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PubMedDate not supplied

[The content of D-dimer in peripheral blood as observed studied in thrombohemorrhagic lesions of the retina].

The content of D-dimer in peripheral blood was studied in thrombohemorrhagic lesions of the retina. 60 patients with retinal pathology of the retina, i.e. thrombosis of retinal veins, exudative-hemorrhagic stage of central chorioretinal dystrophy and preproliferative diaichbetic retinopathy with pronounced exudative hemorrhagic maculopathy, were examined. A higher concentration of D-dimer in peripheral blood was shown to be indicative of affected general hemostasis. The below main parameters, which matter in progression of thrombohemorrhagic conditions should be determined, apart from D-dimer, for choosing an adequate medicamental therapy: aggregation ability of platelets, activated partial thromboplastin time, antithrombin-III, protein-C, prothrombin time, soluble complexes of fibrinmonomer, thrombin time, plasma fibrinogen and fibrinolytic plasma activity.

Biomarkers↗

PubMed1986

Role of specific IgE antibodies in peroxidase (EPO) release from human eosinophils.

After the demonstration of cytophilic IgE immunoglobulins (Ig) on human blood and lung eosinophils, their role in cell activation was studied by eosinophil peroxidase (EPO) assay. Hypodense human eosinophils from filariasis-infected patients were activated by anti-human Ig or various antigens. A selective release of EPO occurred after incubation with anti-human IgE, but not with anti-human IgG. The activation by antigens showed a strict antibody specificity of cytophilic IgE antibodies. The direct involvement of IgE antibodies in activation by the specific antigen was evidenced by inhibition experiments with aggregated human IgE myeloma protein. Circulating IgE antibodies exhibiting the same specificity and able to induce EPO release were detected in the sera from filariasis patients by a passive sensitization assay. Only the hypodense eosinophils were able to release EPO after IgE-dependent activation both in the direct assay and in the passive sensitization test, confirming the functional heterogeneity of human eosinophils. These results suggest that the interaction between IgE antibodies and human eosinophils can play a role both in protective immunity and pathology by releasing active pharmacologic mediators.

Antibodies, Anti-Idiotypic↗

PubMed2006

Notch-1 immunoexpression is increased in Alzheimer's and Pick's disease.

Notch-1 is a protein that influences cell fate decisions, with its expression occurring primarily during embryogenesis and development. However, Notch-1 is also expressed in the adult brain, in regions with high synaptic plasticity, particularly the hippocampus. Its role in adults is unknown; however, it may impact neurite outgrowth or cell differentiation in adult brain regions undergoing neurogenesis. Notch-1 is increased in Alzheimer's disease (AD); however, its expression in other CNS degenerative diseases has not been described. To begin to define the range of degenerative disorders where Notch-1 expression is altered, we examined Notch-1 immunoreactivity in a variety of neurodegenerative diseases to determine whether its increase is selective for AD. We examined sections of hippocampus from 13 AD, 13 classical Pick's disease (PiD; with Pick bodies), 4 dementia lacking distinctive histopathology (DLDH) and 8 control brains, emphasizing hippocampal (dentate gyrus) pathology. We determined that Notch-1 immunoexpression is increased in AD and PiD relative to control cases. DLDH cases were not significantly different than control cases with respect to Notch-1 expression. Given the increase in Notch-1 immunoexpression in AD and PiD, two diseases where abnormal tau aggregates are present, and the lack of Notch-1 immunoexpression in DLDH (where tau aggregates are absent), we cannot rule out the possibility that tau aggregates are associated with Notch-1 expression in neurodegenerative diseases.

Aged↗

PubMed2005

Expression of gremlin, a bone morphogenetic protein antagonist, in human diabetic nephropathy.

BACKGROUND: We report the induction of gremlin, a bone morphogenetic protein antagonist, in cultured human mesangial cells exposed to high glucose and transforming growth factor beta (TGF-beta) levels in vitro and kidneys from diabetic rats in vivo. METHODS: Gremlin expression was assessed in human diabetic nephropathy by means of in situ hybridization, immunohistochemistry, and real-time polymerase chain reaction and correlated with clinical and pathological indices of disease. RESULTS: Gremlin was not expressed in normal human adult kidneys. Conversely, abundant gremlin expression was observed in human diabetic nephropathy. Although some gremlin expression was observed in occasional glomeruli, gremlin expression was most prominent in areas of tubulointerstitial fibrosis, where it colocalized with TGF-beta expression. Gremlin messenger RNA levels correlated directly with renal dysfunction, determined by means of serum creatinine level, but not with proteinuria level. There was a strong correlation between gremlin expression and tubulointerstitial fibrosis score. CONCLUSION: In aggregate, these results indicate that the developmental gene gremlin reemerges in the context of tubulointerstitial fibrosis in diabetic nephropathy and suggests a role for TFG-beta as an inducer of gremlin expression in this context.

Bone Morphogenetic Proteins↗

PubMed2004

Mechanisms of Suppression of {alpha}-Synuclein Neurotoxicity by Geldanamycin in Drosophila.

Parkinson's disease is a common neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of the protein alpha-synuclein into aggregates called Lewy bodies and Lewy neurites. Parkinson's disease can be modeled in Drosophila where directed expression of alpha-synuclein induces compromise of dopaminergic neurons and the formation of Lewy body-like aggregates. The molecular chaperone Hsp70 protects cells from the deleterious effects of alpha-synuclein, indicating a potential therapeutic approach to enhance neuron survival in Parkinson's disease. We have now investigated the molecular mechanisms by which the drug geldanamycin protects neurons against alpha-synuclein toxicity. Our studies show that geldanamycin sensitizes the stress response within normal physiological parameters to enhance chaperone activation, offering protection against alpha-synuclein neurotoxicity. Further, geldanamycin uncouples neuronal toxicity from Lewy body and Lewy neurite formation such that dopaminergic neurons are protected from the effects of alpha-synuclein expression despite the continued presence of (and even increase in) inclusion pathology. These studies indicate that compounds that modulate the stress response are a promising approach to treat Parkinson's disease.

Animals↗

PubMed1991

Effect of ubiquitin on platelet functions: possible identity with platelet activity suppressive lymphokine (PASL).

In an attempt to clone a suppressive lymphokine of platelet function (PASL), we have obtained a cDNA clone coding for the previously described human ubiquitin-80 amino acid fusion protein. Our clone differs from the described sequence in that it contains the complete amino acid sequence of ubiquitin as well as a short (25 bp) 5' noncoding region. In addition the 3' untranslated region is slightly longer than that previously shown. Like PASL, purified ubiquitin can inhibit the cytotoxic properties of platelets and the production of oxygen metabolites by these cells. Moreover, this molecule is able to act as a proaggregating factor and seems of a great interest in pathologies involving defects in platelet aggregation. Ubiquitin could also have a potential use in the regulation of immunological disorders in which platelets seem to be implicated such as hymenoptera venom hypersensitivity and aspirin-sensitive asthma, since in both situations, ubiquitin is able, as is PASL, to inhibit the cytotoxic function of platelets. Indeed ubiquitin possesses important pharmacological potentialities which have not been previously described. This molecule and PASL share several similarities in their functional and physicochemical properties. PASL could therefore belong to the family of ubiquitins.

Adenosine Diphosphate↗

PubMed1998

Evolution of the primate androgen receptor: a structural basis for disease.

Androgen effects mediated by the androgen receptor (AR) are essential for male reproductive development and virilization. Comparison of AR DNA coding sequence from five primate species, Homo sapiens (human), Pan troglodytes (chimpanzee), Papio hamadryas (baboon), Macaca fascicularis (macaque), and Eulemur fulvus collaris (collared brown lemur), supports their phylogeny with complete conservation of the DNA and steroid binding domain protein sequence. A linear increase in trinucleotide repeat expansion of homologous CAG and GGC sequences occurs in the NH2-terminal transcriptional activation region and is proportional to the time of species divergence. A serine phosphate/glutamine repeat interaction is observed where increasing CAG repeat length is associated with an increased rate of serine 94 phosphorylation. Disparity in the calculated and apparent molecular weight with CAG repeat expansion of an AR NH2-terminal fragment suggests self-aggregation with increasing glutamine repeat length into the pathological range. These results suggest that a CAG/glutamine repeat expanded during divergence of the higher primate species, which may have a direct effect on AR structure and support a common pathway in CAG trigenic diseases in the pathophysiology of neurodegeneration observed in X-linked spinal bulbar and muscular atrophy.

Amino Acid Sequence↗

PubMed1997

Dot blot chemiluminescence assay for studying food protein binding to small intestinal brush border membranes in vitro.

Interactions of food proteins with the apical membrane of small intestinal epithelial cells can influence enterocytic antigen handling. For studying these interactions in vitro, isolated brush border membrane vesicles are a widely accepted model. In order to improve measurement of food protein binding, we developed a sensitive dot blot chemiluminescence assay. This assay comprises immobilization of membrane vesicles on nitrocellulose, detection of bound biotinylated food proteins by a peroxidase-catalyzed chemiluminescence reaction, and densitometric quantitation of signal intensities. By using this assay, saturation of brush border membrane binding of food proteins (gliadin peptides, alpha-casein, beta-lactoglobulin, ovalbumin) was demonstrated. Inhibition studies indicated components of specific membrane binding of gliadin peptides, alpha-casein and beta-lactoglobulin, whereas aggregation tendency of ovalbumin interfered with inhibition experiments. Maximal binding intensities of gliadin peptides (22.2 +/- 1.2 densitometric units (d.u.)/microgram membrane protein), alpha-casein (27.9 +/- 1.7 d.u./microgram) and ovalbumin (21.3 +/- 1.6 d.u./microgram) were comparable to sugar-specific lectin binding (range from 23.4 to 35.1 d.u./microgram), in contrast to significantly less binding of beta-lactoglobulin (6.8 +/- 0.6 d.u./microgram). The dot blot chemiluminescence assay is appropriate for characterizing interactions between food proteins and brush border membranes. Its sensitivity makes investigation of pathological membrane alterations possible. Besides, it might be useful for any studies defining ligand-membrane interactions.

Animals↗

PubMed2006

Methods of studying the planar distribution of objects in histological sections of brain tissue.

This article reviews the statistical methods that have been used to study the planar distribution, and especially clustering, of objects in histological sections of brain tissue. The objective of these studies is usually quantitative description, comparison between patients or correlation between histological features. Objects of interest such as neurones, glial cells, blood vessels or pathological features such as protein deposits appear as sectional profiles in a two-dimensional section. These objects may not be randomly distributed within the section but exhibit a spatial pattern, a departure from randomness either towards regularity or clustering. The methods described include simple tests of whether the planar distribution of a histological feature departs significantly from randomness using randomized points, lines or sample fields and more complex methods that employ grids or transects of contiguous fields, and which can detect the intensity of aggregation and the sizes, distribution and spacing of clusters. The usefulness of these methods in understanding the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and Creutzfeldt-Jakob disease is discussed.

Alzheimer Disease↗

PubMedDate not supplied

[Effect of veinotonyl 75 on the capillary permeability test using technetium albumin in cyclic orthostatic edemas].

The purpose of this trial was to evaluate the clinical effect of Veinotonyl 75 in 42 women, 42 +/- 11 years old, with orthostatic cyclic edema. The main evaluation criterion was the result of a capillary filtration test with 99 mTc albumin which was performed at day 0 and at day 30 after treatment. At day 0, all the women had abnormal results ie an albumin retention > or = 8% (mean: 14.3% +/- 4.8%). At day 30, 75% of the patients were normalized in the Veinotonyl 75 group versus 38% in the placebo group (p < 0.02). The albumin retention in Veinotonyl 75 group was under the pathological level (mean: 5.2% +/- 4.8%) while it was over in the placebo group (mean: 9.4% +/- 7%). This study confirms the activity of Veinotonyl 75 on capillar protein hyperfiltration and on return venous circulation.

Adult↗

PubMed2003

Clinical and molecular findings in a patient with a novel mutation in the deafness-dystonia peptide (DDP1) gene.

The Mohr-Tranebjaerg syndrome (MTS) is a rare neurodegenerative disorder characterized by early-onset deafness, dystonia and further neurological abnormalities such as cortical blindness, spasticity, dementia and mental retardation. Causative mutations were identified within the deafness-dystonia peptide (DDP1/TIMM8a) gene on the X-chromosome. The DDP1 protein is located in the intermembrane space of human mitochondria. Here, it acts in a complex together with its partner protein Tim13 in a chaperone-like manner to facilitate the import of nuclear-encoded precursor proteins into the mitochondrial inner membrane. Thus, MTS is a novel type of mitochondrial disorder. To obtain more insight into the pathophysiology of this neurodegenerative disorder, we performed for the first time a comprehensive clinical and functional characterization of a patient suffering from MTS. This patient exhibited a typical combination of deafness, dystonia and visual loss. Sequence analysis of the patient's DDP1 gene revealed a G to C transversion at nucleotide position 38 of the first exon. The mutation affects the ATG start codon, thereby changing methionine to isoleucine (M1I), and leads to a complete absence of the DDP1 protein. In addition, the partner protein Tim13 was found to be significantly reduced, suggesting that Tim13 requires the presence of DDP1 for its stabilization. The assessment of mitochondrial functions showed the enzyme activities of the mitochondrial energy-generating systems to be normal in the muscle biopsy. Structural abnormalities or aggregations of mitochondria were absent. Electron microscopy revealed only a mild neurogenic atrophy. Neurophysiological investigations showed cochlear dysfunction and disturbance of visual pathways. PET and MRI studies revealed a multifocal pattern of neurodegeneration with hypometabolic areas predominantly located over the right striatum and parietal cortex and marked atrophy of the occipital lobes. Although the visual loss is caused predominantly by neurodegeneration of the visual cortex, degeneration of the retina and the optic nerve contributes to the visual impairment. The pathological changes in basal ganglia and sensory cortex demonstrate the disintegration of subcortico-cortical circuits and correlate well with the clinical presentation of multifocal dystonia. The data presented here showed that, in contrast to most of the known mitochondrial disorders, MTS appears not to be associated with a functional defect of the energy generation system of the mitochondria. Whereas the specific mitochondrial dysfunction leading to neuronal loss in MTS remains to be clarified, the electrophysiological and neuroimaging findings allowed the multifocal manifestation of neurodegenerative lesions in MTS to be characterized specifically.

Adult↗

PubMed2006

Cytosolic prion protein toxicity is independent of cellular prion protein expression and prion propagation.

Prion diseases are transmissible neurodegenerative diseases caused by a conformational isoform of the prion protein (PrP), a host-encoded cell surface sialoglycoprotein. Recent evidence suggests a cytosolic fraction of PrP (cyPrP) functions either as an initiating factor or toxic element of prion disease. When expressed in cultured cells, cyPrP acquires properties of the infectious conformation of PrP (PrP(Sc)), including insolubility, protease resistance, aggregation, and toxicity. Transgenic mice (2D1 and 1D4 lines) that coexpress cyPrP and PrP(C) exhibit focal cerebellar atrophy, scratching behavior, and gait abnormalities suggestive of prion disease, although they lack protease-resistant PrP. To determine if the coexpression of PrP(C) is necessary or inhibitory to the phenotype of these mice, we crossed Tg1D4(Prnp(+/+)) mice with PrP-ablated mice (TgPrnp(o/o)) to generate Tg1D4(Prnp(o/o)) mice and followed the development of disease and pathological phenotype. We found no difference in the onset of symptoms or the clinical or pathological phenotype of disease between Tg1D4(Prnp(+/+)) and Tg1D4(Prnp(o/o)) mice, suggesting that cyPrP and PrP(C) function independently in the disease state. Additionally, Tg1D4(Prnp(o/o)) mice were resistant to challenge with mouse-adapted scrapie (RML), suggesting cyPrP is inaccessible to PrP(Sc). We conclude that disease phenotype and cellular toxicity associated with the expression of cyPrP are independent of PrP(C) and the generation of typical prion disease.

Animals↗

PubMed1995

Accumulation of amyloid precursor protein-like immunoreactivity in rat brain in response to thiamine deficiency.

Thiamine deficiency (TD) is a classical model of impaired cerebral oxidation. As in Alzheimer's disease (AD), TD is characterized by selective neuronal loss, decreased activities of thiamine pyrophosphate-dependent enzymes, cholinergic deficits and memory loss. Amyloid beta-protein (A beta), a approximately 4 kDa fragment of the beta-amyloid precursor protein (APP), accumulates in the brains of patients with AD or Down's syndrome. In the current study, we examined APP and A beta immunoreactivity in the brains of thiamine-deficient rats. Animals received thiamine-deficient diet ad libitum and daily injections of the thiamine antagonist, pyrithiamine. Immunocytochemical staining and immunoblotting utilized a rabbit polyclonal antiserum against human APP645-694 (numbering according to APP695 isoform). Three, 6 and 9 days of TD did not appear to damage any brain region nor change APP-like immunoreactivity. However, 13 days of TD led to pathological lesions mainly in the thalamus, mammillary body, inferior colliculus and some periventricular areas. While immunocytochemistry and thioflavine S histochemistry failed to show fibrillar beta-amyloid, APP-like immunoreactivity accumulated in aggregates of swollen, abnormal neurites and perikarya along the periphery of the infarct-like lesion in the thalamus and medial geniculate nucleus. Immunoblotting of the thalamic region around the lesion revealed increased APP-like holoprotein immunoreactivity. APP-like immunoreactive neurites were scattered in the mammillary body and medial vestibular nuclei where the lesion did not resemble infarcts. In the inferior colliculus, increased perikaryal APP-like immunostaining occurred in neurons surrounding necrotic areas. Regions without apparent pathological lesions showed no alteration in APP-like immunoreactivity. Thus, the oxidative insult associated with cell loss, hemorrhage and infarct-like lesions during TD leads to altered APP metabolism. This is the first report to show a relationship between changes in APP expression, oxidative metabolism and selective cell damage caused by nutritional/cofactor deficiency. This model appears useful in defining the role of APP in the reponse to central nervous system injury, and may also be relevant to the pathophysiology of Wernicke-Korsakoff syndrome and AD.

Amyloid beta-Protein Precursor↗

PubMed2006

Interaction of huntingtin fragments with brain membranes--clues to early dysfunction in Huntington's disease.

Abstract Huntingtin is a large, multi-domain protein of unknown function in the brain. An abnormally elongated polyglutamine stretch in its N-terminus causes Huntington's disease (HD), a progressive neurodegenerative disorder. Huntingtin has been proposed to play a functional role in membrane trafficking via proteins involved in endo- and exocytosis. Here, we supply evidence for a direct association between huntingtin and membranes. In the brains of R6/2 mice with HD pathology, a 64 kDa N-terminal huntingtin fragment accumulated in postsynaptic membranes during the pre-symptomatic period of 4-8 weeks of age. In addition, an oligomeric fragment of approximately 200 kDa was detected at 8 weeks of age. Simultaneous progressive changes in distribution of amphiphysin, synaptojanin, and subunits of NMDA- and AMPA-receptors provide a strong indication of dysfunctional synaptic trafficking. Composition of the major phospholipids in the synaptic membranes was unaffected. In vitro, large unilamellar vesicles of brain lipids readily associated with soluble N-terminal huntingtin exon 1 fragments and stimulated fibrillogenesis of mutant huntingtin aggregates. Moreover, interaction of both mutant and wild-type huntingtin exon 1 fragments with brain lipids caused bilayer perturbation, mediated through a proline-rich region adjacent to the polyglutamines. This suggests that lipid interactions in vivo could influence misfolding of huntingtin and may play an early role in HD pathogenesis.

Age Factors↗

PubMed2006

Hypothalamic-endocrine aspects in Huntington's disease.

Huntington's disease (HD) is a hereditary and fatal disorder caused by an expanded CAG triplet repeat in the HD gene, resulting in a mutant form of the protein huntingtin. Wild-type and mutant huntingtin are expressed in most tissues of the body but the normal function of huntingtin is not fully known. In HD, the neuropathology is characterized by intranuclear and cytoplasmic inclusions of huntingtin aggregates, and cell death primarily in striatum and cerebral cortex. However, hypothalamic atrophy occurs at early stages of HD with loss of orexin- and somatostatin-containing cell populations. Several symptoms of HD such as sleep disturbances, alterations in circadian rhythm, and weight loss may be due to hypothalamic dysfunction. Endocrine changes including increased cortisol levels, reduced testosterone levels and increased prevalence of diabetes are found in HD patients. In HD mice, alterations in the hypothalamic-pituitary-adrenal axis occurs as well as pancreatic beta-cell and adipocyte dysfunction. Increasing evidence points towards important pathology of the hypothalamus and the endocrine system in HD. As many neuroendocrine factors are secreted into the cerebrospinal fluid, blood and urine, it is possible that their levels may reflect the disease state in the central nervous system. Investigating neuroendocrine changes in HD opens up the possibility of finding biomarkers to evaluate future therapies for HD, as well as of identifying novel targets for therapeutic interventions.

Animals↗

PubMed1999

Presenilins: multifunctional proteins involved in Alzheimer's disease pathology.

Early-onset aggressive forms of Alzheimer's disease (AD) are of genetic nature and have been linked to inherited mutations located on chromosomes 21, 14, and 1. The gene products of chromosomes 14 and 1, which are responsible for most of these familial forms of the disease (FAD), have been recently identified and referred to as presenilin 1 and 2 (PS1, PS2), respectively. Several lines of evidence derived from neuropathological, cell biology, and transgenesis approaches indicate that PS could interfere with the processing of the beta-amyloid precursor protein (betaAPP). Thus, FAD-linked mutations in PS exacerbate the production of Abeta42, the readily aggregable Abeta species corresponding to one of the main constituents of the senile plaques that invade the cortical areas of affected brains. Recent studies indicate that PS functions could be intimately related with the susceptibility of PS to further processing by caspase-like enzymes and other unknown proteolytic activities. Here I briefly report on the post-translational events undergone by PS and examine recent advances concerning their possible roles in development, cell signaling, and apoptosis. Possible alterations brought by FAD-linked mutations will be discussed.

Alzheimer Disease↗

PubMed2006

The interaction between cytoplasmic prion protein and the hydrophobic lipid core of membrane correlates with neurotoxicity.

Prion protein (PrP), normally a cell surface protein, has been detected in the cytosol of a subset of neurons. The appearance of PrP in the cytosol could result from either retro-translocation of misfolded PrP from the endoplasmic reticulum (ER) or impaired import of PrP into the ER. Transgenic mice expressing cytoplasmic PrP (cyPrP) developed neurodegeneration in cerebellar granular neurons, although no detectable pathology was observed in other brain regions. In order to understand why granular neurons in the cerebellum were most susceptible to cyPrP-induced degeneration, we investigated the subcellular localization of cyPrP. Interestingly, we found that cyPrP is membrane-bound. In transfected cells, it binds to the ER and plasma/endocytic vesicular membranes. In transgenic mice, it is associated with synaptic and microsomal membranes. Furthermore, the cerebellar neurodegeneration in transgenic mice correlates with the interaction between cyPrP and the hydrophobic lipid core of the membrane but not with either the aggregation status or the dosage of cyPrP. These results suggest that lipid membrane perturbation could be a cellular mechanism for cyPrP-induced neurotoxicity and explain the seemingly conflicting results concerning cyPrP.

Animals↗

PubMed2006

Oxidative stress induces nuclear translocation of C-terminus of alpha-synuclein in dopaminergic cells.

Growing evidence suggests that oxidative stress is involved in the neuronal degeneration and can promote the aggregation of alpha-synuclein. However, the role of alpha-synuclein under physiological and pathological conditions remains poorly understood. In the present study, we examined the possible interaction between the alpha-synuclein and oxidative stress. In a dopaminergic cell line MES23.5, we have found that the 200microM H(2)O(2) treatment induced the translocation of alpha-synuclein from cytoplasm to nuclei at 30min post-treatment. The immunoactivity of alpha-synuclein became highly intensive in the nuclei after 2h treatment. The protein translocated to nucleus was a 10kDa fragment of C-terminus region of alpha-synuclein, while full-length alpha-synuclein remained in cytoplasm. Thioflavine-S staining suggested that the C-terminal fragment in the nuclei has no beta-sheet structures. Our present results indicated that 200microM H(2)O(2) treatment induces the intranuclear accumulation of the C-terminal fragment of alpha-synuclein in dopaminergic neurons, whose role remains to be investigated.

Active Transport, Cell Nucleus↗