMRFamide immunoreactivity in the nervous system of the medusa Polyorchis penicillatus  

DEFF Research Database (Denmark)

Three different antisera to the molluscan neuropeptide Phe-Met-Arg-Phe-amide (FMRFamide) and two different antisera to the fragment RFamide were used to stain sections or whole mounts of the hydrozoan medusa Polyorchis penicillatus. All antisera stained the same neuronal structures. Strong immunoreactivity was found in neurons of the ectodermal nerve nets of the manubrium and tentacles, in neurons of the sensory epithelium, and in neurons at the periphery of the sphincter muscle. Strong immunoreactivity was also present in processes and perikarya of the whole outer nerve ring, in the ocellar nerves, and in nerve cells lying at the periphery of the ocellus. The inner nerve ring contained a moderate number of immunoreactive processes and perikarya, which were distinct from the swimming motor neurons. In contrast to the situation in the hydrozoan polyp Hydra attenuata, no immunoreactivity was found with several antisera to oxytocin/vasopressin and bombesin/gastrin-releasing peptide. The morphology and location of most FMRFamide-immunoreactive neurons in Polyorchis coincides with two identified neuronal systems, which have been recently discovered from neurophysiological studies.

Grimmelikhuijzen, C J; Spencer, A N

1984-01-01

166

Abnormal waves during Hurricane Camille  

Science.gov (United States)

A reanalysis is reported of the wave time series recorded during Hurricane Camille having as objective the identification of individual waves that satisfy current criteria defining abnormal or freak waves. It is shown that during the hurricane development, a very nonstationary situation has occurred during which the second-order sea state parameters changed significantly with time. The parameters of the largest individual waves in sea states which identify abnormal waves did not show any clear trend, and such waves occurred during the development stage and not when the significant wave height was the largest. It is argued that the present criteria of identification of abnormal waves are not satisfactory, as they do not take into account the nature of the sea states in which the waves occur.

Guedes Soares, C.; Cherneva, Z.; AntăO, E. M.

2004-08-01

167

Complex patterns of abnormal heartbeats  

Science.gov (United States)

Individuals having frequent abnormal heartbeats interspersed with normal heartbeats may be at an increased risk of sudden cardiac death. However, mechanistic understanding of such cardiac arrhythmias is limited. We present a visual and qualitative method to display statistical properties of abnormal heartbeats. We introduce dynamical "heartprints" which reveal characteristic patterns in long clinical records encompassing approximately 10(5) heartbeats and may provide information about underlying mechanisms. We test if these dynamics can be reproduced by model simulations in which abnormal heartbeats are generated (i) randomly, (ii) at a fixed time interval following a preceding normal heartbeat, or (iii) by an independent oscillator that may or may not interact with the normal heartbeat. We compare the results of these three models and test their limitations to comprehensively simulate the statistical features of selected clinical records. This work introduces methods that can be used to test mathematical models of arrhythmogenesis and to develop a new understanding of underlying electrophysiologic mechanisms of cardiac arrhythmia.

Schulte-Frohlinde, Verena; Ashkenazy, Yosef; Goldberger, Ary L.; Ivanov, Plamen Ch; Costa, Madalena; Morley-Davies, Adrian; Stanley, H. Eugene; Glass, Leon

2002-01-01

168

Galanin immunoreactivity in the brain of the desert lizard Uromastyx acanthinura during activity season.  

Science.gov (United States)

The distribution of galanin immunoreactive perikarya and nerve fibers in the brain of the desert lizard U. acanthinura was studied by means of immunofluorescence using an antiserum against rabbit galanin. The animals were captured during the activity season in March (wet season) just before reproduction period and in June (arid season) after ovulation period. Immunoreactive neurons were mostly detected in the mediobasal and the infundibular recess nuclei, the nucleus of the paraventricular organ, the paraventricular organ, the periventricular nucleus and in the anterior hypothalamus at the level of the periventricular nucleus, the paraventricular nucleus and the supraoptic nucleus. The differences in brain galanin expression between animals collected under both sets of environmental conditions indicated changes which occur during the annual and reproductive cycles. The wide hypothalamic and extrahypothalamic distribution of galanin immunoreactive fibers suggests that this peptide may have hypophysiotropic, neuromodulator and neurotransmitter roles in the lizard U. acanthinura. PMID:23690217

Hammouche, Sadjia Benmansour; Bennis, Mohammed

2013-01-01

169

Distribution of somatostatin-immunoreactivity in the brain of the larval lamprey (Petromyzon marinus).  

Science.gov (United States)

The detailed distribution of somatostatinergic neurons and fibre tracts in the brain of larval lamprey was studied in serially sectioned material using immunocytochemical techniques. Neurons were found to be arranged in four nuclei: a hypothalamic nucleus consisting of both small cerebrospinal fluid-contacting neurons and larger non-contacting neurons, a thalamomesencephalic nucleus and two isthmotrigeminal reticular nuclei. The hypothalamic nucleus is the first to differentiate. Analysis of young larvae showed that somatostatin-immunoreactivity first appeared in hypothalamic cells (12 mm larvae), while it appeared later in the other nuclei. The different somatostatin-immunoreactive fibre tracts innervate different regions of the brain. In addition, somatostatin-immunoreactive fibres originating from hypothalamic neurons were found in the anterior neurohypophysis, which suggests the presence of a hypothalamohypophysial somatostatinergic system in lampreys. PMID:1362063

Yáńez, J; Rodríguez-Moldes, I; Anadón, R

1992-01-01

170

Tyrosine hydroxylase-like immunoreactivity in the brain of the teleost fish Tinca tinca.  

Science.gov (United States)

The distribution of tyrosine hydroxylase-like immunoreactivity has been studied in the central nervous system of the tench (Tinca tinca) using a monoclonal antibody and the avidin-biotin-immunoperoxidase technique. Immunoreactive elements were found in all brain subdivisions. Thus, catecholaminergic neurons and fibers were detected in most nuclei of the ventral telencephalon and in the pars centralis and lateralis of the dorsal telencephalon. The diencephalon was the brain subdivision where largest density of immunoreactive elements were found, mainly located in the periventricular region. The mesencephalon and metencephalon only demonstrated immunoreactive fibers, and no immunoreactive cell bodies were observed in these regions. The myelencephalon showed three groups of immunoreactive neurons located at isthmal level, in the central medullary area, and at the medullary-spinal cord transition area. The distribution of catecholaminergic elements in the tench brain revealed a general pattern shared by most teleosts. The number and distribution of catecholaminergic elements was similar to those described in other teleostean species in the caudal region of the brain. However, noticeable differences were found in areas related to the integration of different sensory information, specially in the telencephalon and diencephalon, suggesting a relationship among the functional level of each sensorial system and the complexity of the catecholaminergic innervation of their integration regions. Additionally, this study revealed the presence of an important number of cerebrospinal fluid-contacting cells in the organum paraventricularis expressing tyrosine hydroxylase that in most investigated teleostean species were tyrosine hydroxylase-immunonegative despite they contained catecholamines. This data argues for distinct evolutionary patterns in the hypothalamic catecholaminergic system among different teleostean species. PMID:9492943

Brińón, J G; Arévalo, R; Weruaga, E; Crespo, C; Alonso, J R; Aijón, J

1998-01-01

171

Neonatal screening for cystic fibrosis using immunoreactive trypsinogen and direct gene analysis: four years' experience.  

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OBJECTIVE--To assess the performance and impact of a two tier neonatal screening programme for cystic fibrosis based on an initial estimation of immunoreactive trypsinogen followed by direct gene analysis. DESIGN--Four year prospective study of two tier screening strategy. First tier: immunoreactive trypsinogen measured in dried blood spot samples from neonates aged 3-5 days. Second tier: direct gene analysis of cystic fibrosis mutations (delta F508, delta I506, G551D, G542X, and R553X) in sa...

Ranieri, E.; Lewis, B. D.; Gerace, R. L.; Ryall, R. G.; Morris, C. P.; Nelson, P. V.; Carey, W. F.; Robertson, E. F.

1994-01-01

172

Substance P-like immunoreactivity in the nervous system of hydra  

DEFF Research Database (Denmark)

Using immunocytochemistry we find substance P-like material in nerve cells of hydra. These nerve cells are situated in the ectoderm of the basal disk and tentacles. Radioimmunoassay of hydra extracts gives dilution curves parallel to that of synthetic substance P, from which it can be calculated that one animal contains at least 0.6 fmol substance P-like immunoreactivity. After chromatography on Biogel P-100, the substance P-like immunoreactivity elutes as a peak in the void volume and a peak at the position of synthetic substance P.

Grimmelikhuijzen, C J; Balfe, A

1981-01-01

173

Histamine-immunoreactive neurons in the brain of the teleost Gasterosteus aculeatus L. Correlation with hypothalamic tyrosine hydroxylase- and serotonin-immunoreactive neurons.  

Science.gov (United States)

The distribution of putative histaminergic neurons in the brain of a teleost, the three-spined stickleback, was investigated by means of immunocytochemistry using specific antibodies against histamine (HA), and conventional microscopy as well as confocal laser scanning microscopy. Histamine-immunoreactive (HAir) neurons form discrete populations ventral to the nucleus of the posterior recess (NRP) and in the nucleus saccus vasculosus (NSV), which belong to the periventricular hypothalamic nuclei. The neuronal somata are subependymally located, and do not possess apical neurites contacting the cerebrospinal fluid. They give rise to both long-range and local axonal projections. The local projections give rise to a field of dense punctate immunoreaction dorsal to the NRP and lateral to the NSV. Long-range projections are comprised of ascending projections to the thalamus, habenula, preoptic area and dorsal telencephalon; and descending projections via the posterior tuberal nucleus, ventrally to the nucleus interpeduncularis, and dorsally into the central gray. HAir neurons occur together with serotoninergic cerebrospinal fluid-contacting (CSFc) neurons in the NRP, and with tyrosine hydroxylase-immunoreactive (THir) neurons in the NSV. Although HAir elements occur together with THir ones in many brain areas, direct contacts between the two neurotransmitter systems are rare. The putative histaminergic neurons in the brain of the three-spined stickleback constitute a very discrete neuronal system, with a major projection area in the dorsal telencephalon in a region which is considered homologous with the dorsal pallium of land vertebrates. PMID:7598814

Ekström, P; Holmqvist, B I; Panula, P

1995-02-01

174

Distribution and developmental expression of octopamine-immunoreactive neurons in the central nervous system of the leech.  

Science.gov (United States)

Octopamine, a biogenic amine analogous to norepinephrine, plays an important role in the orchestration and modulation of invertebrate behavior. In the leech, the behavioral actions of octopamine have been demonstrated; however, identification of octopaminergic neurons had not been determined by using immunohistochemical techniques. Thus, we used an antibody highly specific to octopamine to examine the distribution of octopamine-immunoreactive neurons in the segmental ganglia of American and European medicinal leeches (Macrobdella decora and Hirudo medicinalis). One pair of octopamine-immunoreactive neurons was located in the dorsolateral ganglionic region of anterior ganglia 1-6 and posterior ganglia 15-21. No corresponding octopamine-immunoreactive neurons were found in midbody ganglia 7-14. Using Neutral Red staining in combination with intracellular Neurobiotin injections and octopamine immunostaining, we determined the identity of the dorsolateral octopamine-immunoreactive cells. The dorsolateral octopamine-immunoreactive neuron (the DLO) was not cell 21, the only previously reported Neutral Red staining neuron in the dorsolateral position. We also determined that the Leydig neuron was not octopamine immunoreactive in either of the two medicinal leech species. Octopamine immunostaining in the sex ganglia revealed hundreds of immunoreactive neurons in sexually mature leeches. Such neurons were not observed in juvenile leeches. The developmental time course of octopamine immunoreactivity in the dorsolateral octopamine-immunoreactive neurons was also investigated by staining embryonic Hirudo medicinalis. Octopamine expression occurred relatively late as compared with the detectable onset of serotonin expression. Octopamine expression in the dorsolateral octopamine-immunoreactive cells was not detectable at early to mid-embryonic stages, and must commence during late embryonic to early juvenile stages. The identification of octopamine-immunoreactive cells now sets the stage for further investigations into the functional role of octopamine in leech behavior and the development of behavior. PMID:7751442

Gilchrist, L S; Klukas, K A; Jellies, J; Rapus, J; Eckert, M; Mesce, K A

1995-03-13

175

Amyotrophic lateral sclerosis mutant vesicle-associated membrane protein-associated protein-B transgenic mice develop TAR-DNA-binding protein-43 pathology.  

LENUS (Irish Health Repository)

Cytoplasmic ubiquitin-positive inclusions containing TAR-DNA-binding protein-43 (TDP-43) within motor neurons are the hallmark pathology of sporadic amyotrophic lateral sclerosis (ALS). TDP-43 is a nuclear protein and the mechanisms by which it becomes mislocalized and aggregated in ALS are not properly understood. A mutation in the vesicle-associated membrane protein-associated protein-B (VAPB) involving a proline to serine substitution at position 56 (VAPBP56S) is the cause of familial ALS type-8. To gain insight into the molecular mechanisms by which VAPBP56S induces disease, we created transgenic mice that express either wild-type VAPB (VAPBwt) or VAPBP56S in the nervous system. Analyses of both sets of mice revealed no overt motor phenotype nor alterations in survival. However, VAPBP56S but not VAPBwt transgenic mice develop cytoplasmic TDP-43 accumulations within spinal cord motor neurons that were first detected at 18 months of age. Our results suggest a link between abnormal VAPBP56S function and TDP-43 mislocalization.

Tudor, E L

2010-05-19

176

Kisspeptin-like immunoreactive neuron distribution in the green anole (Anolis carolinensis).  

Science.gov (United States)

Kisspeptins are a recently identified class of neuropeptides belonging to the RFamide peptide family. Despite growing evidence supporting kisspeptin as a key regulator of reproduction, data addressing whether kisspeptin is a conserved reproductive signal are lacking. We investigated the distribution of kisspeptin in adult green anole lizards (Anolis carolinensis) via immunohistochemistry. Additionally, we examined the possibility of a sexual dimorphism in kisspeptin expression. Kisspeptin immunoreactivity was observed rostrally in the preoptic area and caudally in an area lateral to the dorsal hypothalamic nucleus in both male and female anoles. These kisspeptin immunoreactive cells are associated with vesiculated fibers traveling through the paraventricular zone of the hypothalamus and preoptic area and extending into the rostral telencephalon. Preabsorption of the antiserum with gonadotropin inhibitory hormone (GnIH), a second RFamide peptide known to cross-react with the kisspeptin antiserum, eliminated staining of the caudal population of cells but retained staining in the rostral population, suggesting that kisspeptin is present in this area. Preabsorption with kisspeptin eliminated all immunoreactivity. These preabsorption results suggest that kisspeptin is restricted to a single population in the preoptic area in anoles. No sex differences were found in kisspeptin immunoreactive cell number. The presence of kisspeptin RFamide peptide in the green anole suggests that this reproductive regulatory signal is indeed evolutionarily conserved. Whether this reproductive signal functions similarly in regulating the reproductive axis of ectotherms requires further study. PMID:19420914

Dunham, Leslie A; Lutterschmidt, Deborah I; Wilczynski, Walter

2009-01-01

177

Immunoreactive intensity of FXPRL amide neuropeptides in response to environmental conditions in the silkworm, Bombyx mori.  

Science.gov (United States)

In the silkworm Bombyx mori, the diapause hormone-pheromone biosynthesis activating neuropeptide gene, DH-PBAN, is a neuropeptide gene that encodes a polypeptide precursor consisting in five Phe-X-Pro-Arg-Leu-NH(2) (FXPRL) amide (FXPRLa) neuropeptides; DH (diapause hormone), PBAN (pheromone-biosynthesis-activating neuropeptide) and ?-, ?- and ?-SGNPs (subesophageal ganglion neuropeptides). These neuropeptides are synthesized in DH-PBAN-producing neurosecretory cells contained within three neuromeres, four mandibular cells, six maxillary cells, two labial cells (SLb) and four lateral cells of the subesophageal ganglion. DH is solely responsible, among the FXPRLa peptide family, for embryonic diapause. Functional differentiation has been previously suggested to occur at each neuromere, with the SLb cells releasing DH through brain innervation in order to induce embryonic diapause. We have investigated the immunoreactive intensity of DH in the SLb when thermal (25°C or 15°C) and light (continuous illumination or darkness) conditions are altered and following brain surgery that induces diapause or non-diapause eggs in the progeny. We have also examined the immunoreactivity of the other FXPRLa peptides by using anti-?-SGNP and anti-PBAN antibodies. Pupal SLb somata immunoreactivities seem to be affected by both thermal and light conditions during embryogenesis. Thus, we have been able to identify a close correlation between the immunoreactive intensity of neuropeptides and environmental conditions relating to the determination of embryonic diapause in B. mori. PMID:21103995

Hagino, Ayako; Kitagawa, Norio; Imai, Kunio; Yamashita, Okitsugu; Shiomi, Kunihiro

2010-12-01

178

Influence of resting tension on immunoreactive atrial natriuretic peptide secretion by rat atria superfused in vitro  

International Nuclear Information System (INIS)

Atrial natriuretic peptide is a potent diuretic hormone secreted by the atria in response to volume expansion. We examined the effect of resting tension on atrial natriuretic peptide secretion by rat atria superfused in vitro. Left atria were hooked between an electrode and force transducer and superfused with medium 199. The atria were studied at a pacing frequency of 0 or 3 Hz. Atrial natriuretic peptide content of the superfusate was measured by radioimmunoassay. In nonpaced and paced atria, increasing resting tension three- to five-fold caused immunoreactive atrial natriuretic peptide secretion to increase by 35 +/- 5% (mean +/- SEM, n = 6, p less than 0.01) and 30 +/- 3% (n = 4, p less than 0.01), respectively. Lowering resting tension by 50% in nonpaced and paced atria lowered immunoreactive atrial natriuretic peptide secretion by 30 +/- 3% (n = 7, p less than 0.01) and 24 +/- 3% (n = 6, p less than 0.01), respectively. To exclude the possibility that release of norepinephrine or acetylcholine from endogenous nerve endings was mediating this effect, the atria were superfused with the combination of propranolol 0.1 microM, phentolamine 1.0 microM, and atropine 10 microM. These concentrations of the antagonists were 125-fold or higher than their Kd for binding to their respective receptors. The antagonists did not block the rise in immunoreactive atrial natriuretic peptide secretion; neither did they inhibit an established rise in immunoreactive atrial natriuretic peptide secretion induced by increasing the resting tension

179

[Alterations of immunoreactivity in cnemical production workers in dependence on dose exposure to toxicants].  

Science.gov (United States)

The immunological examination of employees working in the production of caustic soda, vinyl chloride, polyvinyl chloride and epichlorohydrin has been performed. The features of the relationship between alterations in indices of immunoreactivity and dose exposure for total years of employment in persons exposed to various chemical substances have been established. PMID:23082668

2012-01-01

180

Increased immunoreactivity of cathepsins in the rat esophagus under chronic acid reflux esophagitis.  

Science.gov (United States)

We have designed a stable rat chronic acid reflux esophagitis (RE) model. In gastrointestinal lesions, several lysosomal cathepsins are known to participate in epithelial permeability in cell-cell connections, such as tight junctions in ulcerative colitis. However, very few studies have focused on the distribution of cathepsins in the esophageal multilayer squamous epithelium. Therefore to clarify the role of cathepsins in RE, we investigated their immunohistological localization in the esophageal epithelium under normal conditions and after RE. Of the cathepsins examined (cathepsins B, C, D, F, H, L, S, and X), granular immunoreactivity for cathepsins B, C, D and L was observed in the control esophageal epithelia; although, their distribution differed depending on the enzyme examined. In the RE model, immunoreactivity of these cathepsins was increased in esophageal epithelial cells and activated macrophages. The immunoreactivity for cathepsins F, H, S and X was barely detectable in the control esophageal epithelium. However, in the RE model, we noticed a slight increase in the expression of cathepsins H and X in the epithelial cells. Furthermore, activated macrophages of the RE model possessed intense immunoreactivity for these cathepsins, which may have been related to esophageal inflammatory mechanisms. PMID:24943348

Suyama, Masayuki; Koike, Masato; Asaoka, Daisuke; Mori, Hiroki; Oguro, Masako; Ueno, Takashi; Nagahara, Akihito; Watanabe, Sumio; Uchiyama, Yasuo

2014-09-01

 
 
 
 
181

Detection of 2 immunoreactive antigens in the cell wall of Sporothrix brasiliensis and Sporothrix globosa.  

Science.gov (United States)

The cell wall of members of the Sporothrix schenckii complex contains highly antigenic molecules which are potentially useful for the diagnosis and treatment of sporotrichosis. In this study, 2 immunoreactive antigens of 60 (Gp60) and 70 kDa (Gp70) were detected in the cell wall of the yeast morphotypes of Sporothrix brasiliensis and Sporothrix globosa. PMID:24827145

Ruiz-Baca, Estela; Hernández-Mendoza, Gustavo; Cuéllar-Cruz, Mayra; Toriello, Conchita; López-Romero, Everardo; Gutiérrez-Sánchez, Gerardo

2014-07-01

182

Extraurophyseal distribution of urotensin II immunoreactive neuronal perikarya and their processes  

Science.gov (United States)

The use of the unlabeled antibody enzyme method on serially adjacent sections permitted the demonstration of urotensin II (UII) and urotensin I (UI) immunoreactivities colocalized in most of the cells of the caudal neurosecretory system of Catostomus commersoni. The study of the upper regions of the central nervous system from the spinal cord anterior to the fifth preterminal vertebral region up to and including the brain stem revealed the presence of UII immunoreactivity in cerebrospinal fluid-contacting neurons, located ventral to the central canal along the entire length of the spinal cord and medulla. Beaded nerve fibers were observed projecting to the ventrolateral surface of the spinal cord and also forming a seemingly ascending immunoreactive-UII longitudinal bundle directed toward the brain. The presence of this “extraurophyseal” system of immunoreactive-UII cells and fibers suggests that the UII peptide may be released in upper regions of the central nervous system in response to stimuli conveyed via the cerebral spinal fluid. Thus, separate functions may be postulated for the urophyseal and the cerebral spinal fluid-contacting urotensin II systems. Images PMID:16593763

Yulis, C. R.; Lederis, K.

1986-01-01

183

Association of alpha-synuclein immunoreactivity with inflammatory activity in multiple sclerosis lesions.  

Science.gov (United States)

Multiple sclerosis (MS) has neurodegenerative features including neuronal and axonal loss and widespread atrophy of the brain and spinal cord. The cause of this neurodegeneration has been largely attributed to inflammation, but other mechanisms, including those associated with classic neurodegenerative diseases such as the alpha-synucleinopathies, might also be involved in MS pathogenesis. In this study, 96 brain lesions containing varying degrees of inflammatory activity from 12 autopsied MS cases were compared with corresponding regions from 6 neuropathologically normal controls; 2 cerebral biopsy lesions from an MS patient were also studied. We found alpha-synuclein immunoreactivity in the cytoplasm of cells in MS lesions with inflammatory activity but not in control samples. alpha-Synuclein-immunoreactive cells were identified in active (15/15 lesions in the brainstem, 9/13 in cerebral hemispheres) and chronic active (14/15 in the brainstem, 12/22 in cerebral hemispheres) lesions but were absent in chronic inactive lesions (0/31); the greater immunoreactivity in brainstem compared with cerebral hemisphere lesions was significant (p < 0.05). Double-immunofluorescence staining revealed localization of alpha-synuclein immunoreactivity mostly in neurons, microglia/macrophages, and oligodendrocytes, and only rarely in astrocytes. The results suggest that alpha-synuclein expression regulated by inflammatory signals may contribute to neurodegenerative processes in MS lesions. PMID:19151622

Lu, Jian-Qiang; Fan, Yan; Mitha, Alim P; Bell, Robert; Metz, Luanne; Moore, G R Wayne; Yong, V Wee

2009-02-01

184

FMRFamide immunoreactivity is generally occurring in the nervous systems of coelenterates  

DEFF Research Database (Denmark)

Abundant FMRFamide immunoreactivity has been found in the nervous systems of all hydrozoan, anthozoan, scyphozoan and ctenophoran species that were looked upon. This general and abundant occurrence shows that FMRFamide-like material must play a crucial role in the functioning of primitive nervous systems.

Grimmelikhuijzen, C J

1983-01-01

185

Insulin immunoreactive sites demonstrated in the Golgi apparatus of pancreatic B cells.  

Science.gov (United States)

Insulin immunoreactive sites were localized in the Golgi apparatus of pancreatic B cells by light and electron microscopy. Identification of the Golgi apparatus by immunofluorescence required the prior degranulation of B cells with glibenclamide to reduce the insulin immunostaining due to secretory granules. In such cells, insulin immunofluorescence revealed brightly stained, crescent-shaped strands with form and location super-imposable on that of Golgi complexes seen in thin sections of the same cells. With the electron microscope, the insulin immunoreactive sites revealed by the protein A/gold technique were localized in the cisternae and vesicles of the Golgi apparatus of glibenclamide-treated and control B cells and over maturing and mature secretory granules. The quantitative evaluation of the intensity of the insulin immunoreactive sites in the Golgi apparatus revealed a density of sites 4 times more than cellular background values. The demonstration of insulin immunoreactivity in the Golgi apparatus provides direct evidence for the involvement of this compartment in the transport and maturation of proinsulin into insulin. PMID:7029541

Ravazzola, M; Perrelet, A; Roth, J; Orci, L

1981-09-01

186

Leydig cells in the lingual epithelium of the axolotl, Ambystoma mexicanum, are immunoreactive for serotonin.  

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The Leydig cells in the lingual epithelium of the axolotl were investigated by immunohistochemistry using serotonin antiserum. Serotonin-immunoreactivity was found in their secretory granules. The physiological role of serotonin in the Leydig cell, a type of exocrine cell, is unknown.

Toyoshima, K.; Shimamura, A.

1992-01-01

187

Progesterone attenuates several hippocampal abnormalities of the Wobbler mouse.  

Science.gov (United States)

It is now recognised that progesterone plays a protective role for diseases of the central nervous system. In the Wobbler mouse, a model of motoneurone degeneration, progesterone treatment prevents spinal cord neuropathology and clinical progression of the disease. However, neuropathological and functional abnormalities have also been discovered in the brain of Wobbler mice and patients with amyotrophic lateral sclerosis. The present study examined the hippocampus of control and afflicted Wobbler mice and the changes in response to progesterone treatment. Mice received either a single progesterone implant (20 mg for 18 days). We found that the hippocampal pathology of the untreated Wobblers involved a decreased expression of brain-derived neurotrophic factor (BDNF) mRNA, decreased astrogliosis in the stratum lucidum, stratum radiatum and stratum lacunosum-moleculare, decreased doublecortin (DCX)-positive neuroblasts in the subgranular zone of the dentate gyrus and a decreased density of GABA immunoreactive hippocampal interneurones and granule cells of the dentate gyrus. Although progesterone did not change the normal parameters of control mice, it attenuated several hippocampal abnormalities in Wobblers. Thus, progesterone increased hippocampal BDNF mRNA expression, decreased glial fibrillary acidic protein-positive astrocytes and increased the number of GABAergic interneurones and granule cells. The number of DCX expressing neuroblasts and immature neurones remained impaired in both progesterone-treated and untreated Wobblers. In conclusion, progesterone treatment exerted beneficial effects on some aspects of hippocampal neuropathology, suggesting its neuroprotective role in the brain, in agreement with previous data obtained in the spinal cord of Wobbler mice. PMID:23157231

Meyer, M; Gonzalez Deniselle, M C; Gargiulo-Monachelli, G; Lima, A; Roig, P; Guennoun, R; Schumacher, M; De Nicola, A F

2013-03-01

188

Ontogeny of GnRH-like immunoreactive neuronal systems in the forebrain of the Indian major carp, Cirrhinus mrigala.  

Science.gov (United States)

GnRH immunoreactivity appeared in the medial olfactory placode very early in the development of Cirrhinus mrigala. The immunoreactive elements were divisible into distinct migratory and non-migratory components. The migratory component appeared as a patch of intensely immunoreactive cells located close to the olfactory epithelium in day 6 post-fertilization larvae. Subsequently, these neurons migrate caudally along the ventromedial aspect of the developing forebrain and enroute give rise to GnRH immunoreactive neurons in the (1) nervus terminalis located in ventral and caudal part of the olfactory bulb (day 8), and (2) basal telencephalon (day 9). The non-migratory GnRH immunoreactive component appeared in the olfactory placode of day 1 post-fertilization larvae. It consisted of few olfactory receptor neuron (ORN)-like cells with distinct flask-shaped somata, dendrites that communicate with the periphery and a single axon on the basal side; GnRH immunoreactivity was seen throughout the neuron. Considerable increase in the number of immunoreactive ORNs was encountered in day 2 post-fertilization larvae. On day 3, the dendrites of ORNs sprout bunches of apical cilia, while on the basal side the axonal outgrowths can be traced to the olfactory bulb. GnRH immunoreactive fibers were distributed in the olfactory nerve layer in the periphery of the bulb and glomeruli-like innervation was clearly established in 5 days old larvae. The innervation to the olfactory bulb showed a considerable increase in GnRH immunoreactivity in 9 and 19 days old larvae. However, GnRH immunoreactivity in non-migratory as well as migratory components gradually diminished and disappeared altogether by the age of 68 days. Results of the present study suggest that GnRH may serve a neurotransmitter role in the ORNs during early stages of development in C. mrigala. PMID:15748717

Biju, K C; Gaikwad, Archana; Sarkar, Sumit; Schreibman, Martin P; Subhedar, Nishikant

2005-04-01

189

Echocardiographic abnormalities in hypertensive patients  

International Nuclear Information System (INIS)

A descriptive cross-sectional study was carried out in 120 hypertensive patients with a course of 5 or more years, who went to the emergency room of 'Saturnino Lora' Provincial Teaching Hospital from November 2010 to November 2011 in order to determine the presence or absence of echocardiographic abnormalities typical of hypertension. Of these, 78,3 % was affected, most of whom reported not to continue with regular previous medical treatment, and 21,7 % had not these abnormalities. Age group of 50-60 years, males and blacks prevailed in the case material. The most significant echocardiographic findings were left ventricular hypertrophy and heart failure with ejection fraction of left ventricle preserved

190

Glial abnormalities in mood disorders.  

Science.gov (United States)

Multiple lines of evidence indicate that mood disorders are associated with abnormalities in the brain's cellular composition, especially in glial cells. Considered inert support cells in the past, glial cells are now known to be important for brain function. Treatments for mood disorders enhance glial cell proliferation, and experimental stimulation of cell growth has antidepressant effects in animal models of mood disorders. These findings suggest that the proliferation and survival of glial cells may be important in the pathogenesis of mood disorders and may be possible targets for the development of new treatments. In this article we review the evidence for glial abnormalities in mood disorders, and we discuss glial cell biology and evidence from postmortem studies of mood disorders. The goal is not to carry out a comprehensive review but to selectively discuss existing evidence in support of an argument for the role of glial cells in mood disorders. PMID:25377605

Ongür, Dost; Bechtholt, Anita J; Carlezon, William A; Cohen, Bruce M

2014-01-01

191

Is Dark Energy Abnormally Weighting?  

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We present a new interpretation of dark energy in terms of an \\textit{Abnormally Weighting Energy} (AWE). This means that dark energy does not couple to gravitation in the same way as ordinary matter, yielding a violation of the weak and strong equivalence principles on cosmological scales. The resulting cosmological mechanism accounts for the Hubble diagram of type Ia supernovae in terms of both cosmic acceleration and variation of the gravitational constant while still acc...

Fuzfa, A.; Alimi, J. -m

2006-01-01

192

Radiological appearances of sinonasal abnormalities  

Energy Technology Data Exchange (ETDEWEB)

The aim of this pictorial review is to present a variety of abnormalities of the sinonasal cavities to emphasize the diversity of lesions occurring in this region. These include congenital, neoplastic and granulomatous disorders and some allergic and inflammatory lesions with uncommon radiological appearances, as well as expanding lesions of the facial bones or of dental origin with secondary involvement of the related sinus(es). El-Beltagi, A.H. et al. (2002). Clinical Radiology 57, 702-718.

El-Beltagi, A.H.; Sobeih, A.A.; Valvoda, M.; Dahniya, M.H.; Badr, S.S

2002-08-01

193

Mastoid abnormalities in Down syndrome  

International Nuclear Information System (INIS)

Hearing loss and otitis media are commonly associated with Down syndrome. Hypoplasia of the mastoids is seen in many affected children and sclerosis of mastoid bones is not uncommon in Down syndrome. Awareness and early recognition of mastoid abnormality may lead to appropriate and timely therapy, thereby preserving the child's hearing or compensating for hearing loss; factors which are important for learning and maximum development. (orig.)

194

Computed tomography abnormalities in hanging  

International Nuclear Information System (INIS)

The CT pattern of bilateral and symmetrical round low density areas in the globi pallidi has been observed in a young man who attempted suicide by hanging. These CT abnormalities are similar to those described in other conditions such as carbon monoxide, hydrogen sulfide, cyanide and methanol poisoning, hypoglycaemia, drowning and acute global central nervous system hypoperfusion.The findings appear to be correlated with acute cerebral hypoxia. (orig.)

195

Imaging of pediatric mesenteric abnormalities  

International Nuclear Information System (INIS)

The relative paucity of mesenteric fat seen in the pediatric population can make detection and localization of processes in the mesentery difficult. This pictorial essay reviews pediatric mesenteric disorders and presents criteria that help localize processes to the mesentery. Disorders are categorized by specific patterns of involvement, which can readily be identified by imaging: developmental abnormalities of mesenteric rotation, diffuse mesenteric processes, focal mesenteric masses, and multifocal mesenteric masses. (orig.)

196

Computed tomography of thymic abnormalities  

Energy Technology Data Exchange (ETDEWEB)

Computed tomographic examinations of 38 patients with surgically and histologically proven diagnosis were reviewed. Twenty subjects (52%) had an invasive thymoma and 16% an hyperplastic thymus. Myasthenia gravis was present in 6 cases (16%) of thymic abnormalities, four (10,5%) with invasive thymoma and two (5%) with thymic hyperplasia. Graves' disease was also present in one case of thymic hyperplasia. We emphasize the contribution of CT to the diagnosis and the prognosis.

Schnyder, P.; Candardjis, G.

1987-05-01

197

Direct reticular projections of trigeminal sensory fibers immunoreactive to CGRP: potential monosynaptic somatoautonomic projections  

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Full Text Available Few trigeminal sensory fibers project centrally beyond the trigeminal sensory complex, with only projections of fibers carried in its sensory anterior ethmoidal (AEN and intraoral nerves described. Fibers of the AEN project into the brainstem reticular formation where immunoreactivity against substance P and CGRP are found. We investigated whether the source of these peptides could be from trigeminal ganglion neurons by performing unilateral rhizotomies of the trigeminal root and looking for absence of label. After an 8-14d survival, substance P immunoreactivity in the trigeminal sensory complex was diminished, but we could not conclude that the sole source of this peptide in the lateral parabrachial area and lateral reticular formation arises from primary afferent fibers. Immunoreactivity to CGRP after rhizotomy however was greatly diminished in the trigeminal sensory complex, confirming the observations of others. Moreover, CGRP immunoreactivity was nearly eliminated in fibers in the lateral parabrachial area, the caudal ventrolateral medulla, both the peri-ambiguus and ventral parts of the rostral ventrolateral medulla, in the external formation of the nucleus ambiguus, and diminished in the caudal pressor area. The nearly complete elimination of CGRP in the lateral reticular formation after rhizotomy suggests this peptide is carried in primary afferent fibers. Moreover, the arborization of CGRP immunoreactive fibers in these areas mimics that of direct projections from the AEN. Since electrical stimulation of the AEN induces cardiorespiratory adjustments including an apnea, peripheral vasoconstriction, and bradycardia similar to those seen in the mammalian diving response, we suggest these perturbations of autonomic behavior are enhanced by direct somatic primary afferent projections to these reticular neurons. We believe this to be first description of potential direct somatoautonomic projections to brainstem neurons regulating autonomic activity.

W MichaelPanneton

2014-06-01

198

Loss of non-phosphorylated neurofilament immunoreactivity in temporal cortical areas in Alzheimer's disease  

Science.gov (United States)

The distribution of immunoreactive neurons with non-phosphorylated neurofilament protein (SMI32) was studied in temporal cortical areas in normal subjects and in patients with Alzheimer’s disease (AD). SMI32 immunopositive neurons were localized mainly in cortical layers II, III, V and VI, and were medium to large sized pyramidal neurons. Patients with AD had prominent degeneration of SMI32 positive neurons in layers III and V of Brodmann areas 38, 36, 35, 20; in layers II and IV of the entorhinal cortex (Brodmann area 28); and hippocampal neurons. Neurofibrillary tangles (NFTs) were stained with thioflavin-S and with an antibody (AT8) against hyperphosphorylated tau. The NFT distribution was compared to that of the neuronal cytoskeletal marker SMI32 in these temporal cortical regions. The results showed that the loss of SMI32 immunoreactivity in temporal cortical regions of AD brain is paralleled by an increase in NFTs and AT8 immunoreactivity in neurons. The SMI32 immunoreactivity was drastically reduced in the cortical layers where tangle-bearing neurons are localized. A strong SMI32 immunoreactivity was observed in numerous neurons containing NFTs by double-immunolabelling with SMI32 and AT8. However, few neurons were labeled by AT8 and SMI32. These results suggest that the development of NFTs in some neurons results from some alteration in SMI32 expression, but does not account for all, particularly, early NFT related changes. Also, there is a clear correlation of NFTs with selective population of pyramidal neurons in the temporal cortical areas and these pyramidal cells are specifically prone to formation of paired helical filaments. Furthermore, these pyramidal neurons might represent a significant portion of the neurons of origin of long corticocortical connection, and consequently contribute to the destruction of memory-related input to the hippocampal formation. PMID:19250962

Thangavel, Ramasamy; Sahu, Shailendra K.; Van Hoesen, Gary W.; Zaheer, Asgar

2009-01-01

199

Enteroendocrine profile of ?-transducin immunoreactive cells in the gastrointestinal tract of the European sea bass (Dicentrarchus labrax).  

Science.gov (United States)

In vertebrates, chemosensitivity of nutrients occurs through the activation of taste receptors coupled with G-protein subunits, including ?-transducin (G(?tran)) and ?-gustducin (G(?gust)). This study was aimed at characterising the cells expressing G(?tran) immunoreactivity throughout the mucosa of the sea bass gastrointestinal tract. G(?tran) immunoreactive cells were mainly found in the stomach, and a lower number of immunopositive cells were detected in the intestine. Some G(?tran) immunoreactive cells in the stomach contained G(?gust) immunoreactivity. Gastric G(?tran) immunoreactive cells co-expressed ghrelin, obestatin and 5-hydroxytryptamine immunoreactivity. In contrast, G(?tran) immunopositive cells did not contain somatostatin, gastrin/cholecystokinin, glucagon-like peptide-1, substance P or calcitonin gene-related peptide immunoreactivity in any investigated segments of the sea bass gastrointestinal tract. Specificity of G(?tran) and G(?gust) antisera was determined by Western blot analysis, which identified two bands at the theoretical molecular weight of ~45 and ~40 kDa, respectively, in sea bass gut tissue as well as in positive tissue, and by immunoblocking with the respective peptide, which prevented immunostaining. The results of the present study provide a molecular and morphological basis for a role of taste-related molecules in chemosensing in the sea bass gastrointestinal tract. PMID:23748963

Latorre, Rocco; Mazzoni, Maurizio; De Giorgio, Roberto; Vallorani, Claudia; Bonaldo, Alessio; Gatta, Pier Paolo; Corinaldesi, Roberto; Ruggeri, Eugenio; Bernardini, Chiara; Chiocchetti, Roberto; Sternini, Catia; Clavenzani, Paolo

2013-12-01

200

Calretinin/PSA-NCAM immunoreactive granule cells after hippocampal damage produced by kainic acid and DEDTC treatment in mouse.  

Science.gov (United States)

There is a dramatic increase in the number of lightly immunoreactive calretinin cells in the granular layer of the dentate gyrus of the mouse hippocampus 1 day after excitotoxic injury using kainic acid combined with the zinc chelator diethyldithiocarbamate. At 7 days after treatment, these cells are strongly immunoreactive for calretinin and for the polysialated form of the glycoprotein neural cell adhesion molecule (PSA-NCAM). The reexpression of calretinin and PSA-NCAM after treatment corresponds well with the loss of input from the damaged hilar mossy cells. These cells could be considered immature granule cells since they are immunoreactive to markers for immature cells such as PSA-NCAM, and are not immunoreactive to calbindin D28k and neuronal nuclear specific protein NeuN (present in mature granule cells), or GABA (present in interneurons). Ultrastructural analysis of these cells indicates that they are immature. Labelling of cell proliferation with 5-bromo-2'-deoxyuridine (BrdU) shows that by day 1 no calretinin immunoreactive cell of the dentate gyrus corresponds to newly generated cells. By day 7 only 6% of the calretinin immunoreactive cells in the dentate gyrus are marked for BrdU. Our data indicate that the CR/PSA-NCAM immunoreactive cells of the dentate gyrus, in spite of their immature characteristics, are not the products of reactive neurogenesis. These cells could represent a reservoir of pre-existing not completely differentiated granule cells that react to damage. PMID:12618344

Domínguez, María Isabel; Blasco-Ibáńez, José Miguel; Crespo, Carlos; Marqués-Marí, Ana Isabel; Martínez-Guijarro, Francisco José

2003-03-21

 
 
 
 
201

MR imaging of abnormal synovial processes  

International Nuclear Information System (INIS)

MR imaging can directly image abnormal synovium. The authors reviewed over 50 cases with abnormal synovial processes. The abnormalities include Baker cysts, semimembranous bursitis, chronic shoulder bursitis, peroneal tendon ganglion cyst, periarticular abscesses, thickened synovium from rheumatoid and septic arthritis, and synovial hypertrophy secondary to Legg-Calve-Perthes disease. MR imaging has proved invaluable in identifying abnormal synovium, defining the extent and, to a limited degree, characterizing its makeup

202

Hippocampal T2 abnormalities in healthy adults.  

Science.gov (United States)

We compared hippocampal abnormalities in 42 healthy adults identified by voxel-based relaxometry (VBR) and by visual inspection. Hippocampal abnormalities were seen in 8 (19.0%) and 10 (23.8%) of subjects by VBR and visual inspection, respectively (p>0.05). Notably, 50% of the abnormalities seen by visual inspection were likely false positive. This suggests that VBR is a more specific measure and should be considered in subjects with questionable hippocampal abnormalities. PMID:21550208

Sumar, Imran; Kosior, Robert K; Frayne, Richard; Federico, Paolo

2011-08-01

203

Pathology Case Study: Sensory Abnormalities  

Science.gov (United States)

The Department of Pathology at the University of Pittsburgh Medical Center has compiled a wide range of pathology case studies to aid students and instructors in the medical/health science field. This particular case focuses on a 30-year-old man with a history of focal numbness, bladder and bowel dysfunction, and progressive sensory abnormalities. The patientâÂÂs history, images from an MRI, microscopic images of a specimen collected during his laminectomy, and final diagnosis are provided in this case for your review. Students will find this resource especially helpful, as it provides experience with patient history, lab results, and diagnostics.

Duggal, Neil; Hammond, Robert R.; Lownie, Steven P.; Smith, Sharyn

2007-12-10

204

Responses of plasma cyclic AMP, serum immunoreactive insulin, C-peptide immunoreactivity and blood sugar levels to glucagon in patients with liver diseases.  

Directory of Open Access Journals (Sweden)

Full Text Available Levels of plasma cyclic AMP, serum immunoreactive insulin (IRI, serum c-peptide immunoreactivity (CPR and blood sugar (BS were determined 0, 15, 30, 45 and 60 min after a glucagon injection (0.01 mg per kg body weight in normal controls, patients with acute hepatitis and liver cirrhosis. Plasma cyclic AMP responses to glucagon in liver disease patients varied widely in peak value, and only in patients with fulminant hepatitis and decompensated liver cirrhosis with poor prognosis was the response suppressed. The peak response of BS was found significantly later in liver cirrhosis patients than in normal controls. IRI and CPR responses to glucagon were lower in acute hepatitis patients than in normal controls and liver cirrhosis patients. IRI levels and their sum were also lower in acute hepatitis patients, although CPR levels were not significantly different. Thus, the ratio of the sum of CPR from 0 to 60 min to that of IRI was significantly higher in acute hepatitis, indicating impaired pancreatic secretion of insulin to glucagon stimulation as well as increased uptake of insulin by the liver in acute hepatitis.

Shimamura,Junnosuke

1985-10-01

205

Operator training for the abnormal  

International Nuclear Information System (INIS)

Training of nuclear power plant control room operators, on actions to be taken for an abnormal event, has classically been limited to discussion, on-shift and/or during requalification training classes, of symptoms, logical thought processes, systems analysis, and operator experience. The prerequisites for these discussions are a common technical vocabulary, and a minimum basic comprehension of nuclear power plant fundamentals, plant component theory of operation, system configuration, system control philosophy and operating procedures. Nuclear power plant control room operators are not the only personnel who are or should be involved in these discussions. The shift supervisors, operations management, and auxiliary equipment operators require continuing training in abnormal operations, as well. More in-depth training is necessary for shift supervisors and control room operators. The availability of vendor simulators has improved the effectiveness of training efforts for these individuals to some extent by displaying typical situations and plant performance characteristics and by providing a degree of ''hands on'' experience. The evolution of in-depth training with these simulators is reviewed

206

Genetics of abnormal human fertilization.  

Science.gov (United States)

The purpose of this study was to assess the genetic status of abnormal zygotes following assisted fertilization. Dispermic, monopronucleated and digynic zygotes were allowed to cleave intact or after enucleation, and on the biopsied blastomeres, multiplex polymerase chain reaction and fluorescent in-situ hybridization were performed. It was found that the distal pronucleus was usually male in origin in dispermic embryos, and that the sex ratio was restored when they were enucleated; however, they became mosaic at metaphase and their genetic heterogeneity was not restored after enucleation. Monopronucleated zygotes derived from standard in-vitro insemination can be transferred to the patient, since they usually showed normal diploid complement in their cells. On the contrary, single-pronucleated zygotes derived from intracytoplasmic sperm injection were usually activated parthenogenetically, but not fertilized. Digynic embryos, unlike dispermic ones, had a very low incidence of mosaicism, and when present, such mosaicism originated at a later embryo division. Most of the digynic embryos were triploid, indicating that the first division was normal and bipolar; moreover, when the female pronucleus was removed, they became diploid and their genetic status was considered normal. The recognition and understanding of fertilization abnormalities allow the identification of methods leading to their avoidance or correction. PMID:8592028

Palermo, G D; Munné, S; Colombero, L T; Cohen, J; Rosenwaks, Z

1995-10-01

207

Ablation of prion protein immunoreactivity by heating in saturated calcium hydroxide  

Directory of Open Access Journals (Sweden)

Full Text Available Abstract Background Prions, the infectious agents that cause transmissible spongiform encephalopathies (TSEs, are relatively resistant to destruction by physical, enzymatic, and chemical treatments. Hydrolysis in boiling saturated calcium hydroxide (limewater utilizes inexpensive chemicals to digest protein components of offal. The purpose of this work was to determine if incubating brain material from scrapie-infected sheep in near-boiling saturated calcium hydroxide solution (Ca(OH2 would abolish immunoreactivity of the infectious prion (PrPSc as determined by western blot. Findings After incubating for as few as 10 minutes in saturated calcium hydroxide at 99°C, immunoreactivity of protease resistant bands by western blot analysis is completely lost. Conclusion Boiling in limewater may offer an alternative for disposal of carcasses and enable alternative uses for rendered products from potentially infected carcasses.

Holtzapple Mark T

2008-10-01

208

[Digoxin-like immunoreactivity in newborn infants--a pitfall of digoxin therapy?].  

Science.gov (United States)

Endogenous digoxin-like immunoreactive substances (DLIS) show crossreactions with different immunoassays used for digoxin drug monitoring. In 61 blood samples of 47 eutrophic healthy newborns with jaundice, digoxin serum concentrations were measured during examination of serum bilirubin using a digoxin polarisation immunoassay. Although there was no digoxin therapy in any case, we found positive serum digoxin immunoreactivity (> or = 0.2 ng/ml) in 86% of serum samples. The mean DLIS-concentration was 0.43 +/- 0.19 ng/ml with a maximum of 0.9 ng/ml. We found a significant indirect correlation (rs = -0.34; p = 0.05) between age and serum DLIS concentration. A case report demonstrates the possibility of DLIS interference on digoxin drug monitoring. PMID:8326698

Heise, H R; Vorwerk, P; Fritsche, K; Richter, R

1993-05-01

209

Gastrin/CCK-like immunoreactivity in the nervous system of coelenterates  

DEFF Research Database (Denmark)

Using immunocytochemistry, gastrin/CCK-like immunoreactivity is found in sensory nerve cells in the ectoderm of the mouth region of hydra and in nerve cells in the endoderm of all body regions of the sea anemone tealia. These results are corroborated by radioimmunoassay: One hydra contains at least 5 fmole and one tealia at least 2 nmole gastrin/CCK-like immunoreactivity. Reactivities towards gastrin and CCK antisera with different specificities suggest that the coelenterate gastrin/CCK-like peptide contains the C-terminal amino-acid sequence common to mammalian gastrin and CCK. In addition the radioimmunochemical data indicate that the coelenterate peptide also contains an amino-acid sequence that resembles the sequence 20-30 of porcine CCK-33, but that no other sequences of gastrin are present. Thus, it is probably more CCK-like than gastrin-like.

Grimmelikhuijzen, C J; Sundler, F

1980-01-01

210

Immunoreactivity of mycobacterial 70 kDa protein in different physico-chemical forms.  

Science.gov (United States)

The immunoreactivity of 70 kDa culture filtrate protein of Mycobacterium tuberculosis H37 Ra has been examined as such and by increasing its hydrophobicity through its conjugation to stearic acid ester (70 kDa-FAester). The cell mediated immune responses produced by 70 kDa-FAester encapsulated in phosphatidylcholine (PC) liposomes were significantly higher particularly at the 3rd week post immunization (wk p. im.) than that produced by the 70 kDa protein in PC liposomes, whereas humoral immune responses were non-significant. Further, these immune responses were comparable to that elicited by 70 kDa protein complexed with Freund's incomplete adjuvant (70 kDa-FIA). Results of this study suggest that changes in physicochemical nature of 70 kDa protein influences both the humoral and cellular immunoreactivity. PMID:9248209

Verma, I; Yadav, D; Sharma, S; Sinha, R; Khuller, G K

1997-07-01

211

Effect of immunomodulators on immunoreactivity recovery following combined effect of radiation and thermal injury  

International Nuclear Information System (INIS)

It is shown that certain immunomodulators products a sufficient effect on immunoreactivity recovery only after combined effect of radiation and thermal injury in non-lethal doses. It is notable that in this case the antiboby formation level exceeds sufficiently the similar index even in healthy animals. Early injection of thymoptine immunostimulator as well as its combination with cystamine radioprotector are inefficient for antibody formation recovery under combined radiation-thermal injury. 4 refs

212

Sexually Dimorphic Effects of Melatonin on Brain Arginine Vasotocin Immunoreactivity in Green Treefrogs (Hyla cinerea)  

Science.gov (United States)

Arginine vasotocin (AVT) and its mammalian homologue, arginine vasopressin (AVP), regulate a variety of social and reproductive behaviors, often with complex species-, sex-, and context-dependent effects. Despite extensive evidence documenting seasonal variation in brain AVT/AVP, relatively few studies have investigated the environmental and/or hormonal factors mediating these seasonal changes. In the present study, we investigated whether the pineal hormone melatonin alters brain AVT immunoreactivity in green treefrogs (Hyla cinerea). Reproductively active male and female frogs were collected during the summer breeding season and a melatonin-filled or blank silastic capsule was surgically implanted subcutaneously. The duration of hormone treatment was 4 weeks, at which time frogs were euthanized and the brains and blood collected and processed for AVT immunohistochemistry and steroid hormone assay. We quantified AVT-immunoreactive (AVT-ir) cell bodies in the nucleus accumbens (NAcc), caudal striatum and amygdala (AMG), anterior preoptic area (POA), suprachiasmatic nucleus (SCN), and infundibular region of the ventral hypothalamus (VH). Sex differences in AVT-ir cell number were observed in all brain regions except the anterior POA and VH, with males having more AVT-ir cells than females in the NAcc, AMG, and SCN. Brain AVT was sensitive to melatonin signaling during the breeding season, and the effects of melatonin varied significantly with both region and sex. Treatment with melatonin decreased AVT immunoreactivity in both the NAcc and SCN in male H. cinerea. In contrast, brain AVT was relatively insensitive to melatonin signaling in females, indicating that the regulation of the AVT/AVP neuropeptide system by melatonin may be sexually dimorphic. Finally, melatonin did not significantly influence testosterone or estradiol concentrations of male or female frogs, respectively, suggesting that the effects of melatonin on AVT immunoreactivity are independent of changes in gonadal sex steroid hormones. Collectively, our results indicate that the AVT/AVP neuronal system may be an important target for melatonin in facilitating seasonal changes in reproductive physiology and social behavior. PMID:22906877

Lutterschmidt, Deborah I.; Wilczynski, Walter

2012-01-01

213

Laminar and subcellular heterogeneity of GLAST and GLT-1 immunoreactivity in the developing postnatal mouse hippocampus.  

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Astrocytes express two sodium-coupled transporters, glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1), which are essential for the maintenance of low extracellular glutamate levels. We performed a comparative analysis of the laminar and subcellular expression profile of GLAST and GLT-1 in the developing postnatal mouse hippocampus by using immunohistochemistry and western blotting and employing high-resolution fluorescence microscopy. Astrocytes were identified by costaining with glial fibrillary acidic protein (GFAP) or S100?. In CA1, the density of GFAP-positive cells and GFAP expression rose during the first 2 weeks after birth, paralleled by a steady increase in GLAST immunoreactivity and protein content. Upregulation of GLT-1 was completed only at postnatal days (P) P20-25 and was thus delayed by about 10 days. GLAST staining was highest along the stratum pyramidale and was especially prominent in astrocytes at P3-5. GLAST immunoreactivity indicated no preferential localization to a specific cellular compartment. GLT-1 exhibited a laminar expression pattern from P10-15 on, with the highest immunoreactivity in the stratum lacunosum-moleculare. At the cellular level, GLT-1 immunoreactivity did not entirely cover astrocyte somata and exhibited clusters at processes. In neonatal and juvenile animals, discrete clusters of GLT-1 were also detected at perivascular endfeet. From these results, we conclude there is a remarkable subcellular heterogeneity of GLAST and GLT-1 expression in the developing hippocampus. The clustering of GLT-1 at astrocyte endfeet indicates that it might serve a specialized functional role at the blood-brain barrier during formation of the hippocampal network. PMID:23939750

Schreiner, Alexandra E; Durry, Simone; Aida, Tomomi; Stock, Martin C; Rüther, Ulrich; Tanaka, Kohichi; Rose, Christine R; Kafitz, Karl W

2014-01-01

214

Tyrosine hydroxylase-immunoreactive cell groups in the brain of the teleost fish Gnathonemus petersii.  

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Different antibodies against tyrosine hydroxylase (TH) were used to obtain detailed information about the distribution, morphology and chemical differentiation of catecholaminergic neurons in the highly differentiated brain of the electric mormyrid fish Gnathonemus petersii. The results show that the distribution of catecholaminergic neurons is much more widespread than was previously thought on the basis of dopamine and noradrenaline immunohistochemistry. Tyrosine hydroxylase-immunoreactive neurons were observed not only in clearly dopaminergic regions (the suprachiasmatic nucleus, the magnocellular hypothalamic nucleus and the area postrema) and noradrenergic cell groups (the locus coeruleus and inferior reticular cell group), but also in regions that do not, or only fragmentarily, display dopamine or noradrenaline immunoreactivity, including the ventral and intermediate telencephalon, the anterior and posterior preoptic cell group, the ventromedial thalamus, the pretectal region and the nucleus of the solitary tract, suggesting that they either represent depleted dopaminergic cell groups or L-dihydroxy phenylalanine-producing nuclei. Most TH-immunoreactive neurons are rather small (cerebrospinal fluid-contacting neurons do not synthesize catecholamines, but acquire them from external sources. Comparison with other teleosts shows that the catecholaminergic system in the brain of Gnathonemus is similarly organized as in Carassius, Gasterosteus, Anguilla and Aperonotus, with some variations that may partly be due to technical reasons, and partly reflect true species differences. However, TH-immunoreactive neurons in the midbrain tegmentum were not observed, confirming previous conclusions that a major difference between teleosts and mammals concerns the absence of dopaminergic midbrain groups and correlated mesencephalo-telencephalic projections in teleosts. PMID:7908204

Meek, J; Joosten, H W

1993-01-01

215

Enkephalin-like immunoreactivity of olivocochlear nerve fibers in cochlea of guinea pig and cat  

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The distribution of enkephalin-like immunoreactivity in the cochlea of the guinea pig and cat was studied. Indirect immunofluorescence immunohistochemistry using antisera generated against a methionine enkephalin-bovine thyroglobulin conjugate was applied to surface preparations of the organ of Corti and cryostat sections of the whole of the cochlea. In the cochlear osseous spiral lamina, immunofluorescence was localized to unmyelinated fibers of the intraganglionic spiral bundle. In the orga...

Fex, Jo?rgen; Altschuler, Richard A.

1981-01-01

216

Immunoreactive epitopes on an expressed recombinant flagellar protein of Borrelia burgdorferi.  

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A recombinant Borrelia burgdorferi flagellin protein expressed in Escherichia coli is bound by a murine monoclonal antiflagellin antibody (H9724) and by antibodies in the sera of patients with Lyme disease. Immunoreactive epitopes on the flagellar protein were identified by immunoblot analysis of antibody binding to expressed truncated flagellar proteins. The epitope recognized by the murine monoclonal antibody is within the central heterologous region of the flagellar protein (amino acids 90...

1991-01-01

217

Neuromedin B-like immunoreactivity in the brain of the green frog (Rana esculenta L.).  

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Three rabbit polyclonal antisera, originally developed against neuromedin B and highly selective against ranatensin subfamily molecules, were used to study the distribution of neuromedin B-like immunoreactivity in the brain of Rana esculenta. Immunopositive cell bodies were observed in several brain regions, including medial and lateral septal nuclei, nucleus of the diagonal band of Broca, medial amygdala, ventral striatum, ventromedial and posterior thalamic nuclei, nucleus of the periventri...

Panzanelli, Patrizia; Fasolo, Aldo

1991-01-01

218

Pattern of secretion of bioactive and immunoreactive gonadotrophins in normal pubertal children.  

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OBJECTIVE: The aim was to investigate the relationship between the nocturnal pulsatile secretory patterns of immunoreactive and bioactive luteinizing hormone in normal children at various stages of puberty. DESIGN: Blood samples were taken at 15-minute intervals from 2000 hours to 0800 hours. Pubertal stage was assessed by the method of Tanner (1962). PATIENTS: Thirty-four healthy siblings (17 males, 17 females) of diabetic children were recruited (median age 13.1, range 9.1-20.9 years). They...

Dunger, Db; Villa, Ak; Matthews, DR; Edge, Ja; Jones, J.; Rothwell, C.; Preece, Ma; Robertson, Wr

1991-01-01

219

CHROMOSOMAL ABNORMALITIES IN PATIENTS WITH RECURRENT MISCARRIAGE  

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Full Text Available Chromosomal abnormalities are involved in the etiology of recurrent spontaneous pregnancy loss and sub-fertility. The purpose of this study was to determine the frequency and contribution of chromosomal abnormalities in recurrent miscarriages. The results obtained and literature review are helpful in understanding the importance of cytogenetics analysis of female infertility. To investigate the distribution of chromosomal abnormalities in the Romanian population with recurrent miscarriage, karyotype analysis by G-banding was performed from peripheral blood in 967 women infertility. Results: Chromosomal abnormalities were found to 79 women (8,17%. The percentage of chromosomal abnormalities in the studied population correlates with the data in the literature. Chromosomal abnormalities could play the important role in etiology of infertility and are more frequently detected in this group of patients compared to general population. In the infertile couples balanced chromosomal abnormalities are the main cause of spontaneous abortions.

Veronica Stoian

2012-06-01

220

The Characteristics of Immunoreactivity of Alpha-fetoprotein Producing Gastric Cancer  

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Full Text Available Alphafetoprotein (AFP producing gastric cancer (AFP-GC is very malignant and highly metastatic compared with common gastric cancer. We encountered six patients with AFP-GC. The purpose of this study was to characterize the immunoreactivity of alpha-fetoprotein producing gastric cancer, using a panel of hepatocytic markers, including alpha-fetoprotein, hepatocyte antigen, carcinoembryonic antigen, and CD10. Five of 6 cases showed cytoplasmic reactivity for alpha-fetoprotein. Immunoreactivity with a cytoplasmic, membranous, or canalicular pattern, or a mixed pattern was found for polyclonal CEA. Positive immunostaining for hepatocyte antigen was noted in only 2 of 6 cases. Negative immunostaining was found in all 6 patients for CD10. This study demonstrated that most AFP producing gastric cancer, hepatoid or non-hepatoid, were immunoreactive for AFP and p-CEA, but non-reactive for CD10. Therefore, CD-10 might be helpful to distinguish primary hepatocellular carcinoma from AFP-GC when it metastasizes to the liver. In this small series of patients with gastric cancer, AFP production indicated the poor prognosis, regardless hepatoid or non-hepatoid.

Swei H Tsung

2012-11-01

 
 
 
 
221

Na,K-ATPase ? Subunit-like Immunoreactive Proteins in Human Body Fluids  

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Full Text Available Na,K-ATPase was recently considered a target for breast cancer treatment since its potent inhibitors ouabain and related digitalis compounds that were reported circulating in body fluids before, were found to possess potent anti-breast cancer activity. Based on this finding, it is hypothesized that Na,K-ATPase derivatives could be circulating in the body and potential candidate biomarkers for early disease detection. Western blotting analysis was employed to investigate the possible presence of Na,K-ATPase-like proteins in cerebrospinal fluid (CSF and plasma using previously prepared antisera against Na,K-ATPase α�subunit and its formic acid-derived fragments. Results from this analysis show that human Na,K-ATPase α��subunit-like immunoreactive proteins with apparent molecular weights of 97, 68, 66, 57 and 55 kDa in the CSF, as well as 68, 66, 57 and 55 kDa in the plasma have been identified. By combining immunoaffininty binding and electroelution, these immunoreactive proteins were purified from human body fluids. This is the first report of the presence in the body fluids of immunoreactive proteins cross-reacted with anti-human Na,K-ATPase catalytic α subunit antibodies. These results suggest that these proteins are probably Na,K-ATPase derivatives resulting from degradation and released in vivo during cellular metabolism.

F. Peng Jeng-Hsiung

2006-01-01

222

Heterogeneity of human plasma insulin: techniques for separating immunoreactive components and their determination by radioimmunoassay  

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When human plasma is filtered on Sephadex G-SO fine, insulin immunoreactivity is recovered in two peaks: 'big insulin', the higher molecular weight component and 'little insulin', the lower molecular component, having elution volumes that correspond to those of porcine proinsulin 125I and porcine insulin 125I respectively. The presence of another form of immunoreactive insulin 'big big insulin' was detected from an insuloma suspect and its elution pattern corresponding to serum albumin. The eluates correspondent to 'big' and 'little' insulin as well as 'big big' component were assayed by radioimmunoassay using crystalline human insulin as a standard, porcine insulin 125 tracer and anti insulin serum. The antibody, raised in guinea-pigs, was sensitive and potent being adequate for the assay. The reactivity of insulin and proinsulin was tested against the antibody. The relative proportions of several components of total immunoreactive insulin in plasma were studied in basal conditions in five normal subjects and in the patient JSC with pancreatic insulin-secreting tumor as well as after glucose stimuli in all tolbutamide in JSC. (author)

223

Simultaneous detection of Clavibacter michiganensis subsp. nebraskensis and Pantoea stewartii subsp. stewartii based on microsphere immunoreaction.  

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Clavibacter michiganensis subsp. nebraskensis (Cmn) and Pantoea stewartii subsp. stewartii (Pss) are two plant pathogens that can cause tremendous agricultural economic losses. This novel method based on microsphere immunoreaction was developed for the simultaneous detection of Cmn and Pss in maize. This multiplex method was constructed based on microsphere immunodetection with fluorescent labels such as quantum dots (QDs) and R-phycoerythrin (R-PE) for the detection of Cmn and Pss. Captured QDs and R-PE serve as signal reporters for fluorescent readout. The principle of this method is based on a sandwich immunoreaction. Cmn and Pss captured by the microspheres were detected using flow cytometry. The limit of detection of this method was 10 times lower than the enzyme-linked immunosorbent assay (ELISA), and its analysis time (1 h) was much shorter compared with ELISA (6-8 h). The method, which has been proven to be an effective approach to multiplex detection of plant bacteria (Cmn and Pss as models), not only increased the varieties but also improved the sensitivity. The microsphere immunoreaction provides a universal method for the multiplex determination of microbes because of its high sensitivity, specificity, and speed. In the future, the method will be more fully validated in vivo to detect diversiform bacteria. PMID:23169888

Zhang, Fan; Li, Jinfeng; Zou, Mingqiang; Chen, Yan; Wang, Yanfei; Qi, Xiaohua

2013-04-01

224

Somatostatin-28 like immunoreactivity in normal and tumour tissue from duodenum and pancreas  

International Nuclear Information System (INIS)

Radioimmunoassay using labelled somatostatin-14 revealed that components of somatostatin-28 antisera cross-reactive to somatostatin-14 were removed by absorption of somatostatin-28 antisera with sepharose 4B-somatostatin-14. Indirect immunofluorescence techniques using specific antisera against somatostatin-28 were carried out in normal pancreas, duodenum, a somatostatinoma in the duodenum, and pancreatic tumour cells containing somatostatin-14 positive cells, in order to establish if somatostatin-28 is present in normal and pathological tissues. Somatostatin-28 like immunoreactivity was present in pancreatic islets cells and in the epithelial cells of the duodenum as well as in the duodenal somatostatinoma and in pancreatic tumour cells. Furthermore, cells reacting with specific antisera against somatostatin-28 were identical to those with somatostatin-14 antisera in normal and pathological tissues. The findings suggested that somatostatin-28 like immunoreactivity may be constantly present in the tissues where somastostatin like immunoreactivity was detected using somatostatin-14 antisera. However, further studies are necessary to clarify whether somatostatin-28 and somatostatin-14 were independently present in these tissues, in other words, whether somatostatin-14 may be produced from somatostatin-28 or not, since somatostatin-14 antisera had cross-reactivities to somatostatin-28. (authors)

225

Distribution and characterization of enterostatin-like immunoreactivity in human cerebrospinal fluid.  

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Enterostatins belong to a family of peptides (e.g., Val-Pro-Asp-Pro-Arg, VPDPR; Ala-Pro-Gly-Pro-Arg, APGPR; and Val-Pro-Gly-Pro-Arg, VPGPR) derived from the tryptic cleavage of amino-terminal pentapeptide from procolipase. Pharmacologic studies have suggested a role for these peptides in appetite regulation and insulin secretion. Studies into the distribution of enterostatins or the role of endogenous peptides have not been possible until now due to the lack of a suitable method for assay. Using two polyclonal antibodies raised against VPDPR and APGPR and different chromatographic methods, we have examined the nature and distribution of enterostatin-like immunoreactivity in human cerebrospinal fluid. The results reported here show for the first time the presence of enterostatin-like immunoreactivity in the human cerebrospinal fluid. Further characterization of cerebrospinal fluid enterostatin-like immunoreactivity revealed that it is not due to APGPR, VPGPR, or VPDPR but to another peptide similar to VPDPR. PMID:9809653

Imamura, M; Sumar, N; Hermon-Taylor, J; Robertson, H J; Prasad, C

1998-01-01

226

Arginine vasopressin immunoreactivity is decreased in the hypothalamic suprachiasmatic nucleus of subjects with suprasellar tumors.  

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Suprasellar tumors with compression of the optic chiasm are associated with an impaired sleep-wake rhythm. We hypothesized that this reflects a disorder of the biological clock of the human brain, the suprachiasmatic nucleus (SCN), which is located just above the optic chiasm. In order to test this hypothesis, we investigated the expression of two key neuropeptides of the SCN, that is, arginine vasopressin (AVP) and vasoactive intestinal peptide (VIP), as assessed by quantitative immunocytochemistry in post-mortem hypothalamic tissue of patients with a suprasellar tumor inducing permanent visual field defects. Post-mortem hypothalamic tissue of 5 patients with a suprasellar tumor inducing permanent visual field defects (acromegaly n = 2, nonfunctioning macro-adenoma n = 1, macroprolactinoma n = 1, infundibular metastasis of a colorectal adenocarcinoma n = 1) and 15 age- and gender-matched controls was obtained from the Netherlands Brain Bank. Total AVP immunoreactivity in the SCN was lower in patients with a suprasellar tumor than in controls (P = 0.03). By contrast, total VIP immunoreactivity was not different between patients and controls (P = 0.44). Suprasellar tumors leading to permanent visual field defects are associated with reduced AVP, but not VIP immunoreactivity, in the SCN. These findings raise the possibility that selective impairment of the SCN contributes to sleep-wake disturbances in these patients. PMID:23278971

Borgers, Anke J; Fliers, Eric; Siljee, Jacqueline E; Swaab, Dick F; Van Someren, Eus J W; Bisschop, Peter H; Alkemade, Anneke

2013-07-01

227

ECG ABNORMALITIES IN RURAL AREAS  

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Full Text Available A survey was carried out in the summer of 1972 in east Azerbaijan, northwest Iran, to determine the prevalence of cardiovascular disease. ECG tracings were prepared from 198 women and 178 men aged 40-60. Only 45% of the tracings were completely normal. Q/QS abnormalities were found in 4.7% of tracings, left axis deviation in 4% tall R wave in 37%, ST depression in 3.9% of men and 14.1% of women and T wave inversion in 2.2% of men and 11.6% of women. Further studies are recommended to explain this high prevalence of ST depression and T wave inversion in the women of this area.

M. Daneshapjooh

1975-08-01

228

Abnormal Returns and Contrarian Strategies  

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Full Text Available We test the hypothesis that strategies which are long on portfolios of looser stocks and short on portfolios of winner stocks generate abnormal returns in Brazil. This type of evidence for the US stock market was interpreted by The Bondt and Thaler (1985 as reflecting systematic evaluation mistakes caused by investors overreaction to news related to the firm performance. We found evidence of contrarian strategies profitability for horizons from 3 months to 3 years in a sample of stock returns from BOVESPA and SOMA from 1986 to 2000. The strategies are more profitable for shorter horizons. Therefore, there was no trace of the momentum effect found by Jagadeesh and Titman (1993 for the same horizons with US data. There are remaing unexplained positive returns for contrarian strategies after accounting for risk, size, and liquidity. We also found that the strategy profitability is reduced after the Real Plan, which suggests that the Brazilian stock market became more efficient after inflation stabilization.

Ivana Dall'Agnol

2003-12-01

229

Abnormal Iron Homeostasis and Neurodegeneration  

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Full Text Available Abnormal iron metabolism is observed in many neurodegenerative diseases, however only two have shown dysregulation of brain iron homeostasis as the primary cause of neurodegeneration. Herein, we review one of these - hereditary ferritinopathy (HF or neuroferritinopathy, which is an autosomal dominant, adult onset degenerative disease caused by mutations in the ferritin light chain (FTL gene. HF has a clinical phenotype characterized by a progressive movement disorder, behavioral disturbances, and cognitive impairment. The main pathologic findings are cystic cavitation of the basal ganglia, the presence of ferritin inclusion bodies (IBs, and substantial iron deposition. Mutant FTL subunits have altered sequence and length but assemble into soluble 24-mers that are ultrastructurally indistinguishable from those of the wild type. Crystallography shows substantial localized disruption of the normally tiny 4-fold pores between the ferritin subunits because of unraveling of the C-termini into multiple polypeptide conformations. This structural alteration causes attenuated net iron incorporation leading to cellular iron mishandling, ferritin aggregation, and oxidative damage at physiological concentrations of iron and ascorbate. A transgenic murine model parallels several features of HF, including a progressive neurological phenotype, ferritin IB formation, and misregulation of iron metabolism. These studies provide a working hypothesis for the pathogenesis of HF by implicating (1 a loss of normal ferritin function that triggers iron accumulation and overproduction of ferritin polypeptides, and (2 a gain of a toxic function through radical production, ferritin aggregation, and oxidative stress. Importantly, the finding that ferritin aggregation can be reversed by iron chelators and oxidative damage can be inhibited by radical trapping may be used for clinical investigation. This work provides new insights into the role of abnormal iron metabolism in neurodegeneration.

RubenVidal

2013-07-01

230

Abnormal iron homeostasis and neurodegeneration.  

Science.gov (United States)

Abnormal iron metabolism is observed in many neurodegenerative diseases, however, only two have shown dysregulation of brain iron homeostasis as the primary cause of neurodegeneration. Herein, we review one of these - hereditary ferritinopathy (HF) or neuroferritinopathy, which is an autosomal dominant, adult onset degenerative disease caused by mutations in the ferritin light chain (FTL) gene. HF has a clinical phenotype characterized by a progressive movement disorder, behavioral disturbances, and cognitive impairment. The main pathologic findings are cystic cavitation of the basal ganglia, the presence of ferritin inclusion bodies (IBs), and substantial iron deposition. Mutant FTL subunits have altered sequence and length but assemble into soluble 24-mers that are ultrastructurally indistinguishable from those of the wild type. Crystallography shows substantial localized disruption of the normally tiny 4-fold pores between the ferritin subunits because of unraveling of the C-termini into multiple polypeptide conformations. This structural alteration causes attenuated net iron incorporation leading to cellular iron mishandling, ferritin aggregation, and oxidative damage at physiological concentrations of iron and ascorbate. A transgenic murine model parallels several features of HF, including a progressive neurological phenotype, ferritin IB formation, and misregulation of iron metabolism. These studies provide a working hypothesis for the pathogenesis of HF by implicating (1) a loss of normal ferritin function that triggers iron accumulation and overproduction of ferritin polypeptides, and (2) a gain of toxic function through radical production, ferritin aggregation, and oxidative stress. Importantly, the finding that ferritin aggregation can be reversed by iron chelators and oxidative damage can be inhibited by radical trapping may be used for clinical investigation. This work provides new insights into the role of abnormal iron metabolism in neurodegeneration. PMID:23908629

Muhoberac, Barry B; Vidal, Ruben

2013-01-01

231

Uncoupling protein 2/3 immunoreactivity and the ascending dopaminergic and noradrenergic neuronal systems: relevance for volume transmission.  

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Uncoupling proteins in the inner mitochondrial membrane uncouples oxidative phosphorylation from ATP synthesis. It has been suggested that these proteins are involved in thermogenesis as well as in the regulation of reactive oxygen species production in the mitochondria. The present work was conducted to investigate the localization of the uncoupling protein 2-like immunoreactivity (uncoupling protein 2/3 immunoreactivity) in the main catecholaminergic projection fields in the rat brain as well as in the areas of the dopaminergic and noradrenergic nerve cell groups. In particular, the relationships of tyrosine hydroxylase, dopamine beta-hydroxylase and uncoupling protein 2/3 immunoreactivity were assessed by double immunolabeling and confocal laser microscopy analysis associated with computer-assisted image analysis. Uncoupling protein 2/3 immunoreactivity was observed in discrete dopaminergic terminals in the nucleus accumbens and in the cerebral cortex whereas it was found in scattered noradrenergic terminals in the caudate putamen and Islands of Calleja Magna. One interesting finding was that uncoupling protein 2/3 immunoreactivity together with tyrosine hydroxylase immunoreactivity in the shell of nucleus accumbens was observed surrounding the previously characterized D1 receptor rich nerve cell column system characterized by a relative lack of tyrosine hydroxylase immunoreactivity. Moreover, in animal models of dopaminergic pathway degeneration, plastic changes in uncoupling protein 2/3 terminals have been shown in the cerebral cortex and striatum as seen from the increased size and intensity of uncoupling protein 2/3 immunoreactivity of their varicosities. Taken together, these findings open up the possibility that uncoupling protein 2/3 could play an important role modulating the dopaminergic and noradrenergic neurotransmission within discrete brain regions. PMID:16387447

Rivera, A; Agnati, L F; Horvath, T L; Valderrama, J J; de La Calle, A; Fuxe, K

2006-01-01

232

Transient up-regulation of cocaine- and amphetamine-regulated transcript peptide (CART) immunoreactivity following ethanol withdrawal in rat hypothalamus.  

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We investigated the profile of CART immunoreactivity in some discrete hypothalamic nuclei following chronic ethanol treatment and withdrawal conditions. Adult, male, Sprague-Dawley rats were fed with liquid diet (pair-fed) or liquid diet containing ethanol (ethanol-fed) for 15 days. Thereafter, all the animals were given access to ethanol free nutritionally balanced liquid diet and killed at 0, 24, 48 and 72 h post-withdrawal, and their brains processed for immunocytochemistry using monoclonal antibodies against CART. CART-immunoreactive fibers, but not the cells, were significantly increased in the paraventricular nucleus (PVN). However, the profile of CART-immunoreactive cells and/or fibers in the periventricular area (PeA), arcuate nucleus (ARC), perifornical area inclusive of lateral hypothalamus (LH) and tuber cinereum (TC), dorsomedial (DMH), and ventromedial (VMH) hypothalamus at the 0 h ethanol withdrawal time point was quite similar to that in the pair-fed control rats. Twenty-four hours following ethanol withdrawal, the immunoreactivity in all these areas was dramatically increased. While significant reduction in CART immunoreactivity was noticed in the PVN, PeA, ARC and VMH at 48 h, immunoreactive profile was restored to normal by 72 h post-ethanol withdrawal. The immunoreactive profile in the LH, TC and DMH resembled that of the pair-fed groups at 48 and 72 h post-withdrawal intervals. However, CART-immunoreactive profile in the supraoptic nucleus did not respond to the chronic ethanol treatment and/or withdrawal. We suggest that transient up-regulation of CART in some discrete hypothalamic nuclei following ethanol withdrawal, at least in part, may contribute to the pathogenesis of ethanol withdrawal-induced symptoms like anxiety and anorexia. PMID:18823957

Dandekar, Manoj P; Singru, Praful S; Kokare, Dadasaheb M; Subhedar, Nishikant K

2008-11-13

233

Placental C4d as a common feature of chromosomally normal and abnormal miscarriages.  

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Placental C4d deposition is a feature of classical complement pathway activation and has been documented in various obstetrical settings. However, it is unknown whether placental C4d deposition is present in miscarriages and its frequency is different between chromosomally normal and abnormal miscarriages. This study was conducted to assess villous C4d deposition in miscarriages and to determine whether its frequency is different between chromosomally normal and abnormal miscarriages. Tissue samples (N?=?58) of elective abortions (n?=?20), miscarriages with normal chromosomes (n?=?15), trisomy 16 (n?=?13), and trisomy 22 (n?=?10) were analyzed. Immunohistochemical staining for C4d and CD138 was done. Placental C4d deposition was defined as linear C4d immunoreactivity along the syncytiotrophoblast. Placental C4d immunoreactivity was detected in 73.3 % (11/15) and 56.5 % (13/23) of miscarriages with normal chromosomes and trisomy cases, respectively, while it was found in 5 % (1/20) of elective abortions (p?recurrent miscarriages (previous spontaneous abortion ?2) than in sporadic miscarriages (76.5 vs. 30.0 %; p?=?0.001). Chronic deciduitis was observed in 20.0 % (3/15) and 30.4 % (7/23) of miscarriages with normal chromosomes and trisomy cases, respectively, but not in elective abortions (p?=?0.07 and 0.01, for each). The frequencies of C4d deposition (46.2 vs. 70.0 %) and chronic deciduitis (38.5 vs. 20.0 %) were not also different between trisomy 16 and trisomy 22 cases. Placental C4d deposition is a prominent feature of miscarriages regardless of their chromosomal status. The overall findings suggest that complement-mediated placental injury is a common pathology of miscarriage with diagnostic values in routine pathology practice. PMID:24671647

Lee, Joong Yeup; Hong, Joon-Seok; Kim, Eun Na; Ahn, Soyeon; Choe, Jin; Hwang, Doyeong; Kim, Ki Chul; Kim, Seok Hyun; Kim, Chong Jai

2014-05-01

234

Apoptosis, cell proliferation and serotonin immunoreactivity in gut of Liza aurata from natural heavy metal polluted environments: preliminary observations  

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Full Text Available In the present paper, the effect of natural environment nonlethal heavy metal concentration on cell renewal of Liza aurata intestinal epithelium, was studied by the TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick end labelling method and anti-PCNA (proliferating cell nuclear antigen immunohistochemistry, in order to detect, respectively, apoptosis and cell proliferation. In addition, the presence and distribution of the cell renewal regulator, serotonin, was immunohistochemically investigated. In order to reduce variability, only immature specimens were considered. The results indicated that in the control specimens from non-polluted areas, the PCNA immunoreactive nuclei of the proximal intestinal epithelium were only located at the bottom of the intestinal folds, together with a few TUNEL-positive nuclei, and goblet mucous differentiated cells. In the specimens from polluted areas, the number of PCNA immunoreactive cells was greatly enhanced, and they extended along the mid portion of the intestinal folds; the number of TUNEL-positive nuclei was enhanced as well, but they were almost exclusively detected in the third apical portion of the intestinal folds. Serotonin immunoreactive nerve elements were more frequently detected in the intestinal wall of L. aurata specimens from polluted areas, and besides that, some serotonin immunoreactive endocrine cells were also present. Variations in distribution and frequency of TUNEL-positive nuclei, PCNA immunoreactive nuclei, and serotonin immunoreactivity put in evidence an alteration of cell renewal with an enhancement of cell proliferation, probably leading to morphological intestinal fold changes.

G Tagliafierro

2005-12-01

235

Short axon cells of the rat olfactory bulb display NADPH-diaphorase activity, neuropeptide Y-like immunoreactivity, and somatostatin-like immunoreactivity.  

Science.gov (United States)

Several types of short axon cells of the mammalian olfactory bulb have been described after Golgi impregnation. Two of these types have been observed in our material after treatment with the NADPH-diaphorase procedure or after immunohistochemistry for neuropeptide-Y (NPY). The cells stained by the two procedures have similar morphologies and distributions. A less extensive series of observations confirms that similar cells also display somatostatin (SS)-like immunoreactivity. One of these cell types corresponds to the superficial short axon cell of Golgi and electron microscopic studies. The dendrites of this cell lie within the periglomerular region and in the superficial external plexiform layer (EPL), generally lying parallel to the glomerular layer. In some cases the axon has been traced across the EPL into the granule cell layer (GCL). This cell may provide another route of interaction between the periglomerular region and the granule cells in addition to the influences conducted by basal dendrites and axon collaterals of some mitral and tufted cells. A type of deep short axon cell is also visible with these two procedures. It lies deep in the granule cell layer, frequently near the ventricular layer and its dendrites lie parallel to that layer. This deep short axon cell is stained with much greater frequency by the NADPH-diaphorase and NPY procedures than is the superficial short axon cell. It corresponds most closely to the Blanes or Golgi cells of the Golgi impregnation literature, but it appears to differ from these cells in the position and orientation of its dendrites. No spines have been observed on either the superficial or deep cells in this series. Many glomeruli are also stained by the NADPH-diaphorase procedure, but are not NPY or SS immunoreactive. This may provide additional evidence for functional differences between glomeruli in local regions of the olfactory bulb. PMID:3298331

Scott, J W; McDonald, J K; Pemberton, J L

1987-06-15

236

Radiologic atlas of pulmonary abnormalities in children  

International Nuclear Information System (INIS)

This book is an atlas about thoracic abnormalities in infants and children. The authors include computed tomographic, digital subtraction angiographic, ultrasonographic, and a few magnetic resonance (MR) images. They recognize and discuss how changes in the medical treatment of premature infants and the management of infection and pediatric tumors have altered some of the appearances and considerations in these diseases. Oriented toward all aspects of pulmonary abnormalities, the book starts with radiographic techniques and then discusses the normal chest, the newborn, infections, tumors, and pulmonary vascular diseases. There is comprehensive treatment of mediastinal abnormalities and a discussion of airway abnormalities

237

Effect of photoperiod on neural estrogen and progestin receptor immunoreactivity in female Syrian hamsters.  

Science.gov (United States)

This study explored the possibility that reduced behavioral responsiveness to estradiol and progesterone in female Syrian hamsters exposed to a short photoperiod is associated with a reduction in the concentration of neural steroid receptors. The effects of long and short photoperiod (LP; SP) exposure on steroid receptor immunoreactivity were examined in the ventromedial hypothalamus (VMH), medial tuberal region (mTu), medial preoptic area (mPOA), medial nucleus of the amygdala (mAMYG), and the arcuate nucleus (ARC) of ovariectomized hamsters. In Experiment 1, exposure to SP for ten weeks attenuated the lordosis response following sequential treatment with estradiol and progesterone. In a separate group of animals not given hormones, SP decreased the staining intensity of estrogen receptor immunoreactive (ERIR) cells in the mPOA while increasing the number of detectable ERIR cells in part of the mAMYG. In Experiment 2, SP diminished the lordosis response as it did in Experiment 1. One week later, the same females were administered estradiol systemically to induce progestin receptors (PR). Animals housed in SP showed significantly reduced progestin receptor immunoreactivity (PRIR) in the VMH, mTu, mPOA, mAMYG, and ARC. Experiment 3 examined whether the results of Experiment 2 might have been influenced by photoperiodic effects on peripheral metabolism of estradiol. Among hamsters housed in LP or SP, PRs were induced by estradiol implanted unilaterally in the medial basal hypothalamus, thus bypassing possible photoperiodic effects on peripheral estradiol availability. This treatment resulted in significantly fewer cells with detectable PRIR in the VMH and mPOA of SP females, suggesting that the photoperiodic influences on PR induction observed in Experiment 2 do not depend on alterations in the peripheral availability of estradiol. PMID:9689455

Mangels, R A; Powers, J B; Blaustein, J D

1998-06-15

238

Bioactive and immunoreactive concentrations of circulating luteinizing hormone during sexual maturation in the bovine.  

Science.gov (United States)

The characteristics of circulating LH during sexual maturation in cattle were assessed by examining bioactive and immunoreactive LH concentrations, as well as their ratio (B/I ratio). Male and female intact control (CONT), gonadectomized (GNX; at 241 +/- 3 days of age, Day 0 of the study), and gonadectomized animals administered 17 beta-estradiol (GNXE) were evaluated. Serum samples were collected at 15-min intervals for 24 h at 1, 7, 13, 17, 21, 25, 29, 33, 37, and 43 wk subsequent to Day 0. Bioactive LH was assessed with an in vitro bioassay using mouse testicular interstitial cells. In initial experiments, immunoreactive LH was quantified in RIAs using three different antibodies. The two RIAs employing polyclonal antibodies overestimated low LH concentrations, but the absolute values obtained in each of the three assays were highly correlated. Hence, immunoreactive LH was measured in an RIA using monoclonal anti-bovine LH (bLH) (JR-518B7). No significant changes in the B/I ratios were observed during individual pulses of LH secretion. Accordingly, pools consisting of equal volumes of the serial blood samples collected during the 24-h period for each animal at each stage of maturation (pools) were compared. LH B/I ratios for GNX females increased significantly with time (p less than 0.01) and the B/I ratios for GNX males were significantly higher than for GNX females (p less than 0.05). Concentrations of LH in most of the pools for GNXE and CONT animals were extremely low or nondetectable until the later bleeding periods.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1391319

Hejl, K M; Wolfe, M W; Kinder, J E; Grotjan, H E

1992-06-01

239

Sexually dimorphic effects of melatonin on brain arginine vasotocin immunoreactivity in green treefrogs (Hyla cinerea).  

Science.gov (United States)

Arginine vasotocin (AVT) and its mammalian homologue, arginine vasopressin (AVP), regulate a variety of social and reproductive behaviors, often with complex species-, sex- and context-dependent effects. Despite extensive evidence documenting seasonal variation in brain AVT/AVP, relatively few studies have investigated the environmental and/or hormonal factors mediating these seasonal changes. In the present study, we investigated whether the pineal hormone melatonin alters brain AVT immunoreactivity in green treefrogs (Hyla cinerea). Reproductively active male and female frogs were collected during the summer breeding season and a melatonin-filled or blank silastic capsule was surgically implanted subcutaneously. The duration of hormone treatment was 4 weeks, at which time frogs were eutha-nized and the brains and blood collected and processed for AVT immunohistochemistry and steroid hormone assay. We quantified AVT-immunoreactive (AVT-ir) cell bodies in the nucleus accumbens (NAcc), caudal striatum and amygda- la (AMG), anterior preoptic area, suprachiasmatic nucleus (SCN) and infundibular region of the ventral hypothalamus. Sex differences in AVT-ir cell number were observed in all brain regions except in the anterior preoptic area and ventral hypothalamus, with males having more AVT-ir cells than females in the NAcc, amygdala and SCN. Brain AVT was sensitive to melatonin signaling during the breeding season, and the effects of melatonin varied significantly with both region and sex. Treatment with melatonin decreased AVT immunoreactivity in both the NAcc and SCN in male H. cinerea. In contrast, brain AVT was relatively insensitive to melatonin signaling in females, indicating that the regulation of the AVT/AVP neuropeptide system by melatonin may be sexually dimorphic. Finally, melatonin did not significantly influence testosterone or estradiol concentrations of male or female frogs, respectively, suggesting that the effects of melatonin on AVT immunoreactivity are independent of changes in gonadal sex steroid hormones. Collectively, our results indicate that the AVT/AVP neuronal system may be an important target for melatonin in facilitating seasonal changes in reproductive physiology and social behavior. PMID:22906877

Lutterschmidt, Deborah I; Wilczynski, Walter

2012-01-01

240

Immunoreactive helix-destabilizing protein localized in transcriptionally active regions of Drosophila polytene chromosomes  

Energy Technology Data Exchange (ETDEWEB)

A highly purified helix-destabilizing protein (HDP) obtained from rat liver has been used to elicit specific, high-titer anti-HDP sera in rabbits. These antisera show immunological crossreaction with single-stranded DNA binding proteins from several very diverse eukaryotic sources, including Drosophila embryos. The use of such antisera in the labeling of Drosophila salivary gland chromosomes buy indirect immunofluorescence shows concentrations of immunoreactive HDP in many regions, but especially in chromosome puffs. There is a striking localization of HDP in heat shock puffs known to be sites of new transcription. The pattern of HDP distribution seems to implicate a transcriptional role, with some specificities independent of puffing itself.

Patel, G. L.; Thompson, P.E

1980-11-01

 
 
 
 
241

Communication problems following abnormal screening mammography  

International Nuclear Information System (INIS)

Sixty-three studies from a sequential group of 1,125 screening mammograms (5.6%) were interpreted as abnormal, and additional views or biopsy were recommended. All reports were communicated in writing, and in addition all abnormal reports were directly communicated by telephone by the radiologist to the office of the referring physicians. Two and a half months following screening, an incomplete workup had been performed or no action had been taken in 40 of the 63 patients with an abnormal report (63%). Following a second call to the physician's office and 3 months after the original study, the number of unresolved cases had dropped to 18 of 63 (29%). Despite repeated reinforcement, ten of 63 patients (16%) had still not undergone the recommended evaluation 3 1/2 months following the abnormal screen. The reasons for referring physician's failure to pursue abnormal reports rapidly will be discussed, as well as the possible implications for those performing screening mammography

242

Report to Congress on abnormal occurrences  

International Nuclear Information System (INIS)

Section 208 of the Energy Reorganization Act of 1974 identifies an abnormal occurrence as an unscheduled incident or event that the Nuclear Regulatory Commission determines to be significant from the standpoint of public health and safety and requires a quarterly report of such events to be made to Congress. This report covers the period January through March 1993. There is one abnormal occurrence at a nuclear power plant disposed in this report that involved a steam generator tube rupture at Palo Verde Unit 2, and none for fuel cycle facilities. Three abnormal occurrences involving medical misadminstrations (two therapeutic and one diagnostic) at NRC-licensed facilities are also discussed in this report. No abnormal occurrences were reported by NRC's Agreement States. The report also contains information updating previously reported abnormal occurrences

243

Abnormal Event Detection Using Local Sparse Representation  

DEFF Research Database (Denmark)

We propose to detect abnormal events via a sparse subspace clustering algorithm. Unlike most existing approaches, which search for optimized normal bases and detect abnormality based on least square error or reconstruction error from the learned normal patterns, we propose an abnormality measurement based on the difference between the normal space and local space. Specifically, we provide a reasonable normal bases through repeated K spectral clustering. Then for each testing feature we first use temporal neighbors to form a local space. An abnormal event is found if any abnormal feature is found that satisfies: the distance between its local space and the normal space is large. We evaluate our method on two public benchmark datasets: UCSD and Subway Entrance datasets. The comparison to the state-of-the-art methods validate our method's effectiveness.

Ren, Huamin; Moeslund, Thomas B.

2014-01-01

244

Non-epileptiform EEG abnormalities: an overview.  

Science.gov (United States)

More than 80 years after its introduction by Hans Berger, the electroencephalogram (EEG) remains as an important supplementary examination in the investigation of neurological disorders and gives valuable and accurate information about cerebral function. Abnormal EEG findings may include ictal patterns, interictal epileptiform activity and non-epileptiform abnormalities. The aim of this study is to make an overview on the main non-epileptiform EEG abnormalities, emphasizing the pathologic findings and the importance of their recognition, excluding periodic patterns and EEG physiologic changes. Scientific articles were selected from MEDLINE and PubMed database. The presence of non-epileptiform EEG abnormalities provide evidence of brain dysfunction that are not specific to a particular etiology and may be related to a number of disorders affecting the brain. Although these abnormalities are not specific, they can direct attention to the diagnostic possibilities and guide the best treatment choice. PMID:22042190

Andraus, Maria Emilia Cosenza; Alves-Leon, Soniza Vieira

2011-10-01

245

Auditory abnormalities in children with autism  

Directory of Open Access Journals (Sweden)

Full Text Available The present study aimed to describe the characteristics of auditory abnormalities present in cases of autism. One hundred and fifty six children with autism and 141matched controls with language delay were investigated via direct observations combined with parent/caregiver reports. All of the autistic individuals demonstrated auditory abnormalities especially in the domain of hyposensitivity, compared with 33.3% of children with language delay. The auditory abnormalities in autism primarily comprised of auditory hyposensitivity, auditory hypersensitivity, phonophobia, and peculiar interests in certain sounds. Participants with autism were rated as having more problems than the language-delayed children in all the items of each domain. No significant difference in the range of auditory abnormalities were observed between mild and severe autistic children except for the presence of phonophobia. Children with autism presented with diverse auditory abnormalities which may be specific features in autism and may play an important role in the early identification of autism.

Li-Bo Wang

2012-01-01

246

Analgesic doses of morphine do not reduce noxious stimulus-evoked release of immunoreactive neurokinins in the dorsal horn of the spinal cat.  

Digital Repository Infrastructure Vision for European Research (DRIVER)

1. Antibody microprobes were used to detect immunoreactive neurokinin A release in the dorsal spinal cord of barbiturate-anaesthetized spinal cats. 2. Noxious mechanical stimulation of the ipsilateral hind paw and electrical stimulation (suprathreshold for unmyelinated primary afferent fibres) of the ipsilateral tibial nerve evoked immunoreactive neurokinin A release. 3. Systemic morphine, 5 mg kg-1, i.v., did not block immunoreactive neurokinin A release in response to these stimuli. 4. Subs...

Lang, C. W.; Duggan, A. W.; Hope, P. J.

1991-01-01

247

Phosphoproteomic analysis reveals site-specific changes in GFAP and NDRG2 phosphorylation in frontotemporal lobar degeneration  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disease characterized by behavioral abnormalities, personality changes, language dysfunction, and can co-occur with the development of motor neuron disease. One major pathological form of FTLD is characterized by intracellular deposition of ubiquitinated and phosphorylated TAR DNA binding protein-43 (TDP-43), suggesting that dysregulation in phosphorylation events may contribute to disease progression. However, to dat...

Herskowitz, Jeremy H.; Seyfried, Nicholas T.; Duong, Duc M.; Xia, Qiangwei; Rees, Howard D.; Gearing, Marla; Peng, Junmin; Lah, James J.; Levey, Allan I.

2010-01-01

248

Protein Misdirection Inside and Outside Motor Neurons in Amyotrophic Lateral Sclerosis (ALS): A Possible Clue for Therapeutic Strategies  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive muscle wasting and weakness with no effective cure. Emerging evidence supports the notion that the abnormal conformations of ALS-linked proteins play a central role in triggering the motor neuron degeneration. In particular, mutant types of superoxide dismutase 1 (SOD1) and TAR DNA binding protein 43kDa (TDP-43) are key molecules involved in the pathogenesis of familial and sporadic ALS...

Akemi Ido; Makoto Urushitani; Hidenao Fukuyama

2011-01-01

249

Clinicopathologic features of autosomal recessive amyotrophic lateral sclerosis associated with optineurin mutation.  

Science.gov (United States)

We performed clinicopathological analyses of two amyotrophic lateral sclerosis (ALS) patients with homozygous Q398X optineurin (OPTN) mutation. Clinically, both patients presented signs of upper and lower motor neuron degeneration, but only Patient 1 showed gradual frontal dysfunction and extrapyramidal signs, and temporal lobe and motor cortex atrophy. Neuropathological examination of Patient 1 revealed extensive cortical and spinal motor neuron degeneration and widespread degeneration of the basal ganglia. Bilateral corticospinal tracts exhibited degeneration. Loss of spinal anterior horn cells (AHCs) and gliosis were observed, whereas posterior columns, Clarke's columns, intermediate lateral columns, and the Onuf's nucleus were spared. In the brainstem, moderate neuronal loss and gliosis were noted in the hypoglossal and facial motor nuclei. No Bunina bodies were found in the surviving spinal and brainstem motor neurons. Transactivation response (TAR) DNA-binding protein 43 (TDP-43)-positive neuronal and glial cytoplasmic inclusions were observed throughout the central nervous system. The Golgi apparatus in motor neurons of the brainstem and spinal cord was often fragmented. Immunoreactivity for OPTN was not observed in the brain and spinal cord, consistent with nonsense-mediated mRNA decay of OPTN. The TDP-43 pathology of Q398X was similar to that of an autosomal dominant E478G mutation. This result suggests that the loss-of-function, but not the proteinopathy itself, of OPTN results in TDP-43 deposits in neuronal and glial cytoplasm and Golgi apparatus fragmentation, leading to multisystem neurodegeneration. PMID:23889540

Kamada, Masaki; Izumi, Yuishin; Ayaki, Takashi; Nakamura, Masataka; Kagawa, Seiko; Kudo, Eiji; Sako, Wataru; Maruyama, Hirofumi; Nishida, Yoshihiko; Kawakami, Hideshi; Ito, Hidefumi; Kaji, Ryuji

2014-02-01

250

Localization of 4-hydroxy 2-nonenal immunoreactivity in aging human retinal Müller cells.  

Science.gov (United States)

Müller cells play a pivotal role in maintaining retinal homeostasis of the extracellular fluid environment. Information on whether human retinal Müller cells suffer from oxidative stress with normal aging is lacking. We examined post mortem human retinas for the localization of a biomarker of lipid peroxidation (4-hydroxy 2-nonenal, 4-HNE) by immunohistochemistry. We procured human eyes from donors (N=11; age: 45-91 years; post mortem delay: 1-3h), who had no history of ocular diseases. They were fixed in 4% paraformaldehyde and the retinas cryosectioned and labeled against anti-4-HNE employing the immunoperoxidase method. Compared to the lower age group (45-56 years), in the advanced age group (67-91 years), immunoreactivity (IR) to 4-HNE was prominent in peripheral Müller cell end-feet, select cells in the inner nuclear layer and in outer fibers located in the macular fiber layer of Henle. Colocalization with glutamine synthetase revealed that the 4-HNE positive profiles in the inner nuclear layer were Müller cells. Quantitative analysis revealed that the percentage of immunopositive cells in the inner nuclear layer as well as the grey levels of the immunoreaction products in the parafoveal and peripheral retinal regions significantly increased in the advanced age group. The findings indicate that Müller cells of human retina suffer from lipid peroxidation and are susceptible to damage in the course of normal, advanced aging. PMID:21454059

Nag, Tapas C; Wadhwa, Shashi; Alladi, Phalguni Anand; Sanyal, Tania

2011-05-01

251

HNK-1 immunoreactivity during early morphogenesis of the head region in a nonmodel vertebrate, crocodile embryo  

Science.gov (United States)

The present study examines HNK-1 immunoidentification of a population of the neural crest (NC) during early head morphogenesis in the nonmodel vertebrate, the crocodile ( Crocodylus niloticus) embryos. Although HNK-1 is not an exclusive NC marker among vertebrates, temporospatial immunoreactive patterns found in the crocodile are almost consistent with NC patterns derived from gene expression studies known in birds (the closest living relatives of crocodiles) and mammals. In contrast to birds, the HNK-1 epitope is immunoreactive in NC cells at the neural fold level in crocodile embryos and therefore provides sufficient base to assess early migratory events of the cephalic NC. I found that crocodile NC forms three classic migratory pathways in the head: mandibular, hyoid, and branchial. Further, I demonstrate that, besides this classic phenotype, there is also a forebrain-derived migratory population, which consolidates into a premandibular stream in the crocodile. In contrast to the closely related chick model, crocodilian premandibular and mandibular NC cells arise from the open neural tube suggesting that species-specific heterochronic behavior of NC may be involved in the formation of different vertebrate facial phenotypes.

Kundrát, Martin

2008-11-01

252

Localization of ATP-gated P2X2 receptor immunoreactivity in the rat hypothalamus.  

Science.gov (United States)

Previous pharmacological studies have indicated that ATP receptors may be involved in the regulation of physiological functions in hypothalamus. In the present study, the distribution of P2X2 receptor in the rat hypothalamus was studied with immunohistochemistry. It was shown that P2X2 immunoreactivity-positive neurons and nerve fibres were localized in many hypothalamic nuclei. Intense labelling of both neuronal cell bodies and nerve fibres was observed in the paraventricular nucleus, arcuate nucleus, retrochiasmatic area, periventricular nucleus, and the ventral part of tuber cinereum area. In supraoptic, circular, and ventral tuberomammillary nuclei the neuronal cell bodies were strongly positive, but few nerve fibres were positive. Axons with strong P2X2 immunoreactivity were found in the organum vasculosum of the lamina terminalis and median eminence. Some scattered positive neurons and nerve fibres were found in many hypothalamic nuclei including preoptic nucleus. The results of the present study demonstrated the existence of P2X receptors in hypothalamus, as a basis for detailed studies of the roles of P2X receptors in the regulation of hypothalamic functions. PMID:9838201

Xiang, Z; Bo, X; Oglesby, I; Ford, A; Burnstock, G

1998-12-01

253

Distribution of substance P-like immunoreactivity in the brain of the elasmobranch Scyliorhinus canicula.  

Science.gov (United States)

Immunohistochemical methods were used to study the distribution of substance P in the brain of the small-spotted dogfish (Scyliorhinus canicula). Substance P-like immunoreactive (SP-IR) cell bodies and fibers were widely distributed. In the telencephalon, sparse populations of SP-IR neurons are present in the olfactory bulbs, pallium, and subpallium. In the subpallium numerous SP-IR boutons form unusual coats ("pericellular appositions") on SP-immunonegative neurons. In the diencephalon numerous SP-IR cerebrospinal fluid-contacting neurons are present in the preoptic recess organ and organon vasculosum hypothalami. Numerous SP-IR fibers also run in the hypothalamus, although no immunoreactivity was observed in the habenulo-interpeduncular system. A terminal field of SP-IR fibers is present in the median eminence. In the mesencephalic tegmentum, SP-IR neurons were observed in the Edinger-Westphal nucleus. SP-IR fibers are present at high density in the basal tegmentum, forming a conspicuous tract. In the hindbrain, numerous SP-IR fibers were observed in the isthmal region, the trigeminal descending root, the visceral sensory area and commissural nucleus, and the visceromotor column. SP-IR fibers occur at high density in the substantia gelatinosa of the rostral spinal cord. PMID:7693771

Rodriguez-Moldes, I; Manso, M J; Becerra, M; Molist, P; Anadon, R

1993-09-01

254

GABA immunoreactivity in the olfactory bulbs of the adult sea lamprey Petromyzon marinus L.  

Science.gov (United States)

The distribution of gamma-aminobutyric acid (GABA) immunoreactivity in the olfactory bulbs of the adult sea lamprey was studied using an antibody against this transmitter. Five types of GABA-immunoreactive (GABAir) cells were observed. Medium-sized GABAir cells (periglomerular cells) were located around the olfactory glomeruli and occasionally within them. In the inner cellular layer of the bulbs and around the olfactory ventricles, two types of GABAir perikarya were present: some medium-sized GABAir cells and numerous small GABAir cells (granules). In the walls of the olfactory ventricle, some medium-sized GABAir cells of cerebrospinal fluid-contacting type were observed. At the entrance of the olfactory nerves, medium-sized GABAir bipolar cells were present, mostly located between the olfactory nerve and the glomerular layer or close to the meninges, but some in the intracranial portion of the olfactory nerve. GABAir processes were present in all layers of the olfactory bulb. In addition there were also GABAir cells in the dorsal interbulbar commissure. The distribution of GABA observed in the olfactory system of lampreys indicates that this transmitter plays a major role in the modulation of bulbar circuits. The presence of granular and periglomerular cells in lampreys indicates that these two intrinsic GABAergic neurons of the olfactory bulbs are shared by most vertebrates, although lampreys have additional GABAir cell types. PMID:11223013

Meléndez-Ferro, M; Pérez-Costas, E; Rodríguez-Muńoz, R; Gómez-López, M P; Anadón, R; Rodicio, M C

2001-03-01

255

Biopsychological changes after bungee jumping: beta-endorphin immunoreactivity as a mediator of euphoria?  

Science.gov (United States)

A study on 12 novice bungee jumpers was performed to investigate the influence of acute psychological stress on levels of cortisol in saliva, beta-endorphin immunoreactivity as well as the number of leukocytes in peripheral blood. In addition, heart rate and blood pressure as well as ratings on emotional states were recorded. Furthermore, correlations between ratings on mood and biochemical stress markers were computed. As expected, subjective ratings on anxiety were increased prior to the jump and were markedly reduced after the jump. Salivary cortisol was also increased after the jump and decreased to baseline within the next hour. In contrast, ratings on euphoria increased markedly after performing the jump and remained highly elevated for the next 30 min. An increase of more than 200% in beta-endorphin immunoreactivity after the jump was observed. In contrast to levels of cortisol, the concentration of beta-endorphin recorded immediately after the jump was significantly correlated with ratings on euphoria obtained at subsequent measurements indicating a relationship between beta-endorphins and euphoria. Additional increase of the number of blood leukocytes and of heart rate and blood pressure indicate that various systems of the organism are markedly affected by the exceptional eustress of bungee jumping. PMID:8127421

Hennig, J; Laschefski, U; Opper, C

1994-01-01

256

Effect of estrogen and neuroleptics on prolactin secretion and immunoreactive prolactin cells.  

Science.gov (United States)

The use of estrogen and dopamine receptor antagonists is associated with elevated prolactin levels and, in rats, chronic estrogen treatment is also associated with lactotroph proliferation. In this study, haloperidol, fluphenazine, sulpiride and metoclopramide, alone or combined with estradiol, were administered to Wistar rats. Pituitary weight, serum prolactin levels and percent of immunoreactive prolactin cells in the anterior pituitary glands were determined at the end of 60 days of treatment. The pituitary weight of rats treated with estrogen alone or in combination with other drugs was significantly higher than the control group. The serum prolactin level was higher than the upper confidence limit in all but three of the 90 treated rats. While in the control group the percent of immunoreactive prolactin cells was 20%, administration of the neuroleptic drugs and metoclopramide increased this percent to approximately 30%, and estrogen alone or in combination with one of the neuroleptic drugs increased it to approximately 40%. The results presented here demonstrate the relationship between prolactin secretion and prolactin cell number when different neuroleptics and related drugs are used. PMID:8736119

Oliveira, M C; Moraes, J T; Barros, H M; Barbosa-Coutinho, L M

1996-04-01

257

Stability and immunoreactivity of the monoclonal anticytokeratin antibody TS1 after different degrees of iodination  

Energy Technology Data Exchange (ETDEWEB)

The immunoreactivity, stability and in vivo kinetics of an anticytokeratin 8 monoclonal antibody, TS1, were investigated following different degrees of labeling with {sup 125}I (0.2, 1 and 2-3 {sup 125}I/TS1 MAb). By testing with ELISA, it was demonstrated that a high degree of iodination, i.e. > 2 {sup 125}I/TS1, caused a rapid decrease in immunoreactivity to almost zero within 10 days. Furthermore, a complete degradation to low molecular weight fragments and free iodine was seen, as shown by SDS PAGE and autoradiography. The differently labeled radionuclide conjugates were injected into nude mice inoculated with HeLa Hep2 cells and tumor doses (estimated by MIRD formalism), tumor:non-tumor dose ratios, % I.D./gram tissue, Gy/MBq and in vivo kinetics of the differently labeled MAbs were determined. Despite the in vitro instability of the highest iodinated radionuclide conjugate, it was possible to deliver high doses to the tumors if the conjugate was injected into the animal immediately after completion of the iodination procedure. Increases from 1.4 Gy to 15.2 Gy delivered tumor dose were obtained with a tenfold increase in the specific activity, without alterations in the tumor:non-tumor tissue dose ratios. There is room for significant improvements in efficacy at radioimmunotherapy, which can be gained by optimizing the degree of iodination. For therapeutical applications a high degree of iodination may be an advantage. (orig.)

Johansson, A.; Sandstroem, P.; Ullen, A.; Stigbrand, T. [Umeaa Univ. (Sweden). Dept. of Immunology; Erlandsson, A.; Sundstroem, B. [Vaermland University Coll. of Health and Caring Sciences, Karlstad (Sweden). Dept. of Biomedical Laboratory Science; Riklund Aahlstroem, K.; Hietala, S.O. [Umeaa Univ. (Sweden). Dept. of Diagnostic Radiology; Johansson, L. [Umeaa Univ. (Sweden). Dept. of Radiation Physics

1999-11-01

258

Reduced microglial immunoreactivity for endogenous NMDA receptor agonist quinolinic acid in the hippocampus of schizophrenia patients.  

Science.gov (United States)

Postmortem and positron emission tomography studies have indicated the pathophysiological involvement of microglial cells in schizophrenia. We hypothesized that the microglial production of quinolinic acid (QUIN), an endogenous N-methyl-d-aspartate receptor (NMDAR) agonist, may be linked to the previously described glutamatergic deficits in the hippocampus of schizophrenia patients. We performed a semi-quantitative assessment of QUIN-immunoreactive microglial cells in schizophrenia patients and matched controls in the CA1, CA2/3, and dentate gyrus (DG) area of the posterior hippocampal formation. Complementary immunostaining of the commonly used microglial surface marker HLA-DR was performed in adjacent histological sections. Fewer QUIN-immunoreactive microglial cells were observed in the CA1 hippocampal subregion of schizophrenia patients compared to controls (left p=0.028, right p=0.018). No significant diagnosis-dependent changes were observed in the CA2/3 and DG regions. These results were controlled for potential confounds by age, duration of disease, autolysis time, psychotropic medication, and hippocampal volume. No diagnosis-related differences were observed for the overall density of microglial cells (HLA-DR expression). Our findings suggest that reduced microglial QUIN content in the hippocampal CA1 region is associated with schizophrenia. We hypothesize that this association may contribute to impaired glutamatergic neurotransmission in the hippocampus of schizophrenia patients. PMID:24886967

Gos, Tomasz; Myint, Aye-Mu; Schiltz, Kolja; Meyer-Lotz, Gabriela; Dobrowolny, Henrik; Busse, Stefan; Müller, Ulf J; Mawrin, Christian; Bernstein, Hans-Gert; Bogerts, Bernhard; Steiner, Johann

2014-10-01

259

Losses of immunoreactive parvalbumin amacrine and immunoreactive alphaprotein kinase C bipolar cells caused by methylmercury chloride intoxication in the retina of the tropical fish Hoplias malabaricus  

Scientific Electronic Library Online (English)

Full Text Available SciELO Brazil | Language: English Abstract in english To quantify the effects of methylmercury (MeHg) on amacrine and on ON-bipolar cells in the retina, experiments were performed in MeHg-exposed groups of adult trahiras (Hoplias malabaricus) at two dose levels (2 and 6 µg/g, ip). The retinas of test and control groups were processed by mouse anti-parv [...] albumin and rabbit anti-alphaprotein kinase C (alphaPKC) immunocytochemistry. Morphology and soma location in the inner nuclear layer were used to identify immunoreactive parvalbumin (PV-IR) and alphaPKC (alphaPKC-IR) in wholemount preparations. Cell density, topography and isodensity maps were estimated using confocal images. PV-IR was detected in amacrine cells in the inner nuclear layer and in displaced amacrine cells from the ganglion cell layer, and alphaPKC-IR was detected in ON-bipolar cells. The MeHg-treated group (6 µg/g) showed significant reduction of the ON-bipolar alphaPKC-IR cell density (mean density = 1306 ± 393 cells/mm˛) compared to control (1886 ± 892 cells/mm˛; P

D.M.O., Bonci; S.M.A. de, Lima; S.R., Grötzner; C.A., Oliveira Ribeiro; D.E., Hamassaki; D.F., Ventura.

2006-03-01

260

Losses of immunoreactive parvalbumin amacrine and immunoreactive alphaprotein kinase C bipolar cells caused by methylmercury chloride intoxication in the retina of the tropical fish Hoplias malabaricus  

Scientific Electronic Library Online (English)

Full Text Available SciELO Brazil | Language: English Abstract in english To quantify the effects of methylmercury (MeHg) on amacrine and on ON-bipolar cells in the retina, experiments were performed in MeHg-exposed groups of adult trahiras (Hoplias malabaricus) at two dose levels (2 and 6 µg/g, ip). The retinas of test and control groups were processed by mouse anti-parv [...] albumin and rabbit anti-alphaprotein kinase C (alphaPKC) immunocytochemistry. Morphology and soma location in the inner nuclear layer were used to identify immunoreactive parvalbumin (PV-IR) and alphaPKC (alphaPKC-IR) in wholemount preparations. Cell density, topography and isodensity maps were estimated using confocal images. PV-IR was detected in amacrine cells in the inner nuclear layer and in displaced amacrine cells from the ganglion cell layer, and alphaPKC-IR was detected in ON-bipolar cells. The MeHg-treated group (6 µg/g) showed significant reduction of the ON-bipolar alphaPKC-IR cell density (mean density = 1306 ± 393 cells/mm˛) compared to control (1886 ± 892 cells/mm˛; P

D.M.O., Bonci; S.M.A. de, Lima; S.R., Grötzner; C.A., Oliveira Ribeiro; D.E., Hamassaki; D.F., Ventura.

 
 
 
 
261

Nesfatin-1/nucleobindin-2 like immunoreactivity in the olfactory system, brain and pituitary of frog, Microhyla ornata.  

Science.gov (United States)

Nesfatin-1 is a recently discovered anorectic protein derived from the precursor nucleobindin-2 (NUCB2). While nesfatin-1 has been widely studied in mammals, and goldfish, there are no reports of nesfatin-1 in amphibians. Using immunohistochemistry and Western blot analysis, this study assessed the distribution of NUCB2/nesfatin-1 in the brain of frog Microhyla ornata. NUCB2/nesfatin-1 like immunoreactivity was found in the olfactory receptor neurons, Bowman's glands and in the olfactory epithelium of medial diverticulum. In the brain, immunoreactive perikarya were seen in the anterior preoptic area, magnocellular nucleus, suprachiasmatic nucleus, ventromedial thalamic nucleus, posterior thalamic nucleus, nucleus infundibularis ventralis and dorsalis, and the cerebellar nucleus. NUCB2/nesfatin-1like immunoreactivity was also detected in the pineal and pituitary glands of frog. The presence of NUCB2/nesfatin-1 in the key brain regions suggest possible roles for this protein in the regulation of physiological processes in frogs. PMID:24768694

Senejani, A G; Gaupale, Tekchand C; Unniappan, Suraj; Bhargava, Shobha

2014-06-01

262

Effect of simulated gastric and intestinal digestion on temporal stability and immunoreactivity of peanut, almond, and pine nut protein allergens.  

Science.gov (United States)

Current models of digestibility utilize pepsin stability to assess the safety of allergenic versus nonallergenic food proteins. Dietary protein digestion in vivo, however, requires acid denaturation and protease cleavage by pepsin, trypsin, and/or chymotrypsin. The ability of this approach to identify food protein stability in the mammalian gut may be limited. We determined the temporal stability and immunoreactivity of almond, pine nut, and peanut allergenic proteins under simulated physiologic gastric and intestinal digestive conditions in vitro. Gel electrophoresis and immunoblot analyses were used to determine protein stability and immunoreactivity, respectively. Peanut, almond, and pine nut proteins were pepsin- and pancreatin-stable and immunoreactive for up to 1 h after initiation of digestion. Moreover, successive acid denaturation and pepsin and pancreatin cleavage were necessary to hydrolyze these allergenic proteins and reduce their IgG- and IgE-binding capacity, which suggests that digestibility models must be improved for more accurate safety assessment of food allergens. PMID:23742710

Toomer, Ondulla T; Do, Andrew; Pereira, Marion; Williams, Kristina

2013-06-19

263

Immunoreactivity, stability, pharmacokinetics and biodistribution of a monoclonal antibody to human leukemic B cells after three different methods of radioiodination  

International Nuclear Information System (INIS)

Dal B02, a murine monoclonal antibody against human chronic lymphocytic leukemia (CLL) was radioiodinated using chloramine T (Chl.T), Bolton-Hunter (B-H) or N-succinimidyl-p-iodobenzoate (PIB). The preparations had comparable radiochemical purity (>97%) and immunoreactive fraction (65-80%) but the Chl.T-based product was most susceptible to deiodination and loss of immunoreactivity. After i.v. injection into CLL-xenografted nude mice, the preparations had identical patterns of clearance from the blood but the PIB-based product led to more radioactivity in liver and spleen and less in the thyroid compared to the other preparations. The Chl.T-based product showed loss of immunoreactivity in circulation and less tumor-localized radioactivity 168 h after administration. The differences between the B-H-based and PIB-based products were less impressive than between PIB-based and Chl.T-based products. (author)

264

Chromosome abnormalities and season of birth  

DEFF Research Database (Denmark)

A study of seasonality has been made of birth of individuals with chromosome abnormalities registered in the Danish Cytogenetic Central Register before January 1, 1981. Significant seasonal variation in birth was found for males with Klinefelter's syndrome born before 1946, but not for those born later, and not for any other sex chromosome abnormality. No significant monthly variation was found for any autosomal abnormality, except a significant increase in the frequency of conceptions for Down's syndrome during the first 4 months of the year, using a chi square with 2 degrees of freedom.

Videbech, P; Nielsen, J

1984-01-01

265

Immunoreactive human chorionic gonadotropin and its free ß-subunit in serum and ascites of patients with malignant tumors  

Digital Repository Infrastructure Vision for European Research (DRIVER)

Human chorionic gonadotropin (hCG) is a clinically relevant marker of trophoblastic and nontrophoblastic malignancies. In the present studies, in addition to determining serum hCG, we investigated the presence and properties of hCG immunoreactivity in ascites of patients with nontrophoblastic malignant tumors and, for comparison, in ascites caused by cirrhotic liver disease. Total hCG immunoreactivity [hCG (+hCG-ß)] was found to be elevated above the reference value (>5 IU/liter) in the seru...

Ho?rmann, Rudolf; Gerbes, Alexander L.; Spo?ttl, Gerald; Ju?ngst, Dieter; Mann, Klaus

1992-01-01

266

Localization of tyrosine hydroxylase and phenylethanolamine N-methyltransferase immunoreactive cells in the medulla of the dog.  

Science.gov (United States)

The tyrosine hydroxylase (TH)- and phenylethanolamine N-methyltransferase (PNMT)-immunoreactive cells of the medulla are closely associated with cardiovascular control in both the cat and rat. Although it is often the species of choice for cardiovascular studies, no previous study had characterized these cell groups in the dog. The TH- and PNMT-immunoreactive cells of the dog were distributed much as they are in both cat and rat but with some species variations, which may be indicative of their functional role. PMID:2575722

Iwamoto, G A; Mitchell, J H; Sadeq, M; Kozlowski, G P

1989-12-15

267

Abnormal Glucose Levels Found in Transportation Accidents.  

Science.gov (United States)

The Federal Aviation Administration's Office of Aviation Medicine (OAM) is responsible for the certification of pilots with diabetic conditions. Therefore, it is essential for OAM to monitor pilots involved in fatal accidents for abnormal glucose levels, ...

D. V. Canfield, A. K. Chaturvedi, H. K. Boren, S. J. H. Veronneau, V. L. White

2000-01-01

268

Abnormality detector for neutron flux monitors  

International Nuclear Information System (INIS)

Purpose: To enable early abnormality detection of neutron-flux monitors even at a state of abnormality smaller than the usual level in a BWR type reactor. Constitution: The detection device mainly comprises a collecting section for collecting actual values from a local power range monitor (LPRM), an estimating section for calculating estimated values of LPRM based on the simulation code of a reactor and a judging section for judging the absence or presence of abnormality in LPRM and outputting the result of the judgement. The judging section, with respect to a certain LPRM, compares the difference between the actually measured value and the estimated value of LPRM at the positions considered symmetrical to the LPRM depending on the state of fuel arrangement and control rod insertion state in the reactor and judges the absence or presence of abnormality in LPRM based on the result. (Kamimura, M.)

269

Abnormal Events for Emergency Trip in HANARO  

International Nuclear Information System (INIS)

This report gathers abnormal events related to emergency trip of HANARO that happened during its operation over 10 years since the first criticality on February 1995. The collected examples will be utilized to the HANARO's operators as a useful guide

270

Possible Early Warning of Pregnancy Abnormalities  

Science.gov (United States)

... Career Development Programs Continuing education courses, training institutes & admin supplements News & Media Join NICHD Listservs Subscribe to ... NICHD Research Supported by NICHD Science Advances Supported Networks, Programs & Initiatives Possible Early Warning of Pregnancy Abnormalities ...

271

Model for quantifying absorption through abnormal skin  

International Nuclear Information System (INIS)

Techniques are available for quantitatively studying factors governing absorption through normal skin (in vivo and in vitro) but relatively little is known about the permeability of abnormal skin. We have designed and evaluated an in vivo model for quantifying absorption through abnormal skin. Absorption of [3H]mannitol and [14C]octyl benzoate was studied through altered rat skin. [3H]Mannitol penetrated normal skin much more slowly than did [14C]octyl benzoate. Abnormal skin was more permeable to [3H]mannitol and [14C]octyl benzoate, absorption was greater than 100X and greater than 2X greater, respectively, than normal. The in vivo model has been successfully used to quantify absorption through abnormal skin

272

Semi-automated imaging system to quantitate estrogen and progesterone receptor immunoreactivity in human breast cancer.  

Science.gov (United States)

A semi-automated imaging system is described to quantitate estrogen and progesterone receptor immunoreactivity in human breast cancer. The system works for any conventional method of image acquisition using microscopic slides that have been processed for immunohistochemical analysis of the estrogen receptor and progesterone receptor. Estrogen receptor and progesterone receptor immunohistochemical staining produce colorimetric differences in nuclear staining that conventionally have been interpreted manually by pathologists and expressed as percentage of positive tumoral nuclei. The estrogen receptor and progesterone receptor status of human breast cancer represent important prognostic and predictive markers of human breast cancer that dictate therapeutic decisions but their subjective interpretation result in interobserver, intraobserver and fatigue variability. Subjective measurements are traditionally limited to a determination of percentage of tumoral nuclei that show positive immunoreactivity. To address these limitations, imaging algorithms utilizing both colorimetric (RGB) as well as intensity (gray scale) determinations were used to analyze pixels of the acquired image. Image acquisition utilized either scanner or microscope with attached digital or analogue camera capable of producing images with a resolution of 20 pixels /10 mu. Areas of each image were screened and the area of interest richest in tumour cells manually selected for image processing. Images were processed initially by JPG conversion of SVS scanned virtual slides or direct JPG photomicrograph capture. Following image acquisition, images were screened for quality, enhanced and processed. The algorithm-based values for estrogen receptor and progesterone receptor percentage nuclear positivity both strongly correlated with the subjective measurements (intraclass correlation: 0.77; 95% confidence interval: 0.59, 0.95) yet exhibited no interobserver, intraobserver or fatigue variability. In addition the algorithms provided measurements of nuclear estrogen receptor and progesterone receptor staining intensity (mean, mode and median staining intensity of positive staining nuclei), parameters that subjective review could not assess. Other semi-automated image analysis systems have been used to measure estrogen receptor and progesterone receptor immunoreactivity but these either have required proprietary hardware or have been based on luminosity differences alone. By contrast our algorithms were independent of proprietary hardware and were based on not just luminosity and colour but also many other imaging features including epithelial pattern recognition and nuclear morphology. These features provide a more accurate, versatile and robust imaging analysis platform that can be fully automated in the near future. Because of all these properties, our semi-automated imaging system 'adds value' as a means of measuring these important nuclear biomarkers of human breast cancer. PMID:17535263

Sharangpani, G M; Joshi, A S; Porter, K; Deshpande, A S; Keyhani, S; Naik, G A; Gholap, A S; Barsky, S H

2007-06-01

273

Remote disassembly of an abnormal multiplication system  

International Nuclear Information System (INIS)

The method of abnormal multiplying systems remote disassembling is described. This method was worked through in actual operations as response to the nuclear accident at the RFNC-VNIIEF criticality test facility FKBN-2M on 17 June 1997. The abnormal assembly was a sphere of 235U (90%), surrounded by a copper reflector. The detailed information on the multiplying system disassembly operations could be of use to the experts at other institutions when they develop emergency response plans. (author)

274

Osteopoikilosis Patient with Abnormal Bone Scan  

Directory of Open Access Journals (Sweden)

Full Text Available Osteopoikilosis a condition mimicking a variety of bone pathology is a rare osteosclerotic displasia. The diagnosis is usually done according to radiographs which are performed incidentally. Although bone scan is usually normal, especially in young patients abnormal tracer uptake can be seen. We report a 25 year-old female osteopoikilosis patient with abnormal bone scan and characteristic radiographic findings who had been diagnosed and treated inappropriately. Turk J Phys Med Rehab 2008;54:69-72

Alev Gürgan

2008-06-01

275

Abnormal ''Contamination' Levels On Garden Appliances  

International Nuclear Information System (INIS)

During routine contamination checks we encountered an abnormal high level of Alpha and Beta emitting radioisotopes on working gloves of employees of the gardening department. It came out that the source was due to ''contamination'' levels on steering wheels of some gardening machines. In order to ensure that no real contamination of these workers was involved , a series of checks was started to identity the source of the abnormal levels found during monitoring

276

Heterotaxy syndromes and abnormal bowel rotation  

Energy Technology Data Exchange (ETDEWEB)

Bowel rotation abnormalities in heterotaxy are common. As more children survive cardiac surgery, the management of gastrointestinal abnormalities has become controversial. To evaluate imaging of malrotation in heterotaxy with surgical correlation and provide an algorithm for management. Imaging reports of heterotaxic children with upper gastrointestinal (UGI) and/or small bowel follow-through (SBFT) were reviewed. Subsequently, fluoroscopic images were re-reviewed in conjunction with CT/MR studies. The original reports and re-reviewed images were compared and correlated with surgical findings. Nineteen of 34 children with heterotaxy underwent UGI, 13/19 also had SBFT. In 15/19 reports, bowel rotation was called abnormal: 11 malrotation, 4 non-rotation, no cases of volvulus. Re-review, including CT (10/19) and MR (2/19), designated 17/19 (90%) as abnormal, 10 malrotation (abnormal bowel arrangement, narrow or uncertain length of mesentery) and 7 non-rotation (small bowel and colon on opposite sides plus low cecum with probable broad mesentery). The most useful CT/MR findings were absence of retroperitoneal duodenum in most abnormal cases and location of bowel, especially cecum. Abnormal orientation of mesenteric vessels suggested malrotation but was not universal. Nine children had elective bowel surgery; non-rotation was found in 4/9 and malrotation was found in 5/9, with discrepancies (non-rotation at surgery, malrotation on imaging) with 4 original interpretations and 1 re-review. We recommend routine, early UGI and SBFT studies once other, urgent clinical concerns have been stabilized, with elective laparoscopic surgery in abnormal or equivocal cases. Cross-sectional imaging, usually obtained for other reasons, can contribute diagnostically. Attempting to assess mesenteric width is important in differentiating non-rotation from malrotation and more accurately identifies appropriate surgical candidates. (orig.)

Newman, Beverley [Stanford University, Lucile Packard Children' s Hospital, Department of Radiology, Stanford, CA (United States); Koppolu, Raji; Sylvester, Karl [Lucile Packard Children' s Hospital at Stanford, Department of Surgery, Stanford, CA (United States); Murphy, Daniel [Lucile Packard Children' s Hospital at Stanford, Department of Cardiology, Stanford, CA (United States)

2014-05-15

277

Heterotaxy syndromes and abnormal bowel rotation  

International Nuclear Information System (INIS)

Bowel rotation abnormalities in heterotaxy are common. As more children survive cardiac surgery, the management of gastrointestinal abnormalities has become controversial. To evaluate imaging of malrotation in heterotaxy with surgical correlation and provide an algorithm for management. Imaging reports of heterotaxic children with upper gastrointestinal (UGI) and/or small bowel follow-through (SBFT) were reviewed. Subsequently, fluoroscopic images were re-reviewed in conjunction with CT/MR studies. The original reports and re-reviewed images were compared and correlated with surgical findings. Nineteen of 34 children with heterotaxy underwent UGI, 13/19 also had SBFT. In 15/19 reports, bowel rotation was called abnormal: 11 malrotation, 4 non-rotation, no cases of volvulus. Re-review, including CT (10/19) and MR (2/19), designated 17/19 (90%) as abnormal, 10 malrotation (abnormal bowel arrangement, narrow or uncertain length of mesentery) and 7 non-rotation (small bowel and colon on opposite sides plus low cecum with probable broad mesentery). The most useful CT/MR findings were absence of retroperitoneal duodenum in most abnormal cases and location of bowel, especially cecum. Abnormal orientation of mesenteric vessels suggested malrotation but was not universal. Nine children had elective bowel surgery; non-rotation was found in 4/9 and malrotation was found in 5/9, with discrepancies (non-rotation at surgery, malrotation on imaging) with 4 original interpretations and 1 re-review. We recommend routine, early UGI and SBFT studies once other, urgent clinical concerns have been stabilized, with elective laparoscopic surgery in abnormal or equivocal cases. Cross-sectional imaging, usually obtained for other reasons, can contribute diagnostically. Attempting to assess mesenteric width is important in differentiating non-rotation from malrotation and more accurately identifies appropriate surgical candidates. (orig.)

278

White matter abnormalities in tuberous sclerosis complex  

International Nuclear Information System (INIS)

The aim of this study was to investigate and describe the range of white matter abnormalities in children with tuberous sclerosis complex by means of MR imaging. Material and Methods: A retrospective cross-sectional study was performed on the basis of MR imaging findings in 20 cases of tuberous sclerosis complex in children aged 17 years or younger. Results: White matter abnormalities were present in 19/20 (95%) cases of tuberous sclerosis complex. These were most frequently (19/20 cases) found in relation to cortical tubers in the supratentorial compartment. White matter abnormalities related to tubers were found in the cerebellum in 3/20 (15%) cases. White matter abnormalities described as radial migration lines were found in relation to 5 tubers in 3 (15%) children. In 4/20 (20%) cases, white matter abnormalities were found that were not related to cortical tubers. These areas had the appearance of white matter cysts in 3 cases and infarction in the fourth. In the latter case there was a definable event in the clinical history, supporting the diagnosis of stroke. Conclusion: A range of white matter abnormalities were found by MR imaging in tuberous sclerosis complex, the commonest being gliosis and hypomyelination related to cortical tubers. Radial migration lines were seen infrequently in relation to cortical tubers and these are thought to represent heterotopic glia and neurons along the expected path of cortical migration. (orig.)n. (orig.)

279

Chromosome abnormalities in newborn children. Physical aspects  

DEFF Research Database (Denmark)

A chromosome examination was made on 11,148 consecutively live-born children: 93 had a chromosome abnormality and 192 a chromosome variant. The physical aspects of the children with chromosome abnormalities and variants were compared with those of the children with normal karyotypes. Children with aneuploid or unbalanced chromosome abnormalities were more immature or not fully developed at birth than those with normal karyotypes. Birth weight was lower in children with all types of chromosome abnormalities, including reciprocal translocations and chromosome variants. The low birth weight in children with chromosome variants was mainly due to the low birth weight of children with G variants. These children were also subject to a higher frequency of special delivery treatment. Heart disorders were increased in children with aneuploid or unbalanced chromosome abnormalities. The frequency of foetal erythroblastosis was increased in children with short Y as well as in children with acentric fragments. Neonatal mortality was higher in children with aneuploid or unbalanced chromosome abnormalities than in children with normal karyotypes.

Nielsen, J; Hansen, K B

1981-01-01

280

White matter abnormalities in tuberous sclerosis complex  

Energy Technology Data Exchange (ETDEWEB)

The aim of this study was to investigate and describe the range of white matter abnormalities in children with tuberous sclerosis complex by means of MR imaging. Material and Methods: A retrospective cross-sectional study was performed on the basis of MR imaging findings in 20 cases of tuberous sclerosis complex in children aged 17 years or younger. Results: White matter abnormalities were present in 19/20 (95%) cases of tuberous sclerosis complex. These were most frequently (19/20 cases) found in relation to cortical tubers in the supratentorial compartment. White matter abnormalities related to tubers were found in the cerebellum in 3/20 (15%) cases. White matter abnormalities described as radial migration lines were found in relation to 5 tubers in 3 (15%) children. In 4/20 (20%) cases, white matter abnormalities were found that were not related to cortical tubers. These areas had the appearance of white matter cysts in 3 cases and infarction in the fourth. In the latter case there was a definable event in the clinical history, supporting the diagnosis of stroke. Conclusion: A range of white matter abnormalities were found by MR imaging in tuberous sclerosis complex, the commonest being gliosis and hypomyelination related to cortical tubers. Radial migration lines were seen infrequently in relation to cortical tubers and these are thought to represent heterotopic glia and neurons along the expected path of cortical migration. (orig.)

Griffiths, P.D. [Sheffield Univ. (United Kingdom). Academic Dept. of Radiology; Bolton, P. [Cambridge Univ. (United Kingdom). Section of Developmental Psychiatry; Verity, C. [Addenbrooke`s NHS Trust, Cambridge (United Kingdom). Dept. of Paediatric Radiology

1998-09-01

 
 
 
 
281

Diagnosing of chromosome abnormalities in Denmark  

DEFF Research Database (Denmark)

A survey of how frequent chromosome abnormalities are diagnosed in Denmark prenatally as well as postnatally compared with the expected incidence in an 11-year period 1970-1980 has been made from the Danish Cytogenetic Central Register. Ten percent of the expected number of Klinefelter's syndrome, 41% of Turner's syndrome and 10% of other sex chromosome abnormalities in children born between 1970 and 1980 have been diagnosed until January 1, 1983. The total frequency of diagnosed cases with sex chromosome abnormalities is 13% of the expected number. Induced abortion was made in 62% of the cases with sex chromosome abnormalities diagnosed prenatally. Ninety percent of all cases with Down's syndrome were diagnosed by chromosome examination, and 10% were diagnosed prenatally and aborted. During the last part of the period from 1977-1980 this had increased to 20%. Thirty-seven percent of cases with other chromosome abnormalities were diagnosed. Among the expected 4,396 children with chromosome abnormalities to beborn between 1970 and 1980, a total of 39% were diagnosed postnatally until January 1, 1983, and 10% were diagnosed prenatally. It is concluded that there is a great need for training consultants in clinical genetics, expansion and further decentralization of cytogenetic service with more cytogenetic laboratories and employment of clinical geneticists in all 14 Danish counties.

Nielsen, J; Videbech, P

1984-01-01

282

Losses of immunoreactive parvalbumin amacrine and immunoreactive alphaprotein kinase C bipolar cells caused by methylmercury chloride intoxication in the retina of the tropical fish Hoplias malabaricus.  

Science.gov (United States)

To quantify the effects of methylmercury (MeHg) on amacrine and on ON-bipolar cells in the retina, experiments were performed in MeHg-exposed groups of adult trahiras (Hoplias malabaricus) at two dose levels (2 and 6 microg/g, ip). The retinas of test and control groups were processed by mouse anti-parvalbumin and rabbit anti-alphaprotein kinase C (alphaPKC) immunocytochemistry. Morphology and soma location in the inner nuclear layer were used to identify immunoreactive parvalbumin (PV-IR) and alphaPKC (alphaPKC-IR) in wholemount preparations. Cell density, topography and isodensity maps were estimated using confocal images. PV-IR was detected in amacrine cells in the inner nuclear layer and in displaced amacrine cells from the ganglion cell layer, and alphaPKC-IR was detected in ON-bipolar cells. The MeHg-treated group (6 microg/g) showed significant reduction of the ON-bipolar alphaPKC-IR cell density (mean density = 1306 +/- 393 cells/mm2) compared to control (1886 +/- 892 cells/mm2; P < 0.001). The mean densities found for amacrine PV-IR cells in MeHg-treated retinas were 1040 +/- 56 cells/mm2 (2 microg/g) and 845 +/- 82 cells/mm2 (6 microg/g), also lower than control (1312 +/- 31 cells/mm2; P < 0.05), differently from the data observed in displaced PV-IR amacrine cells. These results show that MeHg changed the PV-IR amacrine cell density in a dose-dependent way, and reduced the density of alphaKC-IR bipolar cells at the dose of 6 microg/g. Further studies are needed to identify the physiological impact of these findings on visual function. PMID:16501820

Bonci, D M O; Lima, S M A de; Grötzner, S R; Ribeiro, C A Oliveira; Hamassaki, D E; Ventura, D F

2006-03-01

283

Losses of immunoreactive parvalbumin amacrine and immunoreactive alphaprotein kinase C bipolar cells caused by methylmercury chloride intoxication in the retina of the tropical fish Hoplias malabaricus  

Directory of Open Access Journals (Sweden)

Full Text Available To quantify the effects of methylmercury (MeHg on amacrine and on ON-bipolar cells in the retina, experiments were performed in MeHg-exposed groups of adult trahiras (Hoplias malabaricus at two dose levels (2 and 6 µg/g, ip. The retinas of test and control groups were processed by mouse anti-parvalbumin and rabbit anti-alphaprotein kinase C (alphaPKC immunocytochemistry. Morphology and soma location in the inner nuclear layer were used to identify immunoreactive parvalbumin (PV-IR and alphaPKC (alphaPKC-IR in wholemount preparations. Cell density, topography and isodensity maps were estimated using confocal images. PV-IR was detected in amacrine cells in the inner nuclear layer and in displaced amacrine cells from the ganglion cell layer, and alphaPKC-IR was detected in ON-bipolar cells. The MeHg-treated group (6 µg/g showed significant reduction of the ON-bipolar alphaPKC-IR cell density (mean density = 1306 ± 393 cells/mm˛ compared to control (1886 ± 892 cells/mm˛; P < 0.001. The mean densities found for amacrine PV-IR cells in MeHg-treated retinas were 1040 ± 56 cells/mm˛ (2 µg/g and 845 ± 82 cells/mm˛ (6 µg/g, also lower than control (1312 ± 31 cells/mm˛; P < 0.05, differently from the data observed in displaced PV-IR amacrine cells. These results show that MeHg changed the PV-IR amacrine cell density in a dose-dependent way, and reduced the density of alphaKC-IR bipolar cells at the dose of 6 µg/g. Further studies are needed to identify the physiological impact of these findings on visual function.

D.M.O. Bonci

2006-03-01

284

Cogeneration of retrogradely labeled corticocortical projection and GABA-immunoreactive local circuit neurons in cerebral cortex.  

Science.gov (United States)

The times of origin of cortico-cortical projection neurons and local circuit neurons in rat visual cortex were determined. The birthdates of the projection neurons were assessed using a technique that combined retrograde labeling with lectin-bound horseradish peroxidase and tritiated thymidine autoradiography. The birthdates of some cortical local circuit neurons were determined by combining GABA immunocytochemistry with [3H]thymidine autoradiography. Double-labeled neurons (those with retrograde or immunoreactive label in their perikarya and autoradiographic silver grains over their nuclei) were born during the third week of gestation. Projection and local circuit neurons born on gestational day 14, 15, 17, 19 or 20 were located primarily in layer VIb, VIa, V, III or II, respectively. Thus, both populations of neurons are generated by parallel and concurrent inside-to-outside patterns. PMID:3910166

Miller, M W

1985-12-01

285

Tracheal cryopreservation: caspase-3 immunoreactivity in tracheal epithelium and in mixed glands  

Scientific Electronic Library Online (English)

Full Text Available SciELO Brazil | Language: English Abstract in english Cryopreservation has an immunomodulating effect on tracheal tissue as a result of class II antigen depletion due to epithelium exfoliation. However, not all epithelium is detached. We evaluated the role of apoptosis in the remaining epithelium of 30 cryopreserved tracheal grafts. Caspase-3 immunorea [...] ctivity of tracheal epithelium was studied in canine tracheal segments cryopreserved with F12K medium, with or without subsequent storage in liquid nitrogen at -196°C for 15 days. Loss of structural integrity of tracheal mixed glands was observed in all cryopreserved tracheal segments. Caspase-3 immunoreactivity in tracheal mucosa and in mixed glands was significantly decreased, in contrast to the control group and to cryopreserved tracheal segments in which it remained high, due to the effect of storage in liquid nitrogen (P

A., Sotres-Vega; M., Baltazares-Lipp; J., Villalba-Caloca; M.O., Gaxiola-Gaxiola; J.A., Santibańez-Salgado; J.R., Olmos-Zúńiga; R., Jasso-Victoria.

1156-11-01

286

Distribution and location of immunoreactive atrial natriuretic peptides in middle ear mucosa of guinea pig.  

Science.gov (United States)

The distribution and location of atrial natriuretic peptides (ANP) in the middle ear mucosa (MEM) of guinea pigs were studied with immunocytochemistry (avidin-biotin-peroxidase complex method) and immuno-electron microscopy. A great quantity of ANP-immunoreactive (ANP-IR) cells, including oval small cells and irregular large cells, was observed in the tissue of the MEM. The strong ANP-IR product was observed in the inner membrane of the partial capillary walls. Under immuno-electron microscopy, the ANP-IR product was found to be spheres of 250 to 350 nm in diameter. The results of this study suggest that the MEM has the function of secreting ANP. This paper provides the morphological basis for the study of ANP's function in the MEM. PMID:10737307

Chen, H

2000-03-01

287

Immunoreactive and biologically active growth hormone-releasing factor in the rat placenta.  

Science.gov (United States)

Rat placentas from fetuses of 18 and 20 days of gestation were collected, extracted, and examined for their capacity to stimulate GH release in vitro. The crude extract stimulated, in a dose-dependent fashion, GH release by rat anterior pituitary cells in monolayer culture. The biological and immunological activities retained on antirat GH-releasing factor immunoaffinity columns eluted on Sephadex G-75 (fine) columns with an estimated mol wt of 5000 daltons. Reverse phase HPLC of this material revealed the presence of two forms of GRF activity that eluted with retention times identical to those of synthetic rat GRF and its methionine sulfoxide counterpart [Met(O)27]GRF. The results demonstrate the presence of an immunoreactive and biologically active GRF in the rat placenta that is indistinguishable from rat hypothalamic GRF. PMID:3928335

Baird, A; Wehrenberg, W B; Böhlen, P; Ling, N

1985-10-01

288

Serum immunoreactive trypsin, pancreatic polypeptide, and pancreatic isoamylase as diagnostic tests for chronic pancreatitis.  

Science.gov (United States)

The efficiency of immunoreactive trypsin (IRT), pancreatic polypeptide (PP), and pancreatic isoamylase (PI) in the diagnosis of chronic pancreatitis was studied in 80 consecutive patients clinically suspected of having chronic pancreatitis. Twenty-five patients had chronic pancreatitis, and of these, 17 had pancreatic insufficiency. IRT, PP, and PI were of no value in the diagnosis of chronic pancreatitis without insufficiency. The three tests were of equal but limited value in diagnosing pancreatic insufficiency (nosographic sensitivities, 0.53 to 0.59, and predictive values of a negative test, 0.88 to 0.90). The combination of IRT, PP, and PI did not increase the diagnostic efficiency compared with each of the three tests alone. We conclude that IRT, PP, and PI are of similar but limited value as diagnostic tests for pancreatic insufficiency. PMID:6719033

Enslev, L; Andersen, B N; Fahrenkrug, J; Magid, E; Thorsgaard-Pedersen, N

1984-03-01

289

Tracheal cryopreservation: caspase-3 immunoreactivity in tracheal epithelium and in mixed glands  

Scientific Electronic Library Online (English)

Full Text Available SciELO Brazil | Language: English Abstract in english Cryopreservation has an immunomodulating effect on tracheal tissue as a result of class II antigen depletion due to epithelium exfoliation. However, not all epithelium is detached. We evaluated the role of apoptosis in the remaining epithelium of 30 cryopreserved tracheal grafts. Caspase-3 immunorea [...] ctivity of tracheal epithelium was studied in canine tracheal segments cryopreserved with F12K medium, with or without subsequent storage in liquid nitrogen at -196°C for 15 days. Loss of structural integrity of tracheal mixed glands was observed in all cryopreserved tracheal segments. Caspase-3 immunoreactivity in tracheal mucosa and in mixed glands was significantly decreased, in contrast to the control group and to cryopreserved tracheal segments in which it remained high, due to the effect of storage in liquid nitrogen (P

A., Sotres-Vega; M., Baltazares-Lipp; J., Villalba-Caloca; M.O., Gaxiola-Gaxiola; J.A., Santibańez-Salgado; J.R., Olmos-Zúńiga; R., Jasso-Victoria.

290

CD5 immunoreactivity of epithelial cells in thymic carcinoma and CASTLE using paraffin-embedded tissue.  

Science.gov (United States)

Because the histologic features may resemble those of other mediastinal malignancies, thymic carcinoma can be difficult to diagnose, particularly if the primary site is uncertain. In an effort to facilitate this diagnosis, the authors have evaluated the use of immunohistochemistry with an antibody to CD5 (NCL-CD5). Nine thymic carcinomas, 15 thymomas, 8 lymphomas, 10 poorly differentiated lung carcinomas, 10 breast carcinomas, 1 mediastinal seminoma, and 1 thyroid carcinoma showing thymus-like differentiation (CASTLE) were studied. Four of 9 poorly differentiated carcinomas of the thymus were CD5 positive. The one CASTLE was CD5 positive. All other tumors were negative. CD5-positive lymphocytes were internal controls in every case. CD5 labels some thymic carcinomas in paraffin-embedded tissue, whereas other tumors studied were negative. CD5 immunoreactivity of CASTLE appears to support thymic derivation of this tumor. PMID:8853036

Berezowski, K; Grimes, M M; Gal, A; Kornstein, M J

1996-10-01

291

Immunoreactive luteinizing hormone-releasing hormone in the seminal plasma and human semen parameters  

International Nuclear Information System (INIS)

A luteinizing hormone-releasing hormone (LH-RH)-like substance has been detected in human seminal plasma by a radioimmunoassay (RIA) with a highly specific anti-LH-RH antiserum. The seminal samples - not only the plasma itself but also the sample extracted by an acid/alcohol method - showed satisfactory displacement curves in our RIA system. The relationship between fertility and the LH-RH values in the seminal plasma was studied by comparing the peptide levels with sperm concentration and motility. By these two parameters, 103 samples were divided into four groups. In the low-concentration groups (oligozoospermic patients), the hormonal concentrations differed significantly between those specimens demonstrating good and poor motility. These data suggest that this immunoreactive LH-RH may play a role in human spermatogenesis

292

Serum immunoreactive trypsin concentrations in infectious and non-infectious illnesses and in juvenile diabetes.  

Science.gov (United States)

Serum immunoreactive trypsin (SIT) concentrations were measured in 244 patients with infectious illnesses and in 281 children with diabetes of recent onset. Results were compared with reference ranges established in 107 patients with non-infectious, non-diabetic illnesses, in whom SIT concentrations were found to increase with advancing age. Reduced or undetectable concentrations of SIT were associated with diabetes in children and with a few cases of severe childhood infection. Increased SIT concentrations were associated with virologically confirmed cases of infection with mumps and Coxsackie B virus infection, and with clinical diagnoses of mumps, PUO, and meningitis in children, and with Bornholm disease, cardiac infection, and respiratory infection in adults. It is suggested that silent invasion of the exocrine pancreas with elevation of the SIT concentration may accompany infection by Coxsackie B, mumps, and, possibly, other viruses. PMID:512051

Gamble, D R; Moffatt, A; Marks, V

1979-09-01

293

Mapping of neurochemical markers in quail central nervous system: VIP- and SP-like immunoreactivity.  

Science.gov (United States)

The distribution of cells and fibres containing vasoactive intestinal polypeptide (VIP) and substance P (SP) was investigated in the brain of Japanese quail focussing on the centers involved in reproductive activities. SP-immunoreactive (ir) structures were chiefly present within the ventral telencephalic regions, the periventricular hypothalamus and the dorsal aspects of thalamus. VIP immunopositive structures were rarely associated with recognizable nuclei and they were observed in the organum septi laterale (LSO), the lobus paraolfactorius (LPO), the eminentia mediana (ME), the nucleus striae terminalis (nST) and the area ventralis of Tsai (AVT). SP- and VIP-ir structures were both associated with regions implicated in the control of reproduction. SP was mainly distributed within regions that control male copulatory behavior (the preoptic region, the anterior hypothalamus and the central gray), whereas VIP was prevalently located in the mediobasal hypothalamus that is implicated in the control of female reproductive activities. PMID:7541207

Aste, N; Viglietti-Panzica, C; Fasolo, A; Panzica, G C

1995-02-01

294

Presence of immunoreactive atrial natriuretic peptide in follicular fluid, ovary and ovarian perfusates  

International Nuclear Information System (INIS)

Immunoreactive atrial natriuretic peptide (ir-ANP) was measured in the follicular fluid of pig ovarian follicle, and rabbit ovarian homogenates and perfusates using a specific radioimmunoassay (RIA). Serial dilution curves made with the extracts of follicular fluid, ovarian homogenates and perfusates using Sep-Pak C18 cartridges were parallel with the RIA standard curve. On gel filtration chromatography and reverse phase HPLC, all extracted materials showed high and low molecular weight forms of ir-ANP. The amount of ir-ANP in rabbit ovary was 40.7±0.39 pg/mg and that in follicular fluid of pig ovarian follicle was 18.88±2.49 pg/ml

295

Presence of immunoreactive atrial natriuretic peptide in follicular fluid, ovary and ovarian perfusates  

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Immunoreactive atrial natriuretic peptide (ir-ANP) was measured in the follicular fluid of pig ovarian follicle, and rabbit ovarian homogenates and perfusates using a specific radioimmunoassay (RIA). Serial dilution curves made with the extracts of follicular fluid, ovarian homogenates and perfusates using Sep-Pak C18 cartridges were parallel with the RIA standard curve. On gel filtration chromatography and reverse phase HPLC, all extracted materials showed high and low molecular weight forms of ir-ANP. The amount of ir-ANP in rabbit ovary was 40.7{plus minus}0.39 pg/mg and that in follicular fluid of pig ovarian follicle was 18.88{plus minus}2.49 pg/ml.

Kim, Suhn Hee; Cho, Kyung Woo; Seul, Kyung Hwan; Ryu, Hoon; Koh, Gou Young (University Medical School, Jeonju (Korea))

1989-01-01

296

Distribution of Gb3 Immunoreactivity in the Mouse Central Nervous System  

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Full Text Available We have shown previously that neurons in the mouse spinal cord express Gb3. We show in this article that distribution of anti-Gb3-Ab reactivity occurs in many different types of neurons of different areas of the central nervous system (CNS. The immunoreactive neurons are in olfactory bulbs, cerebral cortex, hippocampus, striatum, amygdala, thalamus, hypothalamus, cerebellum, and medulla oblongata. In several different circumventricular organs where vessels do not have the blood-brain-barrier (BBB structure, anti-Gb3-Ab is not positive for vessel structures, while neurons at these regions are positive. Also, within the ventricular area, ependymal cells in the third ventricle express Gb3, as revealed by anti-Gb3-Ab staining and intensity analysis.

Tom Obrig

2010-08-01

297

Immunoreactivity and Radioimmunoscintigraphy of 4-Lysine Single Chain (Fv) Lym-1 Antibody for the Radiometal Chelation  

International Nuclear Information System (INIS)

Small size of recombinant scFv, composed of VH and VL region of IgG, has many advantages such as faster blood clearance, improved tumor localization and reduced human anti-mouse antibody (HAMA) response. On the other hand, owing to small size, number of amino group, which was not involved in binding site, of ScFv lym-1 was insufficient in conjugation with CITC-DTPA chelator for radio metal labeling. The goal of this study is to introduce 4-lysine tag to the end of ScFv lym-1 sequence for radio metal conjugation and to evaluate the immunoreactivity and radioimmunoscintigraphy of chelator conjugated 4-lysine taq scFv lym-1 (4-lys scFv)

298

Immunoreactivity and Radioimmunoscintigraphy of 4-Lysine Single Chain (Fv) Lym-1 Antibody for the Radiometal Chelation  

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Small size of recombinant scFv, composed of VH and VL region of IgG, has many advantages such as faster blood clearance, improved tumor localization and reduced human anti-mouse antibody (HAMA) response. On the other hand, owing to small size, number of amino group, which was not involved in binding site, of ScFv lym-1 was insufficient in conjugation with CITC-DTPA chelator for radio metal labeling. The goal of this study is to introduce 4-lysine tag to the end of ScFv lym-1 sequence for radio metal conjugation and to evaluate the immunoreactivity and radioimmunoscintigraphy of chelator conjugated 4-lysine taq scFv lym-1 (4-lys scFv)

Jung, Jae Ho; Choi, Tae Hyun; Lee, Tae Sup; Uh, Gwang Sun; Chung, Wee Sup; Kim, Eun Jung; Cheon, Gi Jeong; Choi, Chang Woon; Lim, Sang Moo [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

2007-07-01

299

VIP-, substance P-, gastrin/CCK-, bombesin-, somatostatin- and glucagon-like immunoreactivities in the gut of the rainbow trout, Salmo gairdneri.  

Science.gov (United States)

The presence of peptides in the gastrointestinal tract of the rainbow trout, Salmo gairdneri, was investigated immunocytochemically. VIP-like immunoreactivity was demonstrated in nerves in all layers of the stomach and the intestine, whereas substance P-like immunoreactivity was localized to endocrine cells, predominantly in the mucosa of the stomach, and to nerves mainly concentrated in the myenteric plexus throughout the gut. Endocrine cells reactive to gastrin/CCK antiserum were demonstrated in the intestinal mucosa, while no immunoreactivity was found in the stomach. Bombesin-immunoreactive and somatostatin-immunoreactive cells were localized in the stomach mucosa, and cells reactive to glucagon antiserum in the intestinal mucosa. Radioimmunoassay of stomach mucosa and muscle confirmed the presence of VIP-like and substance P-like immunoreactivity in these tissues, while gastrin/CCK-like immunoreactivity was low and bombesin-like immunoreactivity was insignificant. In conclusion, molecules resembling the mammalian brain-gut peptides may be involved in the neuronal and hormonal control of gut function in fish. PMID:6175424

Holmgren, S; Vaillant, C; Dimaline, R

1982-01-01

300

Amyotrophic lateral sclerosis--a model of corticofugal axonal spread.  

Science.gov (United States)

The pathological process underlying amyotrophic lateral sclerosis (ALS) is associated with the formation of cytoplasmic inclusions consisting mainly of phosphorylated 43-kDa transactive response DNA-binding protein (pTDP-43), which plays an essential part in the pathogenesis of ALS. Preliminary evidence indicates that neuronal involvement progresses at different rates, but in a similar sequence, in different patients with ALS. This observation supports the emerging concept of prion-like propagation of abnormal proteins in noninfectious neurodegenerative diseases. Although the distance between involved regions is often considerable, the affected neurons are connected by axonal projections, indicating that physical contacts between nerve cells along axons are important for dissemination of ALS pathology. This article posits that the trajectory of the spreading pattern is consistent with the induction and dissemination of pTDP-43 pathology chiefly from cortical neuronal projections, via axonal transport, through synaptic contacts to the spinal cord and other regions of the brain. PMID:24217521

Braak, Heiko; Brettschneider, Johannes; Ludolph, Albert C; Lee, Virginia M; Trojanowski, John Q; Del Tredici, Kelly

2013-12-01

 
 
 
 
301

Distribution and origin of vesicular glutamate transporter 2-immunoreactive fibers in the rat hippocampus.  

Science.gov (United States)

This study examined the distribution of vesicular glutamate transporter 2 (VGLUT2)-immunoreactive neuronal structures in the ipsilateral and contralateral hippocampi of unilateral fimbria/fornix transected, unilateral entorhinal cortex ablated, and intact female and male rats. In the hippocampi of intact animals, the highest density of VGLUT2-positive boutons was observed in the supragranular layer of the dentate gyrus, followed by the CA2 pyramidal and oriens layers, and the stratum lacunosum-moleculare of the CA1 field. This staining pattern was identical both in males and in females. Electron microscopic examination revealed that the immunolabeling was confined to axon terminals forming exclusively asymmetric synaptic contacts. The quantitative analysis of the synaptic targets of VGLUT2-positive terminals showed that in the dentate gyrus, 59% of the synaptic targets were dendritic spines, followed by dendritic shafts (22%) and granule cell somata (19%). In the pyramidal layer of the CA2 field, VGLUT2-immunoreactive boutons contacted mostly dendritic shafts (85%), only some of which (15%) synapsed with spines. The synaptic targets of VGLUT2-positive varicosities were dendritic spines (71%) and shafts (29%) in the stratum lacunosum-moleculare of the CA1 field. The fimbria/fornix transection caused a significant reduction in the density of VGLUT2-positive boutons only in the CA2 field, while entorhinal cortex ablation elicited no change in fiber density in any of the areas analyzed. Furthermore, our latest experiments on colchicine-treated animals revealed a large population of VGLUT2-positive neurons in the hippocampus that may be a possible intrinsic source of hippocampal VGLUT2 boutons. Our results suggest that the most likely sources of VGLUT2-positive boutons in the dentate supragranular layer, the CA2 area, as well as in the stratum lacunosum-moleculare of the CA1 field, might be the mossy cells, the supramammillary area, and the nucleus reuniens thalami, respectively. PMID:15382259

Halasy, Katalin; Hajszan, Tibor; Kovács, Eva G; Lam, Thien-Tri; Leranth, Csaba

2004-01-01

302

The effects of cysteamine on thyrotropin and immunoreactive beta-endorphin secretion in the rat  

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We examined the effects of the thiol agent cysteamine (CSH), which is known to deplete the hypothalamus of immunoreactive somatostatin, on physiological TSH and beta- endorphin secretion in the adult male rat. CSH at doses of 90 and 300 mg/kg CSH produced a rapid decline in plasma TSH, whereas a dose of 30 mg/kg did not alter plasma TSH levels. After the higher doses of CSH, TSH levels in the blood remained lower than control values on day 2, but returned to normal by 1 week. This decrease in TSH within the plasma was not associated with a reduction in hypothalamic TRH concentrations. The TSH response to 500 ng/kg TRH was normal in CSH-treated animals. Blockade of norepinephrine synthesis with diethyldithiocarbamate (500 mg/kg) or fusaric acid (100 mg/kg) inhibited TSH secretion in a manner similar to that of CSH. beta-Endorphin-like immunoreactivity (bet-End-LI) was elevated in the plasma immediately after CSH (300 mg/kg) administration. This was associated with a 58% reduction in anterior pituitary beta-End-LI and no change in hypothalmic beta-End-LI. Plasma beta-End-LI returned to normal on day 2. The increase in plasma beta-End-LI induced by immobilization stress was not compromised by CSH treatment. The observed effects of CSH on both TSH and beta-End-LI are consistent with a reduction in central norepinephrine neurotransmission through the known actin of CSH to inhibit dopamine-beta-hydroxylase. Acute stress may play a role as well in the observed changes in TSH and beta-End-LI secretion.

Millard, W.J.; Sagar, S.M.; Badger, T.M.; Carr, D.B.; Arnold, M.A.; Spindel, E.; Kasting, N.W.; Martin, J.B.

1983-02-01

303

Prevalence of systemic immunoreactivity to Aggregatibacter actinomycetemcomitans leukotoxin in relation to the incidence of myocardial infarction  

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Full Text Available Abstract Background Chronic infections and associated inflammatory markers are suggested risk factors for cardiovascular disease (CVD. The proinflammatory cytokine, interleukin (IL-1?, is suggested to play a role in the regulation of local inflammatory responses in both CVD and periodontitis. The leukotoxin from the periodontal pathogen Aggregatibacter actinomycetemcomitans has recently been shown to cause abundant secretion of IL-1? from macrophages. The aim of the present study was to compare the prevalence of systemic immunoreactivity to A. actinomycetemcomitans leukotoxin in myocardial infarction (MI cases (n = 532 and matched controls (n = 1,000 in a population-based case and referents study in northern Sweden. Methods Capacity to neutralize A. actinomycetemcomitans leukotoxin was analyzed in a bioassay with leukocytes, purified leukotoxin, and plasma. Plasma samples that inhibited lactate-dehydrogenase release from leukotoxin-lysed cells by ?50% were classified as positive. Results Neutralizing capacity against A. actinomycetemcomitans leukotoxin was detected in 53.3% of the plasma samples. The ability to neutralize leukotoxin was correlated to increasing age in men (n = 1,082 but not in women (n = 450. There was no correlation between presence of systemic leukotoxin-neutralization capacity and the incidence of MI, except for women (n = 146. Women with a low neutralizing capacity had a significantly higher incidence of MI than those who had a high neutralizing capacity. Conclusion Systemic immunoreactivity against A. actinomycetemcomitans leukotoxin was found at a high prevalence in the analyzed population of adults from northern Sweden. The results from the present study do not support the hypothesis that systemic leukotoxin-neutralizing capacity can decrease the risk for MI.

Jansson Jan-Hĺkan

2011-03-01

304

Decreased nucleotide excision repair in steatotic livers associates with myeloperoxidase-immunoreactivity  

International Nuclear Information System (INIS)

Chronic inflammation is characterized by the influx of neutrophils and is associated with an increased production of reactive oxygen species that can damage DNA. Oxidative DNA damage is generally thought to be involved in the increased risk of cancer in inflamed tissues. We previously demonstrated that activated neutrophil mediated oxidative stress results in a reduction in nucleotide excision repair (NER) capacity, which could further enhance mutagenesis. Inflammation and oxidative stress are critical factors in the progression of nonalcoholic fatty liver disease that is linked with enhanced liver cancer risk. In this report, we therefore evaluated the role of neutrophils and the associated oxidative stress in damage recognition and DNA repair in steatotic livers of 35 severely obese subjects with either nonalcoholic steatohepatitis (NASH) (n = 17) or steatosis alone (n = 18). The neutrophilic influx in liver was assessed by myeloperoxidase (MPO) staining and the amount of oxidative DNA damage by measuring M1dG adducts. No differences in M1dG adduct levels were observed between patients with or without NASH and also not between individuals with high or low MPO immunoreactivity. However, we found that high expression of MPO in the liver, irrespective of disease status, reduced the damage recognition capacity as determined by staining for histone 2AX phosphorylation (?H2AX). This reduction in ?H2AX formation in individuals with high MPO immunoreon in individuals with high MPO immunoreactivity was paralleled by a significant decrease in NER capacity as assessed by a functional repair assay, and was not related to cell proliferation. Thus, the observed reduction in NER capacity upon hepatic inflammation is associated with and may be a consequence of reduced damage recognition. These findings suggest a novel mechanism of liver cancer development in patients with nonalcoholic fatty liver disease.

305

Decreased nucleotide excision repair in steatotic livers associates with myeloperoxidase-immunoreactivity  

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Chronic inflammation is characterized by the influx of neutrophils and is associated with an increased production of reactive oxygen species that can damage DNA. Oxidative DNA damage is generally thought to be involved in the increased risk of cancer in inflamed tissues. We previously demonstrated that activated neutrophil mediated oxidative stress results in a reduction in nucleotide excision repair (NER) capacity, which could further enhance mutagenesis. Inflammation and oxidative stress are critical factors in the progression of nonalcoholic fatty liver disease that is linked with enhanced liver cancer risk. In this report, we therefore evaluated the role of neutrophils and the associated oxidative stress in damage recognition and DNA repair in steatotic livers of 35 severely obese subjects with either nonalcoholic steatohepatitis (NASH) (n = 17) or steatosis alone (n = 18). The neutrophilic influx in liver was assessed by myeloperoxidase (MPO) staining and the amount of oxidative DNA damage by measuring M{sub 1}dG adducts. No differences in M{sub 1}dG adduct levels were observed between patients with or without NASH and also not between individuals with high or low MPO immunoreactivity. However, we found that high expression of MPO in the liver, irrespective of disease status, reduced the damage recognition capacity as determined by staining for histone 2AX phosphorylation ({gamma}H2AX). This reduction in {gamma}H2AX formation in individuals with high MPO immunoreactivity was paralleled by a significant decrease in NER capacity as assessed by a functional repair assay, and was not related to cell proliferation. Thus, the observed reduction in NER capacity upon hepatic inflammation is associated with and may be a consequence of reduced damage recognition. These findings suggest a novel mechanism of liver cancer development in patients with nonalcoholic fatty liver disease.

Schults, Marten A.; Nagle, Peter W. [Department of Toxicology, NUTRIM-School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, PO Box 616, 6200 MD Maastricht (Netherlands); Rensen, Sander S. [Department of Surgery, NUTRIM-School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, PO Box 616, 6200 MD Maastricht (Netherlands); Godschalk, Roger W. [Department of Toxicology, NUTRIM-School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, PO Box 616, 6200 MD Maastricht (Netherlands); Munnia, Armelle; Peluso, Marco [Cancer Risk Factor Branch, ISPO Cancer Prevention and Research Institute, Via Cosimo il Vecchio 2, 50139 Florence (Italy); Claessen, Sandra M. [Department of Toxicogenomics, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, PO Box 616, 6200 MD Maastricht (Netherlands); Greve, Jan W. [Department of Surgery, NUTRIM-School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, PO Box 616, 6200 MD Maastricht (Netherlands); Driessen, Ann [Department of Pathology, NUTRIM-School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, PO Box 616, 6200 MD Maastricht (Netherlands); Verdam, Froukje J.; Buurman, Wim A. [Department of Surgery, NUTRIM-School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, PO Box 616, 6200 MD Maastricht (Netherlands); Schooten, Frederik J. van [Department of Toxicology, NUTRIM-School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, PO Box 616, 6200 MD Maastricht (Netherlands); Chiu, Roland K., E-mail: r.k.chiu@med.umcg.nl [Department of Toxicology, NUTRIM-School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, PO Box 616, 6200 MD Maastricht (Netherlands)

2012-08-01

306

Serum immunoreactive and bioactive lactogenic hormones in advanced breast cancer patients treated with bromocriptine and octreotide.  

Science.gov (United States)

6 patients with advanced breast cancer who had failed first and second line endocrine therapies received bromocriptine (1.25-2.5 mg twice daily per os) and octreotide (Sandostatin) via a continuous subcutaneous infusion (200-400 micrograms/24 h) until disease progression. Pre-treatment 24-h profiles of serum lactogenic hormones and their response to standard provocative tests were established and repeated at 2 weeks, and 3 and 6 months (or at tumour progression). Immunoreactive prolactin (ir-PRL), growth hormone (ir-GH) and insulin-like growth factor I (IGF-I) were measured by radioimmunoassay and bioactive lactogenic hormone levels (BLH) were estimated using the Nb2 rat lymphoma cell bioassay. Before treatment all patients showed episodic secretion of ir-PRL, ir-GH and BLH and provocative stimuli resulted in a peak of ir-GH and BLH maximal between 60 and 90 min after injection but no change in ir-PRL. After 2 weeks of treatment, ir-PRL levels were reduced to below the limit of detection in all 6 patients. Peaks of ir-GH and BLH were still apparent, although much reduced. Immunoreactive PRL continued to be profoundly suppressed in 3 of the 4 patients who remained on treatment for 3 to 6 months. Small pulses of ir-GH were still detectable in these patients with which BLH was, again, well correlated. After 2 weeks of treatment, serum IGF-I levels were reduced by 9-54% of the pretreatment values and generally remained suppressed throughout treatment. Clinically, 4 patients did not show disease progression for periods of up to 6 months and side-effects were minimal. PMID:8422285

Anderson, E; Ferguson, J E; Morten, H; Shalet, S M; Robinson, E L; Howell, A

1993-01-01

307

Microalbuminuria, indicated by total versus immunoreactive urinary albumins, in acute ischemic stroke patients.  

Science.gov (United States)

Microalbuminuria, assessed by measuring immunoreactive albumin, is common in patients with cerebrovascular disease and is associated with increased risk of stroke. Total urinary albumin (t-uAlb) comprises both immunoreactive albumin (ir-uAlb) and nonimmunoreactive albumin (nir-uAlb). We hypothesized that t-uAlb is a more sensitive indicator of microalbuminuria than ir-uAlb, and that measurement of t-uAlb will increase the prevalence of microalbuminuria in ischemic stroke patients compared with measurement of ir-uAlb and will show a stronger correlation with the severity of stroke and oxidative stress. In urine samples from 98 patients with ischemic stroke, the albumin-to-creatinine ratios t-uAlb/uCreat and ir-uAlb/uCreat were measured by high-performance liquid chromatography (HPLC) and immunoturbidimetry (IT), and the nir-uAlb/uCreat ratio was calculated. Urinary ortho-tyrosine (o-Tyr/uCreat), an indicator of oxidative stress, was measured by HPLC. The severity of stroke was scored based on the National Institutes of Health Stroke Scale (NIHSS). The prevalence of microalbuminuria detected by HPLC was significantly higher than that detetcted by IT (66.3 vs 36.7%). Although all forms of albumin showed significant correlation with stroke severity (t-uAlb: r = 0.24, P stroke severity (B = 0.20, ? = 0.35, P .05). Our data suggest that in acute ischemic stroke patients, t-uAlb is a more sensitive indicator of microalbuminuria than the presently used ir-uAlb. Future studies should aim to elucidate the underlying mechanisms for the relationship among urinary albumins and cerebrovascular diseases and the role of urinary albumins in risk stratification for stroke. PMID:20813547

Toth, Peter; Koller, Akos; Pusch, Gabriella; Bosnyak, Edit; Szapary, Laszlo; Komoly, Samuel; Marko, Lajos; Nagy, Judit; Wittmann, Istvan

2011-11-01

308

Effects of Dielectrophoresis on Growth, Viability and Immuno-reactivity of Listeria monocytogenes  

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Full Text Available Abstract Dielectrophoresis (DEP has been regarded as a useful tool for manipulating biological cells prior to the detection of cells. Since DEP uses high AC electrical fields, it is important to examine whether these electrical fields in any way damage cells or affect their characteristics in subsequent analytical procedures. In this study, we investigated the effects of DEP manipulation on the characteristics of Listeria monocytogenes cells, including the immuno-reactivity to several Listeria-specific antibodies, the cell growth profile in liquid medium, and the cell viability on selective agar plates. It was found that a 1-h DEP treatment increased the cell immuno-reactivity to the commercial Listeria species-specific polyclonal antibodies (from KPL by ~31.8% and to the C11E9 monoclonal antibodies by ~82.9%, whereas no significant changes were observed with either anti-InlB or anti-ActA antibodies. A 1-h DEP treatment did not cause any change in the growth profile of Listeria in the low conductive growth medium (LCGM; however, prolonged treatments (4 h or greater caused significant delays in cell growth. The results of plating methods showed that a 4-h DEP treatment (5 MHz, 20 Vpp reduced the viable cell numbers by 56.8–89.7 %. These results indicated that DEP manipulation may or may not affect the final detection signal in immuno-based detection depending on the type of antigen-antibody reaction involved. However, prolonged DEP treatment for manipulating bacterial cells could produce negative effects on the cell detection by growth-based methods. Careful selection of DEP operation conditions could avoid or minimize negative effects on subsequent cell detection performance.

Bhunia Arun K

2008-04-01

309

Sodium channel Nav1.7 immunoreactivity in painful human dental pulp and burning mouth syndrome  

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Full Text Available Abstract Background Voltage gated sodium channels Nav1.7 are involved in nociceptor nerve action potentials and are known to affect pain sensitivity in clinical genetic disorders. Aims and Objectives To study Nav1.7 levels in dental pulpitis pain, an inflammatory condition, and burning mouth syndrome (BMS, considered a neuropathic orofacial pain disorder. Methods Two groups of patients were recruited for this study. One group consisted of patients with dental pulpitis pain (n = 5 and controls (n = 12, and the other patients with BMS (n = 7 and controls (n = 10. BMS patients were diagnosed according to the International Association for the Study of Pain criteria; a pain history was collected, including the visual analogue scale (VAS. Immunohistochemistry with visual intensity and computer image analysis were used to evaluate levels of Nav1.7 in dental pulp tissue samples from the dental pulpitis group, and tongue biopsies from the BMS group. Results There was a significantly increased visual intensity score for Nav1.7 in nerve fibres in the painful dental pulp specimens, compared to controls. Image analysis showed a trend for an increase of the Nav1.7 immunoreactive % area in the painful pulp group, but this was not statistically significant. When expressed as a ratio of the neurofilament % area, there was a strong trend for an increase of Nav1.7 in the painful pulp group. Nav1.7 immunoreactive fibres were seen in abundance in the sub-mucosal layer of tongue biopsies, with no significant difference between BMS and controls. Conclusion Nav1.7 sodium channel may play a significant role in inflammatory dental pain. Clinical trials with selective Nav1.7 channel blockers should prioritise dental pulp pain rather than BMS.

Yiangou Yiangos

2010-06-01

310

Production of the recombinant single chain anti-B cell lymphoma antibody and evaluation of immunoreactivity  

International Nuclear Information System (INIS)

Recombinant ScFv lym-1 was produced, using pET vector system for large scale production. ScFv lym-1 gene inserted pET-22b (+) vector, was expressed in E. coli BL-21 strain. ScFv lym-1 antibody extracted from periplasm, was purified with His-Taq column. To evaluated immunoreactivity with Raji cell, ScFv lym-1 was labeled with I-125 and I-125 ScFv lym-1 was purified with desalting column. Raji cell was injected into the C57BR/cdJ SCID mice. Gamma camera imaging were taken time point at 1, 8, 24 and 48 hr with 8 mm pinhole collimator. An active scFv lym-1 could be produced in E. coli with soluble from using pET vector system. Immunoreactivity and affinity constant of lgG lym-1 were 54% and 1.83 x 109 M-1, respectively, and those of scFv lym-1 were 53.7% and 1.46 x 109 M-1, respectively. Biodistribution of I-125 scFv lym-1 antibody showed faster clearance in blood, spleen, kidney and than I-125 lgG lym-1 antibody. Gamma camera image of I-125 scFv lym-1 antibody showed faster clearance and tumor targeting liver than I-125 lgG lym-1 antibody. In vitro properties of scFv lym-1 were similar to those of lgG lym-1. ScFv lym-1 showed faster blood clearance than lgG lym-1. These results suggest that scFv lym-1 antibody can be useful for tumor imaging agent

311

Production of the recombinant single chain anti-B cell lymphoma antibody and evaluation of immunoreactivity  

Energy Technology Data Exchange (ETDEWEB)

Recombinant ScFv lym-1 was produced, using pET vector system for large scale production. ScFv lym-1 gene inserted pET-22b (+) vector, was expressed in E. coli BL-21 strain. ScFv lym-1 antibody extracted from periplasm, was purified with His-Taq column. To evaluated immunoreactivity with Raji cell, ScFv lym-1 was labeled with I-125 and I-125 ScFv lym-1 was purified with desalting column. Raji cell was injected into the C57BR/cdJ SCID mice. Gamma camera imaging were taken time point at 1, 8, 24 and 48 hr with 8 mm pinhole collimator. An active scFv lym-1 could be produced in E. coli with soluble from using pET vector system. Immunoreactivity and affinity constant of lgG lym-1 were 54% and 1.83 x 10{sup 9} M{sup -1}, respectively, and those of scFv lym-1 were 53.7% and 1.46 x 10{sup 9} M{sup -1}, respectively. Biodistribution of I-125 scFv lym-1 antibody showed faster clearance in blood, spleen, kidney and than I-125 lgG lym-1 antibody. Gamma camera image of I-125 scFv lym-1 antibody showed faster clearance and tumor targeting liver than I-125 lgG lym-1 antibody. In vitro properties of scFv lym-1 were similar to those of lgG lym-1. ScFv lym-1 showed faster blood clearance than lgG lym-1. These results suggest that scFv lym-1 antibody can be useful for tumor imaging agent.

Jung, Jae Ho; Choi, Tae Hyun; Woo, Kang Sun; Chung, Wee Sup; Kim, Soo Gwan; Cheon, Gi Jeong; Choi, Chang Woon; Lim, Sang Moo [Korea Institute of Radiological and Medical Science, Seoul (Korea, Republic of)

2006-08-15

312

Genetics Home Reference: X-linked lissencephaly with abnormal genitalia  

Science.gov (United States)

... literature OMIM Genetic disorder catalog Conditions > X-linked lissencephaly with abnormal genitalia On this page: Description Genetic ... definitions Reviewed August 2013 What is X-linked lissencephaly with abnormal genitalia? X-linked lissencephaly with abnormal ...

313

Sperm acrosome antigen-1. Specific tissue distribution of immunoreactivity in a teleost fish, the swordtail ( Xiphophorus helleri).  

Science.gov (United States)

The acrosome reaction is a fundamental requirement for mammalian fertilization. Its exact molecular mechanisms and cellular elements are still poorly understood. We have detected an acrosomal sperm antigen, SAA-1, by monoclonal antibodies directed against SAA-1, that appears to be critically involved in the regulation of the acrosome reaction. SAA-1 is conserved within a broad range of mammalian species, emphasizing its important role in mammalian reproduction. Here we demonstrate that SAA-1 is immunohistochemically detectable in a nonmammalian vertebrate whose sperm do not possess an acrosome. In the swordtail, a live-bearing teleost with special reproductive tactics, we were able to demonstrate immunoreactivity of sperm heads of spermatids and mature sperm in the testis using monoclonal antibodies against SAA-1. Due to the cystic spermatogenesis with synchronous sperm maturation, immunoreactive maturational stages could be clearly identified. Stored immunoreactive sperm were also identified in spermathecal tissue of the female genital tract. Interestingly, immunoreactivity was furthermore detected in defined cells of the compounded endocrine organs pituitary and endocrine pancreas. All these different cell systems are involved in paracrine regulation and exhibit exocytotic properties. The possible nature of SAA-1 is discussed. Additionally, some new aspects of the morphologic composition of the swordtail pituitary are described. PMID:12037583

Breuckmann, A; Brucker, C

2002-05-01

314

Vasoactive intestinal peptide-immunoreactive cerebrospinal fluid-contacting neurons in the reptilian lateral septum/nucleus accumbens.  

Science.gov (United States)

By means of immunocytochemical demonstration of vasoactive intestinal peptide (VIP) an accumulation of cerebrospinal fluid (CSF)-contacting neurons was found in a circumscribed region of the nucleus accumbens/lateral septum of eleven reptilian (chelonian, lacertilian, ophidian, crocodilian) species. Basal processes of these cells contribute to a subependymal plexus whose density displays considerable interspecific variation. VIP-immunoreactive nerve fibers occur also in the lateral septum and the nucleus accumbens where they encompass immunonegative cells in a basket-like pattern. The CSF-contacting neurons are surrounded by columnar ependymocytes frequently arranged in a pseudostratified manner. These specialized arrays of ependymal cells, however, occupy a more extended area than the VIP-immunoreactive CSF-contacting neurons and can be traced from the rostro-ventral pole of the lateral ventricle to the interventricular foramen. These observations suggest the existence of a telencephalic site of CSF-contacting neurons which may be more widespread than hitherto thought and which may participate in a circumventricular system of the lateral ventricle. Previous studies mainly performed with birds indicate that the VIP-immunoreactive CSF-contacting neurons of the nucleus accumbens might form a part of the "encephalic" (extraretinal and extrapineal) photoreceptor. However, further experiments are required to test this supposition since the VIP-immunoreactive neurons of the nucleus accumbens remained unlabeled by antibodies against bovine rodopsin and chicken cone-opsin in all eleven species analysed in this investigation. PMID:8242714

Hirunagi, K; Rommel, E; Oksche, A; Korf, H W

1993-10-01

315

Substance P immunoreactivity in the lumbar spinal cord of the turtle Trachemys dorbigni following peripheral nerve injury  

Scientific Electronic Library Online (English)

Full Text Available SciELO Brazil | Language: English Abstract in english Immunoreactive substance P was investigated in turtle lumbar spinal cord after sciatic nerve transection. In control animals immunoreactive fibers were densest in synaptic field Ia, where the longest axons invaded synaptic field III. Positive neuronal bodies were identified in the lateral column of [...] the dorsal horn and substance P immunoreactive varicosities were observed in the ventral horn, in close relationship with presumed motoneurons. Other varicosities appeared in the lateral and anterior funiculi. After axotomy, substance P immunoreactive fibers were reduced slightly on the side of the lesion, which was located in long fibers that invaded synaptic field III and in the varicosities of the lateral and anterior funiculus. The changes were observed at 7 days after axonal injury and persisted at 15, 30, 60 and 90 days after the lesion. These findings show that turtles should be considered as a model to study the role of substance P in peripheral axonal injury, since the distribution and temporal changes of substance P were similar to those found in mammals.

W.A., Partata; A.M.R., Krepsky; L.L., Xavier; M., Marques; M., Achaval.

2003-04-01

316

Carbamazepine for acute psychosis with eeg abnormalities  

Directory of Open Access Journals (Sweden)

Full Text Available Aim. To investigate the efficacy of carbamazepine as adjuvant drug therapy in acute paranoid psychosis with associated EEG abnormalities, compared to sole antipsychotic treatment. Methods. Eleven medication-naive patients diagnosed with acute paranoid psychosis with associated EEG abnormalities were divided into two treatment groups: sole fluphenazine group, with flexible dosing of 5-10 mg/day (n=6, and carbamazepine group (n=5 with the addition of carbamazepine (600 mg/day to fluphenazine treatment. Clinical Global Impression (CGI, Brief Psychiatric Rating Scale (BPRS, Scale for the Assessment of Negative Symptoms (SANS, and EEG were assessed on the baseline and after 6 weeks of treatment. Paired and two-tailed t-tests were used for statistical significance. Results. All the patients showed significant improvement of mental state after 6 weeks of treatment with no significant differences in CGI, BPRS, and total SANS scores in relation to the therapy with carbamazepine. Nevertheless, after 6 weeks of the treatment, EEG findings were significantly better in carbamazepine group, in relation to the findings from the onset of the treatment, as well as in comparison to sole fluphenazine group. Conclusion. Although carbamazepine stabilized abnormal brain electrical activities it seemed that the associated EEG abnormalities were not significant for acute psychosis observed. These preliminary results suggested that there was no convincing evidence that carbamazepine was efficient as the augmentation of antipsychotic treatment for patients with both acute paranoid psychosis and EEG abnormalities.

Ivkovi? Maja

2004-01-01

317

[Abnormalities of the penis in boys].  

Science.gov (United States)

Abnormalities of the male genitalia have increased in the last 2 decades in numerous developed countries and remain a frequent reason of consultation in pediatric surgery. The diagnostic spectrum is wide, and surgeons should pay particular attention to these abnormalities because of their potential psychological effect. Anatomically, these abnormalities can affect one of three parts of the penis. First, the foreskin may not be fully retracted. This is normal at birth and can be caused by prepuce adherents that can continue until adolescence. Today, true phimosis is treated with topical corticoids from the age of 3 years. If medical treatment fails, a surgical procedure is required. Second, the urethra can be affected by hypospadia, which is the most frequent abnormality of the urethra. It is associated with ectopic urethral meatus, hypoplastic foreskin, and penis curvature. Its pathogenic background is not clearly understood. Surgery options differ according to the type of hypospadia and according to the surgeon's experience. It is sometimes hard to deal with, especially in a perineal form, where genetic and hormonal studies are recommended. These interventions can lead to complications ranging from stenosis to fistula. Therefore, parents have to be informed of the benefits and risks of the surgical procedures. Epispadias is rare but more serious because of the increasing risk of urinary incontinence. Finally, abnormalities of the corpora cavernosa - often associated with hypospadias - can include penis curvature and micropenis, for which an endocrinological analysis is essential. PMID:23121902

Peycelon, M; Parmentier, B; Raquillet, C; Boubnova, J; Chouikh, T; Grosos, C; Honart, J-F; Pichon, A; Auber, F; Larroquet, M; Audry, G

2012-12-01

318

Advances in understanding paternally transmitted Chromosomal Abnormalities  

Energy Technology Data Exchange (ETDEWEB)

Multicolor FISH has been adapted for detecting the major types of chromosomal abnormalities in human sperm including aneuploidies for clinically-relevant chromosomes, chromosomal aberrations including breaks and rearrangements, and other numerical abnormalities. The various sperm FISH assays have been used to evaluate healthy men, men of advanced age, and men who have received mutagenic cancer therapy. The mouse has also been used as a model to investigate the mechanism of paternally transmitted genetic damage. Sperm FISH for the mouse has been used to detect chromosomally abnormal mouse sperm, while the PAINT/DAPI analysis of mouse zygotes has been used to evaluate the types of chromosomal defects that can be paternally transmitted to the embryo and their effects on embryonic development.

Marchetti, F; Sloter, E; Wyrobek, A J

2001-03-01

319

Abnormal head position in infantile nystagmus syndrome.  

Science.gov (United States)

Infantile nystagmus is an involuntary, bilateral, conjugate, and rhythmic oscillation of the eyes which is present at birth or develops within the first 6 months of life. It may be pendular or jerk-like and, its intensity usually increases in lateral gaze, decreasing with convergence. Up to 64% of all patients with nystagmus also present strabismus, and even more patients have an abnormal head position. The abnormal head positions are more often horizontal, but they may also be vertical or take the form of a tilt, even though the nystagmus itself is horizontal. The aim of this article is to review available information about the origin and treatment of the abnormal head position associated to nystagmus, and to describe our treatment strategies. PMID:24533187

Noval, Susana; González-Manrique, Mar; Rodríguez-Del Valle, José María; Rodríguez-Sánchez, José María

2011-01-01

320

Report on Congress on abnormal occurrences  

International Nuclear Information System (INIS)

Section 208 of the energy Reorganization Act of 1974 identifies an abnormal occurrence as an unscheduled incident or event that the Nuclear Regulatory Commission determines to be significant from the standpoint of public health or safety and requires a quarterly report of such events to be made to Congress. This report covers the period from January 1 through March 31, 1991. The report discusses six abnormal occurrences, none of which involved a nuclear power plant. Five of the events occurred at NRC-licensed facilities: one involved a significant degradation of plant safety at a nuclear fuel cycle facility, one involved a medical diagnostic misadministration, and three involved medical therapy misadministrations. An Agreement State (Arizona) reported one abnormal occurrence that involved medical therapy misadministrations

 
 
 
 
321

Chromosomal Abnormalities in Primary Myelodysplastic Syndrome  

International Nuclear Information System (INIS)

Objective: To determine the frequency of cytogenetic abnormalities in patients diagnosed as primary myelodysplastic syndrome (MDS) using conventional karyotyping. Study Design: Case series. Place and Duration of Study: The Clinical Laboratory, The Aga Khan University Hospital, Karachi, between January 2006 - June 2012. Methodology: Patients of all ages and either gender who fulfilled WHO criteria for MDS were included. Cytogenetic analysis was conducted at the time of diagnosis. Patients who had secondary MDS were excluded from analysis. Chromosome identification and karyotype description was done according to the International System for Chromosome Nomenclature (ISCN, 1995) and described as frequency percentage. Results: Out of the 122 cases of MDS, 71 patients had their karyotype done at the time of diagnosis, including 42 males (59.2%) and 29 females (40.8%) with median age of 60 years. Forty one (57.7%) showed normal karyotype and 30 (42.3%) showed clonal karyotypic abnormalities at diagnosis. Out of which 14 (19.7%) had single, 11 (15.5%) had complex and 6 (8.5%) had double cytogenetic abnormalities. The common abnormalities found were: trisomy 8 in 7 cases (9.9%), -7/del (7q) in 3 cases (4.2%), -Y and complex 5q in 2 cases (2.8%) each, complex trisomy 8, del 11q , inversion 9, trisomy 19 and del 20q were found in 1 case (1.4%) each. Other abnormalities were found in 11 cases (15.5%). Conclusion: Trisomy 8 was the most common disorder/abnormality found in this study population followed by the complex cytogenetics. (author)

322

Electrocardiographic abnormalities in patients with subarachnoid hemorrhage.  

Science.gov (United States)

Subarachnoid hemorrhage is a serious neurological disorder that is often complicated by the occurrence of electrocardiographic abnormalities unexplained by preexisting cardiac conditions. These morphological waveform changes and arrhythmias often are unrecognized or misinterpreted, potentially placing patients at risk for inappropriate management. Many previous investigations were retrospective and relied on data collected in an unsystematic manner. More recent studies that included use of serial electrocardiograms and Holter recordings have provided new insight into the high prevalence of electrocardiographic changes in subarachnoid hemorrhage. Research on the prevalence, duration, and clinical significance of these electrocardiographic abnormalities and on associated factors and etiological theories is reviewed. PMID:11785557

Sommargren, Claire E

2002-01-01

323

Occult intraspinal abnormalities and congenital scoliosis  

Directory of Open Access Journals (Sweden)

Full Text Available

BACKGROUND: Congenital scoliosis occurs because of either the failure of formation or the failure of segmentation or both. Evaluation of the incidence and the types of occult intraspinal abnormalities in congenital scoliosis is the subject of this study.

METHODS: During a period of 29 years, 103 patients with congenital scoliosis were studied. MRI was used in 46 patients, myelography or CT myelography was used in 64 patients and both MRI and myelography or CT myelography were used in 7 patients for intraspinal abnormalities.

RESULTS: In the MRI group, among the 46 patients, 19 patients (41.3% had intraspinal abnormalities consisting syringomyelia in 9 (19.5% diastematomyelia in 8 (17.4%, tethered cord syndrome in 6 (13%, low conus in 5 (10.8% and diplomyelia in 3 (6.5% of the patients. In the myelography group, among the 64 patients, 17 (26.5% had intraspinal abnormalities and diastematomyelia was the most common one found in 14 (21.8% patients.

CONCLUSIONS: Intraspinal abnormalities are frequent in congenital scoliosis. Syringomyelia may be associated with congenital scoliosis. In congenital scoliosis, rib fusion may be an indicator of intraspinal abnormalities in MRI. A significant difference between clinical findings and intraspinal anomalies (P<0.05 was noted. Moreover, we believe that total spinal MRI with coronal, sagittal and axial views is a valuable tool in determining the intraspinal abnormalities in congenital scoliosis. This method is highly recommended for detection and neurosurgical intervention before corrective surgeries.

KEY WORDS: Congenital scoliosis, intraspinal abnormalities, diastematomyelia.

Mohammad Ali Erfani

2007-06-01

324

Hemorheological abnormalities in human arterial hypertension  

Science.gov (United States)

Blood rheology is impaired in hypertensive patients. The alteration involves blood and plasma viscosity, and the erythrocyte behaviour is often abnormal. The hemorheological pattern appears to be related to some pathophysiological mechanisms of hypertension and to organ damage, in particular left ventricular hypertrophy and myocardial ischemia. Abnormalities have been observed in erythrocyte membrane fluidity, explored by fluorescence spectroscopy and electron spin resonance. This may be relevant for red cell flow in microvessels and oxygen delivery to tissues. Although blood viscosity is not a direct target of antihypertensive therapy, the rheological properties of blood play a role in the pathophysiology of arterial hypertension and its vascular complications.

Lo Presti, Rosalia; Hopps, Eugenia; Caimi, Gregorio

2014-05-01

325

Evaluation of craniovertebral junction abnormalities by MRI  

International Nuclear Information System (INIS)

Magnetic resonance imaging (MRI) was performed in 45 cases of craniovertebral junction (CVJ) abnormalities ; pathologic conditions including 29 cases of Chiari I malformation, 22 syringomyelia and 24 bony anomaly were studied. Whereas Chiari I malformation was highly associated with syringomyelia and CVJ bony anomaly, there seemed little direct relationship between syringomyelia and CVJ bony anomaly. In syringomyelia, the enlarged cord was seen in younger age disribution than that of normal and small cord. Basal angles of CVJ abnormalities measured on MRI were greater than that of 56 normal results. (author)

326

Automated recognition and counting of the immunoreactive neuroendocrine cells in chronic gastritis (the preliminary study.  

Directory of Open Access Journals (Sweden)

Full Text Available The paper presents the designed software CAMI (Computerized Analysis of Microscopic Images for a digital reconstruction of the diversiform glands seen in chronic inflammatory gastric mucosa, and for automated recognition and quantization of the immunoreactive neuroendocrine (NE cells appearing within mucosal glands. Digital reconstruction of the individual gastric gland is difficult due to variable shapes of the glandular cross-sections. Fifteen gastric biopsy specimens representing chronic gastritis were stained routinely with H+E and immunohistochemically with 3 NE markers: Chromogranin A, Somatostatin and Serotonin. Two expert pathologists counted manually the NE cells with the light microscope in 4 types of glandular cross-sections: round, short- oblique, long- oblique and longitudinal. The automated counting of the NE cells was performed on the digital images presenting the same microscopic areas which were selected for the manual reading. The first step of image analysis was concerned to the cell extraction and recognition of the cytoplasmic immunoreactivity. The unstained nuclei of the NE cells were spotted by the sequential thresholding algorithm combined with the artificial neural network of SupportVector Machine (SVM type. The second step of image analysis comprised reconstruction of the glands. The presumed shape of each gastric gland was defined by the cellular lining of viewed glandular cross-section. The designed algorithm for gland reconstruction was based on the cell masks. The third step of analysis dealt the cell counting. Every recognized gland with the face cells was used for the NE cell evaluation. The results of the automated quantization compared with manual counting results for the number of NE cells showed high concordance in 3 types of glandular cross-sections: round, short- and long- oblique. A difference noticed in the results of the longitudinal glands should be verified in the extended study. The designed software CAMI is more adequate for the gland recognition with an discontinuous gland face seen in the immunohistochemical digital images, which appear to be a difficult problem for the accurate automated analysis of the cellular component of glands.

Cezary Jochymski

2010-05-01

327

Cellular and subcellular localization of syntaxin-like immunoreactivity in the rat striatum and cortex.  

Science.gov (United States)

Syntaxin is a synapse-specific protein previously localized to the plasma membrane of axon terminals. Biochemical and molecular biological studies indicate a prominent role for syntaxin 1A and 1B in synaptic vesicle docking and/or fusion, suggesting that these proteins are localized to active zone regions of most terminal varicosities in the central nervous system. We sought to test this hypothesis by examining the cellular and subcellular immunocytochemical localization of syntaxin 1 proteins in the striatum and frontal cortex of rats. Using either a polyclonal anti-syntaxin antibody, or a monoclonal antibody directed against the identical protein, HPC-1, immunoperoxidase reaction product was localized to preterminal axons and terminal varicosities that made almost exclusively Type I (asymmetric) synapses on dendritic spines or distal shafts. Immunoreactive terminals forming Type II (symmetric) synapses were observed rarely and only in tissue that was pretreated by rapid freeze-thaw to enhance antibody penetration. From a semi-quantitative analysis, it was estimated that at least 48-62% of all vesicle-filled varicosities and 67-69% of all terminals forming Type I synapses were immunoreactive for syntaxin or HPC-1, respectively. Using a pre-embedding immunogold-silver technique to provide a non-diffusible marker for subcellular localization, gold-silver particles for syntaxin or HPC-1 were localized to the cytoplasmic surface of non-synaptic portions of the plasma membrane of preterminal axons and terminal varicosities. Enrichment of presynaptic active zone regions was not observed with immunogold-silver staining. These findings suggest that syntaxin is primarily contained in a subpopulation of terminals that are associated with excitatory amino acid transmitters, but appears not to be ubiquitously expressed in all terminal classes. The results further indicate that syntaxin is localized to non-synaptic regions of axon and terminal membranes, but may not be enriched in presynaptic active zones. The apparent inconsistency between the subcellular localization of syntaxin and its proposed role in vesicle exocytosis is discussed in terms of possible technical limitations and alternative functions for syntaxin. PMID:7675219

Sesack, S R; Snyder, C L

1995-08-01

328

VIP- and PHI-immunoreactivity in olfactory centers of the adult cat.  

Science.gov (United States)

The purpose of the study was to determine the morphology and distribution of vasoactive intestinal polypeptide- and peptide histidine isoleucine-immunoreactive (VIP- and PHI-ir) neurons and innervation patterns in the main and accessory olfactory bulb, anterior olfactory nucleus, and piriform cortex of the adult cat. In these centers, VIP- and PHI-immunoreactive material are present in the same neuronal types, respectively, therefore summarized as VIP/PHI-ir neurons. In the main olfactory bulb, the majority of VIP/PHI-ir neurons are localized in the external plexiform layer. These neurons give rise to two or more locally branching axons. They form boutons on mitral and external tufted cell bodies. According to the morphology and location, we have classified these neurons as Van Gehuchten cells. Some VIP/PHI-ir neurons are present in the glomerular layer. They have small somata and give rise to dendrites branching exclusively into glomeruli. We have classified these neurons as periglomerular cells. In the granule cell layer, neurons with long apical dendrites and one locally projecting axon are present. In the accessory olfactory bulb, VIP/PHI-ir neurons are localized in the mixed external/mitral/internal plexiform layer. They represent Van Gehuchten cells. In the anterior olfactory nucleus and piriform cortex, VIP/PHI-ir bipolar basket neurons are present. They are localized mainly in layers II/III. These neurons are characterized by a bipolar dendritic pattern and by locally projecting axons forming basket terminals on large immunonegative cell somata. Because of their common morphological features, we summarize them as the retrobulbar VIP/PHI-ir interneuron population. The PHI-ir neurons display the same morphology as the VIP-ir cells. However, they are significantly lower in number with a ratio of VIP-ir to PHI-ir cells about 2:1 in the main and accessory olfactory bulb and in the anterior olfactory nucleus. By contrast, in the piriform cortex the ratio is about 1:1. PMID:2341612

Sanides-Kohlrausch, C; Wahle, P

1990-04-15

329

Abnormal spindle behaviour in induced autotetraploid, Physalis pubescens L.  

Science.gov (United States)

In the colchicine induced autotetraploid Physalis pubescens L., meiotic spindle abnormality was observed in one plant. It is probable that the colchicine treatment may have disturbed the spindle organiser, thereby causing abnormal spindle behaviour. The genetic basis for this abnormality (multipolar spindle) could not be established on account of lack of seed set in the plant showing the abnormal spindle behavior. PMID:24270759

Lydia, G; Raja Rao, K G

1982-06-01

330

Gastric emptying abnormal in duodenal ulcer  

International Nuclear Information System (INIS)

To investigate the possibility that an abnormality of gastric emptying exists in duodenal ulcer and to determine if such an abnormality persists after ulcer healing, scintigraphic gastric emptying measurements were undertaken in 16 duodenal ulcer patients before, during, and after therapy with cimetidine; in 12 patients with pernicious anemia, and in 12 control subjects. No difference was detected in the rate or pattern of gastric emptying in duodenal ulcer patients before and after ulcer healing with cimetidine compared with controls, but emptying of the solid component of the test meal was more rapid during treatment with the drug. Comparison of emptying patterns obtained in duodenal ulcer subjects during and after cimetidine treatment with those obtained in pernicious anemia patients and controls revealed a similar relationship that was characterized by a tendency for reduction in the normal differentiation between the emptying of solid and liquid from the stomach. The similarity in emptying patterns in these groups of subjects suggests that gastric emptying of solids may be influenced by changes in the volume of gastric secretion. The failure to detect an abnormality of gastric emptying in duodenal ulcer subjects before and after ulcer healing calls into question the widespread belief that abnormally rapid gastric emptying is a feature with pathogenetic significance in duodenal ulcer disease

331

Abnormal Events for Emergency Trip in HANARO  

Energy Technology Data Exchange (ETDEWEB)

This report gathers abnormal events related to emergency trip of HANARO that happened during its operation over 10 years since the first criticality on February 1995. The collected examples will be utilized to the HANARO's operators as a useful guide.

Ahn, Guk Hun; Choi, M. J.; Park, S. I.; Kim, H. W.; Kim, S. J.; Park, J. H.; Kwon, I. C

2006-12-15

332

Gynecological abnormalities following allogeneic bone marrow transplantation.  

Science.gov (United States)

Forty-four post-pubertal women were studied 261-4628 days after allogeneic transplantation to determine the nature and degree of gynecological abnormalities following bone marrow transplantation. Evaluations included pelvic examinations, exfoliative cytology, serum gonadotropin levels, direct preparations for micro-organisms, and microbial cultures. Pelvic abnormalities were detected in 35 of 44 (80%) women and resembled atrophic changes known to occur after ovarian failure. Findings included reduced vaginal elasticity and rugal folds, pale tissues, small vaginal, uterine and cervical size, atrophic vulvovaginitis, introital stenosis, and loss of pubic hair. Atrophic abnormalities were noted in 33 of 36 recipients of total body irradiation (TBI) compared to two of eight women not prepared with TBI (p = 0.02). Vasomotor symptoms were reported in 67% of TBI recipients compared to 38% of those not given TBI. Elevated serum gonadotropin levels suggested that TBI had caused the ovarian failure. Recognition of these gynecological abnormalities can lead to earlier hormone replacement, alleviating unnecessary discomfort and improving the well-being of the marrow transplant recipient. PMID:2369683

Schubert, M A; Sullivan, K M; Schubert, M M; Nims, J; Hansen, M; Sanders, J E; O'Quigley, J; Witherspoon, R P; Buckner, C D; Storb, R

1990-06-01

333

An abnormal carbohydrate tolerance in acromegaly  

International Nuclear Information System (INIS)

An abnormal secretion of plasma human growth hormore (hGH) and insulin in 67 acromegalic patients had been previously treated by external pituitary radiation were studied. All subjects, following an overnight fast, a standard 100 g oral glucose tolerance test, were performed and venous blood samples were taken at 0, 30, 60, 120 and 180 min. They were measured for blood glucose, plasma insulin and hGH. The results of this study have shown that, of the 67 subjects, 23 cases had an abnormal glucose tolerance(34.32%). Diabetes was detected in 17 cases (23.37%) and 6 patients had decreased glucose tolerance(8.69%). In all, hGH levels were consistantly above 5 ng/ml and were not suppressed after an oral glucose load. In these patients, however, about one-third had abnormal glucose tolerance. Low plasma insulin response to glucose and that of the releasing were evident in them than the normal glucose tolerance and a healthy control group. In addition, the mechanism of the abnormal secretion of hGH and insulin were disscussed

334

Behavioral abnormalities in captive nonhuman primates.  

Science.gov (United States)

In this study, we dealt with 11 species of nonhuman primates across 10 zoos in India. We recorded behavior as instantaneous scans between 9 a.m. and 5 p.m. In the study, we segregated behaviors for analyses into abnormal, undesirable, active, and resting. The 4 types of abnormal behavior exhibited included floating limb, self-biting, self-clasping, and stereotypic pacing. In the study, we recorded 2 types of undesirable behavior: autoerotic stimulation and begging. Langurs and group-housed macaques did not exhibit undesirable behaviors. A male lion-tailed macaque and a male gibbon exhibited begging behavior. autoerotic stimulation and self-biting occurred rarely. Males exhibited higher levels of undesirable behavior than did females. Animals confiscated from touring zoos, circuses, and animal traders exhibited higher levels of abnormal behaviors than did animals reared in larger, recognized zoos. The stump-tailed macaque was the only species to exhibit floating limb, autoerotic stimulation, self-biting, and self-clasping. Our results show that rearing experience and group composition influence the proportions of abnormal behavior exhibited by nonhuman primates in captivity. The history of early social and environmental deprivation in these species of captive nonhuman primates probably is critical in the development of behavioral pathologies. Establishing this will require further research. PMID:14965782

Mallapur, Avanti; Choudhury, B C

2003-01-01

335

Pinna abnormalities and low-set ears  

Science.gov (United States)

Low-set ears; Microtia; "Lop" ear ... Abnormal folds or location of the pinna Low-set ears No opening to the ear canal No ... Common conditions that can cause low-set and unusually formed ears ... cause low-set and malformed ears include: Beckwith-Wiedemann ...

336

Reversible splenial abnormality in hypoglycemic encephalopathy  

Energy Technology Data Exchange (ETDEWEB)

Lesions involving the splenium of the corpus callosum (SCC) have been rarely reported in cases of hypoglycemic brain injury. We identified signal abnormalities in the SCC in three adult patients with hypoglycemic encephalopathy by using diffusion-weighted imaging (DWI) on a 1.5-T MR scanner. Repeat DWI was performed in all patients following a marked clinical improvement, and MR angiography and routine MRI were also performed. We examined each patient's detailed medical history and blood laboratory tests in order to exclude other conditions causing similar SCC abnormalities. Initial DWI was performed during which each patient showed altered mental status that was attributed to profound hypoglycemia. We observed an identical pattern of DWI abnormality characterized by high signals in the SCC with apparent diffusion coefficient reductions that were reversed completely within several days following appropriate correction of hypoglycemia. T2-weighted or FLAIR images also showed no residual lesion in the SCC and MR angiography was normal in all patients. These case reports suggest that the SCC should be added to the list of selective vulnerability to hypoglycemia and that hypoglycemia, in turn, be included in the differential diagnosis of reversible SCC abnormalities. (orig.)

Kim, Ji Hyun; Choi, Jeong Yoon; Koh, Seong-Beom [Korea University School of Medicine, Department of Neurology, Guro Hospital, Seoul (Korea); Lee, Younghen [Korea University School of Medicine, Department of Radiology, Ansan Hospital, Ansan City (Korea)

2007-03-15

337

Abnormally high formation pressures, Potwar Plateau, Pakistan  

Science.gov (United States)

Abnormally high formation pressures in the Potwar Plateau of north-central Pakistan are major obstacles to oil and gas exploration. Severe drilling problems associated with high pressures have, in some cases, prevented adequate evaluation of reservoirs and significantly increased drilling costs. Previous investigations of abnormal pressure in the Potwar Plateau have only identified abnormal pressures in Neogene rocks. We have identified two distinct pressure regimes in this Himalayan foreland fold and thrust belt basin: one in Neogene rocks and another in pre-Neogene rocks. Pore pressures in Neogene rocks are as high as lithostatic and are interpreted to be due to tectonic compression and compaction disequilibrium associated with high rates of sedimentation. Pore pressure gradients in pre-Neogene rocks are generally less than those in Neogene rocks, commonly ranging from 0.5 to 0.7 psi/ft (11.3 to 15.8 kPa/m) and are most likely due to a combination of tectonic compression and hydrocarbon generation. The top of abnormally high pressure is highly variable and doesn't appear to be related to any specific lithologic seal. Consequently, attempts to predict the depth to the top of overpressure prior to drilling are precluded.

Law, B.E.; Shah, S.H.A.; Malik, M.A.

1998-01-01

338

Abnormal fetal head shape: aetiology and management  

DEFF Research Database (Denmark)

Background: Abnormal head shape is an uncommon finding on prenatal ultrasound, often associated with breech presentation, spinabifida, aneuploidy or secondary to oligohydramnios or fetal position. Other aetiologies are rarer and may be more difficult to define. Objective: To determine the aetiology and define management pathways for fetuses with an abnormal skull shape. Methods: Our FMU databases were searched to ascertain all fetuses with an abnormal skull shape. Sonographic findings, diagnosis and outcome were reviewed. Results: Of the 370 cases identified, 31.6% were associated with spinabifida (lemon-shaped), 18.4% with aneuploidy (mostly strawberry-shaped). 19.5% were dolicocephalic, most secondary to fetal position or oligohydramnios (see table). 13 had confirmed craniosynostosis, including thanatophoric dysplasia, Craniofrontonasal dysplasia, Aperts syndrome, Baller-Gerold syndrome, I-cell disease, Muenke craniosynostosis and two with an as yet undefined craniosynostosis syndrome. Overall, 16.5 % had an underlying genetic syndrome. Conclusions: Abnormal fetal head shape may be a normal variant, but is commonly associated with a wide variety of underlying pathologies. In view of the high incidence of genetic syndromes, in the absence of a clear diagnosis, referral to a tertiary centre and genetic input is advised as detection of subtle sonographic features may aid diagnosis, allowing for targeted molecular analysis. An algorithm for management will be proposed.

Petersen, Olav BjŘrn; David, Anna

2007-01-01

339

Parenchymal abnormalities associated with developmental venous anomalies  

International Nuclear Information System (INIS)

To report a retrospective series of 84 cerebral developmental venous anomalies (DVAs), focusing on associated parenchymal abnormalities within the drainage territory of the DVA. DVAs were identified during routine diagnostic radiological work-up based on magnetic resonance imaging (MRI) (60 cases), computed tomography (CT) (62 cases) or both (36 cases). Regional parenchymal modifications within the drainage territory of the DVA, such as cortical or subcortical atrophy, white matter density or signal alterations, dystrophic calcifications, presence of haemorrhage or a cavernous-like vascular malformation (CVM), were noted. A stenosis of the collecting vein of the DVA was also sought for. Brain abnormalities within the drainage territory of a DVA were encountered in 65.4% of the cases. Locoregional brain atrophy occurred in 29.7% of the cases, followed by white matter lesions in 28.3% of MRI investigations and 19.3% of CT investigations, CVMs in 13.3% of MRI investigations and dystrophic calcification in 9.6% of CT investigations. An intracranial haemorrhage possibly related to a DVA occurred in 2.4% cases, and a stenosis on the collecting vein was documented in 13.1% of cases. Parenchymal abnormalities were identified for all DVA sizes. Brain parenchymal abnormalities were associated with DVAs in close to two thirds of the cases evaluated. These abnormalities are thought to occur secondarily, likely during post-natal life, as a result of chronic venous hypertension. Outflow obstruction, progressive thickening of the walls of the DVA and their morphological organization into a venous convergence zone are thought to contribute to the development of venous hypertension in DVA. (orig.)

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Immunoreactivity for Taurine Characterizes Subsets of Glia, GABAergic and non-GABAergic Neurons in the Neo- and Archicortex of the Rat, Cat and Rhesus Monkey: Comparison with Immunoreactivity for Homocysteic Acid.  

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The cerebral cortex is an area rich in taurine (2-aminoethanesulphonic acid), but only limited information exists regarding its cellular distribution. We therefore examined taurine-like immunoreactivity in the cerebral cortex of the rat, cat and macaque monkey using antiserum directed against glutaraldehyde-conjugated taurine. Immunostaining was assessed at the light and electron microscopic level, and patterns obtained in light microscopic studies were compared to those produced with antiser...

Kritzer, Mf; Cowey, A.; Ottersen, Op; Streit, P.; Somogyi, P.

1992-01-01

 
 
 
 
341

Abnormal selective attention normalizes P3 amplitudes in PDD  

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This paper studied whether abnormal P3 amplitudes in PDD are a corollary of abnormalities in ERP components related to selective attention in visual and auditory tasks. Furthermore, this study sought to clarify possible age differences in such abnormalities. Children with PDD showed smaller P3 amplitudes than controls, but no abnormalities in selective attention. Adolescents with PDD showed abnormal selective attention, as reflected by larger auditory Processing Negati...

Hoeksma, Marco Rudolf; Kemner, C.; Kenemans, J. L.; Engeland, H.

2006-01-01

342

Alzheimer's-associated A? oligomers show altered structure, immunoreactivity and synaptotoxicity with low doses of oleocanthal  

International Nuclear Information System (INIS)

It now appears likely that soluble oligomers of amyloid-?1-42 peptide, rather than insoluble fibrils, act as the primary neurotoxin in Alzheimer's disease (AD). Consequently, compounds capable of altering the assembly state of these oligomers (referred to as ADDLs) may have potential for AD therapeutics. Phenolic compounds are of particular interest for their ability to disrupt A? oligomerization and reduce pathogenicity. This study has focused on oleocanthal (OC), a naturally-occurring phenolic compound found in extra-virgin olive oil. OC increased the immunoreactivity of soluble A? species, when assayed with both sequence- and conformation-specific A? antibodies, indicating changes in oligomer structure. Analysis of oligomers in the presence of OC showed an upward shift in MW and a ladder-like distribution of SDS-stable ADDL subspecies. In comparison with control ADDLs, oligomers formed in the presence of OC (A?-OC) showed equivalent colocalization at synapses but exhibited greater immunofluorescence as a result of increased antibody recognition. The enhanced signal at synapses was not due to increased synaptic binding, as direct detection of fluorescently-labeled ADDLs showed an overall reduction in ADDL signal in the presence of OC. Decreased binding to synapses was accompanied by significantly less synaptic deterioration assayed by drebrin loss. Additionally, treatment with OC improved antibody clearance of ADDLs. These results indicate oleocanthal is capable of altering the oligomerization state of ADDLs while protecting neurons from the synaptopathological effects of ADDLs and suggest OC as a lead compound for development in AD therapeutics.

343

Distribution and chemical coding pattern of somatostatin immunoreactivity in the dorsal striatum of the guinea pig  

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Full Text Available The present study provides a detailed description of somatostatin (SOM distribution and the colocalization pattern of SOM, neuropeptide Y (NPY and nitric oxide synthase (NOS in the dorsal striatum (caudate-putamen complex of the guinea pig. Within the dorsal striatum, SOM is found in a population of medium-sized aspiny interneurons. We found that 97% of all SOM-IR neurons expressed NPY simultaneously, while 98% of all NPY-ergic perikarya was simultaneously SOM-IR. On the other hand, while 98% of all SOM-IR cells were simultaneously NOS-IR, only 91% of all NOS-containing neurons exhibited SOM-immunoreactivity. Irrespective of their chemical coding, both types of SOM-IR neurons were scattered throughout the dorsal striatum, sometimes in the form of small, loosely arranged clusters of 2–4 cells. While SOM-IR and NPY-IR nerve fibers were present in all of the studied regions, they were more numerous in the ventro-medial part of the studied structure, with the exception of its caudal portion, where SOM-IR and NPY-IR fibers additionally formed a dense network in the part corresponding to the caudate nucleus. A low expression of staining for NOS-IR fibers was seen throughout the entire dorsal striatum. In some fibers, SOM and NPY were co-expressed. Fibers expressing both SOM and NOS were not found. (Folia Histochemica et Cytobiologica 2011; Vol. 49, No. 4, pp. 690–699

Janusz Najdzion

2012-01-01

344

Perinatal development of galanin-like immunoreactivity in chromaffin tissues of the rabbit.  

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We have analyzed the perinatal development of galanin-like immunoreactivity (GAL-LI) and catecholamines (CA) in the paraaortal paraganglia (PGGL) and adrenal glands. In the PGGL, the tissue content of GAL-LI was highest on the day of birth and decreased postnatally. The fetal levels were lower than at birth. In contrast, the content of CA in the PGGL increased with age. In the adrenal glands, the contents of both GAL-LI and CA also increased with age. During the first postnatal week the contents of both GAL-LI and CA in the PGGL were markedly higher than in the adrenal glands. Chromatographic analysis of GAL-LI in extracts of fetal and postnatal rabbit PGGL, respectively, indicated that most of the GAL-LI from both age groups co-eluted with synthetic porcine GAL. An additional, apparently more polar, component was also detected at both ages, which may represent a differently processed form of the peptide. The high content of GAL-LI in the PGGL at birth may reflect an enhanced synthesis associated with birth. PMID:7683437

Wikström, L M; Rökaeus, A; Fried, G

1993-04-01

345

Analysis of the brain ACTH-immunoreactive peptide spectrum in inbred mice  

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Mice of the BALB/c (C) and C57BL/6 (B6) strains, characterized by high and low emotionality respectively in open field tests, have been shown to differ considerably in both the initial level and the time course of changes in the plasma ACTH concentration after exposure to stress in an open field and after administration of a benzodiazepine tranquilizer. The ACTH concentration in the pituitary gland of animals of these lines also differs. The ACTH molecule is known to contain regions with neurotropic activity. It can therefore be postulated that differences in the level of this hormone and the products of its bioconversion in the brain are an essential factor in the mechanisms of formation of the hereditary features of emotional behavior. In this first stage of this investigation, represented in this paper and undertaken to test this hypothesis, spectra of ACTH-immunoreactive peptides were studied in chromatographic fractions of an acid brain extract as well as in the blood plasma of mice belonging to B6 and C lines and their hybrids. The peptides were determined by radioimmunoassay

346

Oxytocin/vasopressin-like immunoreactivity is present in the nervous system of hydra  

DEFF Research Database (Denmark)

Nerve cells have been found in hydra, which react with antisera to oxytocin, vasopressin and mesotocin. These nerve cells have a high density in the ectoderm of basal disk and tentacles and lower density in the ectoderm of peduncle, gastric region and hypostome. A very small number of nerve cells occur also in the endoderm of foot, gastric region and hypostome. By using a technique for simultaneous visualisation of nerve cells reacting with antisera to oxytocin and vasopressin, it can be shown that these nerve cells belong to a single population. In agreement with this, the staining of the nerve cells can be abolished by absorbing each antiserum with either oxytocin, vasopressin, [Lys8]vasopressin, vasotocin, mesotocin or isotocin, indicating that the antigenic determinant of hydra cross-reacts with those antibody subpopulations, which recognize common portions (sequence 1-2, 5-7, 9) of the oxytocin/vasopressin-like peptides. With radioimmunoassays that are specific for either oxytocin or vasopressin, only very low amounts of immunoreactivity were measured. In addition, the dilution curves in these assays were not parallel to the standards, indicating that the antigenic determinant of hydra is not oxytocin or vasopressin. The presence of oxytocin/vasopressin-like material in coelenterates, shows that this family of peptides is of great antiquity.

Grimmelikhuijzen, C J; Dierickx, K

1982-01-01

347

Microglial dystrophy in the aged and Alzheimer's disease brain is associated with ferritin immunoreactivity.  

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Degeneration of microglial cells may be important for understanding the pathogenesis of aging-related neurodegeneration and neurodegenerative diseases. In this study, we analyzed the morphological characteristics of microglial cells in the nondemented and Alzheimer's disease (AD) human brain using ferritin immunohistochemistry. The central hypothesis was that expression of the iron storage protein ferritin increases the susceptibility of microglia to degeneration, particularly in the aged brain since senescent microglia might become less efficient in maintaining iron homeostasis and free iron can promote oxidative damage. In a primary set of 24 subjects (age range 34-97 years) examined, microglial cells immunoreactive for ferritin were found to constitute a subpopulation of the larger microglial pool labeled with an antibody for HLA-DR antigens. The majority of these ferritin-positive microglia exhibited aberrant morphological (dystrophic) changes in the aged and particularly in the AD brain. No spatial correlation was found between ferritin-positive dystrophic microglia and senile plaques in AD tissues. Analysis of a secondary set of human postmortem brain tissues with a wide range of postmortem intervals (PMI, average 10.94 +/- 5.69 h) showed that the occurrence of microglial dystrophy was independent of PMI and consequently not a product of tissue autolysis. Collectively, these results suggest that microglial involvement in iron storage and metabolism contributes to their degeneration, possibly through increased exposure of the cells to oxidative stress. We conclude that ferritin immunohistochemistry may be a useful method for detecting degenerating microglia in the human brain. PMID:18442088

Lopes, Kryslaine O; Sparks, D Larry; Streit, Wolfgang J

2008-08-01

348

c-Fos immunoreactivity of neural cells in intoxication due to high-dose methamphetamine.  

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Methamphetamine (METH) is a powerful and toxic psychostimulant that is abused worldwide. Although many studies of its toxic functions have been done on animals and humans, the mechanism is still poorly understood. In addition, the doses of METH examined have often been low. Here, we investigated the effects of intoxication due to administration of 20 mg/kg METH on neuronal activity. The mice showed hyperthermia and stereotyped behavior during 60 min after injection. We examined plasma stress hormone levels, which indicated that exposure to METH stimulated the hypothalamic-pituitary-adrenal (HPA) axis and caused release of stress hormones soon after injection. The maximum levels of adrenocorticotropic hormone and corticosterone occurred 10 and 60 min, respectively, after injection. We examined c-Fos protein in 16 different brain regions at 60 min post injection to identify potential brain regions subject to the stimulant effect. Nine regions, including the anterior hypothalamic area, medial preoptic area, lateral hypothalamic area, paraventricular thalamic nucleus, lateral anterior hypothalamic nucleus, lateral septum, striatum, nucleus accumbens, and amygdala, showed a significant increase in c-Fos expression, while the other seven regions did not. These results indicate that responsive neurons in the regions containing c-Fos immunoreactivity (Fos-IR) may undergo cellular reaction to high-dose METH administration. The present study provides support for a relationship among hyperthermia, the HPA axis and neuronal activities in limited brain regions on exposure to 20 mg/kg METH. PMID:24025783

Tomita, Masafumi; Katsuyama, Hironobu; Watanabe, Yoko; Shibaike, Yoshinori; Yoshinari, Haruhiko; Tee, Jia Wei; Iwachidou, Nobuhisa; Miyamoto, Osamu

2013-01-01

349

Chronic corticosterone administration facilitates aversive memory retrieval and increases GR/NOS immunoreactivity.  

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Glucocorticoids are stress hormones that mediate the organism's reaction to stress. It has been previously proposed that the facilitation of emotional aversive conditioning induced by these hormones may involve nitric oxide-pathways. The purpose of the present study was to address this question. For that, male Wistar rats were surgically implanted with slow-release corticosterone (CORT) pellets (21 days) and tested in a step-down inhibitory avoidance task. Additional groups of animals were also submitted to the same treatment conditions and on the 21st day of treatment assayed for GR (glucocorticoid receptors)-nNOS (neuronal nitric oxide synthase) immunoreactivity (GRi-nNOSi) or measurements of plasma CORT. Results showed that CORT treatment induced facilitation of step-down inhibitory avoidance. This same treatment also significantly increased CORT plasma levels and GRi in the medial, basolateral and basomedial amygdala, in the paraventricular hypothalamic nucleus (PVN), in the ventral and dorsal dentate gyrus, in the ventral CA1 region and in the dorsal CA1 and CA3 regions. Furthermore, nNOSi and GRi-nNOSi were significantly increased by CORT treatment in the medial amygdala and basolateral amygdaloid complex, in the PVN, subiculum, in the dorsal CA3 region and in the ventral CA1 and CA3 regions. These results indicate that the facilitation of aversive conditioning induced by CORT involves GR-nNOS pathways activation, what may be of relevance for a better understanding of stress-related psychiatric conditions. PMID:24662151

Santos, Thays B; Céspedes, Isabel C; Viana, Milena B

2014-07-01

350

Immunoreactivity of Hu proteins facilitates identification of myenteric neurones in guinea-pig small intestine.  

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Hu proteins, together with neurone-specific enolase (NSE), protein gene product 9.5 (PGP-9.5), microtubule-associated protein-2 (MAP-2) and tubulin beta III isoform, were evaluated immunohistochemically as neuronal markers in whole-mount preparations and cultures obtained from the myenteric plexus of guinea-pig small intestine. Anti-Hu immunostaining marked the ganglion cell somas and nuclei without staining of the neuronal processes in the whole-mounts and cultures. The ganglion cell bodies were not obscured by staining of multiple neuronal fibres and this facilitated accurate counting of the neurones. MAP2 immunostaining also provided clear images of individual neurones in both whole mounts and cultures. Immunoreactivity for NSE, PGP-9.5 and tubulin beta III isoform provided sharp images of the ganglion cells in culture, but not in whole-mount preparations. Strong staining of the neuronal processes in the whole-mount preparations obscured the profiles of the ganglion cell bodies to such an extent that accurate counting of the total neuronal population was compromised. Anti-Hu immunostaining was judged to be an acceptable method for obtaining reliable estimates of total numbers of myenteric neurones in relation to other specific histochemical properties such as histamine binding. PMID:11975720

Lin, Z; Gao, N; Hu, H-Z; Liu, S; Gao, C; Kim, G; Ren, J; Xia, Y; Peck, O C; Wood, J D

2002-04-01

351

Claudin 3 and 4 Immunoreactivity in Malign Mesothelioma and Lung Adenocarcinoma  

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Full Text Available Objective: The differential diagnosis of malignant pleural mesotheliomas and lung adenocarcinomas is problematic for pathologists especially in small biopsy materials. In this study, we aimed to investigate whether the immunohistochemically determined Claudin 3 and Claudin 4 immunoreactivities are useful in the differential diagnosis between malignant pleural mesotheliomas and lung adenocarcinomas.Material and Method: Using the epitope-specific rabbit antibody Claudin 3 and Claudin 4, 32 cases of malignant pleural mesothelioma (25 epithelioid, 7 biphasic and 14 cases of lung adenocarcinoma were studied immunohistochemicallyResults: None of the cases of malignant pleural mesotheliomas expressed Claudin 4, whereas all lung carcinomas were immunopositive. Claudin 3 expression was immunonegative in 29 (90.6% cases and immunopositive in 3 (9.3% cases of malignant pleural mesothelioma. With Claudin 3, 11/14 (78.9% lung adenocarcinomas and 3/32 (9.4% malignant pleural mesotheliomas were immunopositive (p=0.000.Conclusion: In conclusion, Claudin 4 antibody was found to be a highly sensitive and specific marker for distinguishing between malignant pleural mesothelioma and lung adenocarcinoma.

?ule EK?Z

2009-06-01

352

In vitro release of immunoreactive atrial natriuretic peptide from the rat atria.  

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Full Text Available In vitro release of atrial natriuretic peptide (ANP from atria was examined by ANP radioimmunoassay. Isolated right rat atria were incubated in Krebs-Ringer bicarbonate buffer, and test substances were added to the incubation medium. The fluid was assayed for rat ANP by a radioimmunoassay method recently developed in our laboratory. We produced an antiserum to human ANP(99-216 (alpha-hANP(1-28 which showed a good cross-reactivity of 63% with rat ANP(99-126 (alpha-rANP(1-28 and was useful for measuring rat ANP concentrations of the medium. Application of the medium to a reverse phase high performance liquid chromatography (HPLC system resulted in a single peak of immunoreactive rat ANP corresponding to a small molecular weight synthetic rat ANP of 28 amino acid residues. Catecholamines (epinephrine, norepinephrine and isoproterenol reduced the basal secretion of ANP, whereas acetylcholine stimulated the release of ANP. Forskolin and dibutyryl cyclic AMP did not affect the release of ANP. These results suggest the possibility that the regulation of ANP release may be partially associated with adrenergic and cholinergic mechanisms.

Inoue,Hiroshi

1988-04-01

353

Keratin immunoreactivity as an aid to the diagnosis of persistent adenocarcinoma in irradiated human prostates  

International Nuclear Information System (INIS)

Postirradiation prostatic biopsy is believed by many to be the best measure of radiation effectiveness in prostatic cancer. Therapeutic irradiation may induce prostatic glandular atypia, which in its severe form can be confused with persistent adenocarcinoma on prostatic biopsies. In the current study, 37 postirradiation prostate biopsy specimens were evaluated by immunohistochemistry using a specific monoclonal anticytokeratin antibody (KA1) that reacts with the basal cells of normal or hyperplastic glands, but is nonreactive with the lumenal cells or with prostatic carcinoma cells. Persistent carcinoma was observed in 19 cases in which antibody staining was absent. The noncarcinomatous glands retained reactivity, but this reactivity appeared in a new and previously undescribed pattern. The irradiated lesion was characterized by cellular pleomorphisism, with enlargement of nuclei and loss of polarity. The immunoreactivity was seen in the enlarged basal cells and was seen to focally extend to involve the lumenal cell layer. In five of 37 cases, glands were seen that were so atypical on the routinely stained sections that a distinction from cancer could not be made. These same glands in the adjacent section reacted with KA1 in each case allowing us to conclude that the changes were benign. We conclude that the interpretation of postirradiation prostatic biopsy specimens may be aided by immunohistochemistry with this anticytokeratin antibody

354

Antigen-binding site protection during radiolabeling leads to a higher immunoreactive fraction  

International Nuclear Information System (INIS)

It is generally accepted that the immunointegrity of an antibody (Ab) depends on the preservation of its antigen-binding sites. Our goal was to radiolabel an antibody at several iodine:antibody molar ratios under conditions protecting its combining site and to compare its immunoreactive fraction (IRF) and electrophoretic mobility with those of the same antibody radiolabeled without protection. The data indicate that an antibody radiolabeled while its antigen-binding site is occupied by its antigen had the same IRF, regardless of the number of iodine atoms per antibody molecule. On the other hand, even at an I:Ab ratio of 1:1, the IRF of the same antibody radiolabeled without protection was lower than that of a protected one and decreased with increasing I:Ab ratios. In addition, the iodination of these Ab changes their electrophoretic mobility; however, when the Ab is labeled in the protected state, the degree of change is less. The binding of an antibody to its antigen prior to radiolabeling, therefore, enhances its immuno-integrity and prevents major conformational changes as reflected by electrophoresis

355

Neonatal RU-486 (mifepristone) exposure increases androgen receptor immunoreactivity and sexual behavior in male rats.  

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Progesterone and progestin receptors (PRs) are known to play a role in the development of brain physiology and behavior in many different species. The distribution and regulation of PRs within the developing brain suggest that they likely contribute to the organization of the brain and behavior in a sex-specific manner. We examined the role of PR signaling during development on the organization of adult sexual behavior and androgen receptor (AR) expression in the brain. We administered the PR antagonist, RU-486, subcutaneously to male and female rats on postnatal days 1-7 (0=day of birth) and examined adult sexual behavior and AR-immunoreactivity (AR-ir) in the adult brain. A typical sex difference in lordosis quotient (LQ) was observed and neonatal RU-486 treatment did not alter this behavior. In contrast, neonatal RU-486 treatment increased adult male sexual behavior and AR-ir in several brain areas in males. These data indicate that a transient disruption in PR signaling during development can have lasting consequences on the male brain and may increase male sexual behavior in part by increasing AR expression, and therefore androgen sensitivity, in adulthood. PMID:24239933

Forbes-Lorman, Robin; Auger, Anthony P; Auger, Catherine J

2014-01-16

356

Classification of nAChR?2-immunoreactive retinal ganglion cells and their tectal projections in chicks.  

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The relationship between the type of retinal ganglion cell (RGC) and the retinoreceptive layer of the tectum is investigated by the immunostaining of RGCs with nicotinic acetylcholine receptor?2 (nAChR?2) antibody and intracellular staining by DiI and also by anterograde degeneration and biotinylated dextran amine labeling of retinotectal fibers in chicks. The results strongly suggest that many of the RGCs that express immunoreactivity to nAChR?2 send axons to tectal layer 7 and are mainly classified into the simple-type of Groups II and III, which contain the cells providing middle-sized to large dendritic fields with simple dendritic arborization. These nAChR?2-immunoreactive RGCs receive visual information via the multiple sublayers of the inner plexiform layer. PMID:23990103

Naito, Jumpei; Tanada, Yukiko; Watanabe, Takumi

2013-12-01

357

Leucine-enkephalin-like immunoreactivity is localized in luteinizing hormone-producing cells in the axolotl (Ambystoma mexicanum) pituitary.  

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In this study, we used immunohistochemical techniques to determine the cell type of leucine-enkephalin (Leu-ENK)-immunoreactive cells in the axolotl (Ambystoma mexicanum) pituitary. Immunoreactive cells were scattered throughout the pars distalis except for the dorso-caudal portion. These cells were immuno-positive for luteinizing hormone (LH), but they were immuno-negative for adrenocorticotrophic, growth, and thyroid-stimulating hormones, as well as prolactin. Immunoelectron microscopy demonstrated that Leu-ENK-like substance and LH co-localized within the same secretory granules. Leu-ENK secreted from gonadotrophs may participate in LH secretion in an autocrine fashion, and/or may participate in the release of sex steroids together with LH. PMID:24034715

Suzuki, Hirohumi; Yamamoto, Toshiharu

2014-02-01

358

Neonatal screening for cystic fibrosis in Wales and the West Midlands: 1. Evaluation of immunoreactive trypsin test.  

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A study programme was set up in Wales and the West Midlands to evaluate serum immunoreactive trypsin screening for cystic fibrosis in neonates using blood spots collected for metabolic screening. By screening half the blood spots from each area, it was hoped to generate two comparable groups of fibrocystic children; those detected by screening and those not screened who would be diagnosed clinically. Over almost three years, more than 120,000 specimens were screened and 37 infants detected wi...

Ryley, H. C.; Deam, S. M.; Williams, J.; Alfaham, M.; Weller, P. H.; Goodchild, M. C.; Carter, R. A.; Bradley, D.; Dodge, J. A.

1988-01-01

359

Morphological and laminar distribution of cholescystokinine - immunoreactive neurons in cortex of human inferior parietal lobule and their clinical significance  

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Full Text Available Introduction. Cholecystocinine is a neuropeptide whose function in the cortex has not yet been clarified, although its relation with some psychic disorders has been noticed. Previous studies have not provided detailed data about types, or arrangement of neurons that contain those neuropeptide in the cortex of human inferior parietal lobe. The aim of this study was to examine precisely the morphology and typography of neurons containing cholecytocinine in the human cortex of inferior parietal lobule. Material and methods. There were five human brains on which we did the immunocystochemical research of the shape and laminar distribution of cholecystocinine immunoreactive neurons on serial sections of supramarginal gyrus and angular gyrus. The morphological analysis of cholecystocinine-immunoreactive neurons was done on frozen sections using avidin-biotin technique, by antibody to cholecystocinine diluted in the proportion 1:6000 using diamine-benzedine. Results. Cholecystocinine immunorective neurons were found in the first three layers of the cortex of inferior parietal lobule, and their densest concentration was in the 2nd and 3rd layer. The following types of neurons were found: bipolar neurons, then its fusiform subtype, Cajal-Retzius neurons (in the 1st layer, reverse pyramidal (triangular and unipolar neurons. The diameters of some types of neurons were from 15 to 35 µm, and the diameters of dendritic arborization were from 85-207 µm. A special emphasis is put on the finding of Cajal-Retzius neurons that are immunoreactive to cholecystocinine, which demands further research. Conclusion. Bearing in mind numerous clinical studies pointing out the role of cholecystokinine in the pathogenesis of schizophrenia, the presence of a great number of cholecystokinine immunoreactive neurons in the cortex of inferior parietal lobule suggests their role in the pathogenesis of schizophrenia.

Puškaš Laslo

2008-01-01

360

Changes in Calbindin- D28K Immunoreactivity in the Organotypic Slice Culture of Mouse Hypothalamic Suprachiasmatic Nucleus  

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The hypothalamic suprachiasmatic nucleus (SCN) is of the main circadian pacemaker in mammals. Calbindin-D28k (Calbindin) is a calcium-binding protein that is distributed widely in the mammalian brain. In vivo the localization of Calbindin immunoreactivity (CalB-ir) in mouse SCN was examined before. However, detailed information about the localization and developmental distribution of CalB-ir neurons in the mouse SCN slice culture is lacking. SCN derived from 3 day old mouse, were maintained i...

Tousson, Ehab

2009-01-01

 
 
 
 
361

Lack of relationship between TIMP-1 tumour cell immunoreactivity, treatment efficacy and prognosis in patients with advanced epithelial ovarian cancer  

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Full Text Available Abstract Background Tissue inhibitor of metalloproteinase 1 (TIMP-1 is a natural inhibitor of the matrix metalloproteinases (MMPs which are proteolytic enzymes involved in degradation of extracellular matrix thereby favoring tumour cell invasion and metastasis. TIMP-1 activity in tumour tissue may therefore play an essential role in the progression of a malignant tumour. The primary aim of the present study was to evaluate TIMP-1 protein immunoreactivity in tissue from primary ovarian cancer patients and associate these findings with the course of the disease including response to treatment in the individual patient. Methods TIMP-1 was assessed by immunohistochemistry (in tissue micro arrays in a total of 163 ovarian cancer specimens obtained from primary debulking surgery during 1991-1994 as part of a randomized clinical protocol. Results Positive TIMP-1 immunoreactivity was found in 12.3% of the tumours. The median survival time for the 143 patients with TIMP-1 negative tumours was 23.7 months [19.0-29.4] 95% CI, while the median survival time for the 20 patients with TIMP-1 positive tumours was 15.9 months [12.3-27.4] 95% CI. Although a difference of 7.8 months in median overall survival in favor of the TIMP-1 tumour negative patients was found, this difference did not reach statistical significance (p = 0.28, Kaplan-Meier, log-rank test. Moreover, TIMP-1 immunoreactivity was not associated with CA125 response (p = 0.53 or response at second look surgery (p = 0.72. Conclusion TIMP-1 immunoreactivity in tumour tissue from patients with primary epithelial ovarian cancer did not correlate with patient survival or response to combination platinum/cyclophosphamide therapy.

Bartels Annette

2010-05-01

362

Correlative analysis of immunoreactivity in confocal laser-scanning microscopy and scanning electron microscopy with focused ion beam milling.  

Science.gov (United States)

Recently, three-dimensional reconstruction of ultrastructure of the brain has been realized with minimal effort by using scanning electron microscopy (SEM) combined with focused ion beam (FIB) milling (FIB-SEM). Application of immunohistochemical staining in electron microscopy (EM) provides a great advantage in that molecules of interest are specifically localized in ultrastructures. Thus, we applied immunocytochemistry for FIB-SEM and correlated this immunoreactivity with that in confocal laser-scanning microcopy (CF-LSM). Dendrites of medium-sized spiny neurons in the rat neostriatum were visualized using a recombinant viral vector, which labeled the infected neurons with membrane-targeted GFP in a Golgi stain-like fashion. Moreover, the thalamostriatal afferent terminals were immunolabeled with Cy5 fluorescence for vesicular glutamate transporter 2 (VGluT2). After detection of the sites of terminals apposed to the dendrites by using CF-LSM, GFP and VGluT2 immunoreactivities were further developed for EM by using immunogold/silver enhancement and immunoperoxidase/diaminobenzidine (DAB) methods, respectively. In contrast-inverted FIB-SEM images, silver precipitations and DAB deposits were observed as fine dark grains and diffuse dense profiles, respectively, indicating that these immunoreactivities were as easily recognizable as those in the transmission electron microscopy (TEM) images. Furthermore, in the sites of interest, some appositions displayed synaptic specializations of an asymmetric type. Thus, the present method was useful in the three-dimensional analysis of immunocytochemically differentiated synaptic connections in the central neural circuit. PMID:23443927

Sonomura, Takahiro; Furuta, Takahiro; Nakatani, Ikuko; Yamamoto, Yo; Unzai, Tomo; Matsuda, Wakoto; Iwai, Haruki; Yamanaka, Atsushi; Uemura, Masanori; Kaneko, Takeshi

2013-01-01

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Correlative Analysis of Immunoreactivity in Confocal Laser-Scanning Microscopy and Scanning Electron Microscopy with Focused Ion Beam Milling  

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Full Text Available Three-dimensional reconstruction of ultrastructure of rat brain with minimal effort has recently been realized by scanning electron microscopy combined with focused ion beam milling (FIB-SEM. Because application of immunohistochemical staining to electron microscopy has a great advantage in that molecules of interest are specifically localized in ultrastructures, we here tried to apply immunocytochemistry to FIB-SEM and correlate immunoreactivity in confocal laser-scanning microcopy (CF-LSM with that in FIB-SEM. The dendrites of medium-sized spiny neurons in rat neo