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Pathological Processes (pathological + process)
Selected AbstractsFatty acid metabolism assessed by 125I-iodophenyl 9-methylpentadecanoic acid (9MPA) and expression of fatty acid utilization enzymes in volume-overloaded heartsEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 3 2004T. Miyamoto Abstract Background, The peroxisome proliferator-activated receptor (PPAR) , is a member of the nuclear receptor superfamily and regulates gene expression of fatty acid utilization enzymes. In cardiac hypertrophy and heart failure by pressure-overload, myocardial energy utilization reverts to the fetal pattern, and metabolic substrate switches from fatty acid to glucose. However, myocardial metabolism in volume-overloaded hearts has not been rigorously studied. The aim of the present study was to examine fatty acid metabolism and protein expressions of PPAR, and fatty acid oxidation enzymes in volume-overloaded rabbit hearts. Methods, Volume-overload was induced by carotid-jugular shunt formation. Sham-operated rabbits were used as control. Chronic volume-overload increased left ventricular weight and ventricular cavity size, and relative wall thickness was decreased, indicating eccentric cardiac hypertrophy. 125I-iodophenyl 9-methylpentadecanoic acid (9MPA) was intravenously administered, and animals were sacrificed at 5 min after injection. The 9MPA was rapidly metabolized to iodophenyl-3-methylnonanoic acid (3MNA) by ,-oxidation. Lipid extraction from the myocardium was performed by the Folch method, and radioactivity distribution of metabolites was assayed by thin-layer chromatography. The protein was extracted from the left ventricular myocardium, and levels of PPAR, and fatty acid oxidation enzymes were examined by Western blotting. Results, Myocardial distribution of 9MPA tended to be more heterogeneous in shunt than in sham rabbits (P = 0·06). In volume-overloaded hearts by shunt, the conversion from 9MPA to 3MNA by ,-oxidation was faster than the sham-control hearts (P < 0·05). However, protein levels of PPAR, and fatty acid utilization enzymes were unchanged in shunt rabbits compared with sham rabbits. Conclusions, These data suggest that myocardial fatty acid metabolism is enhanced in eccentric cardiac hypertrophy by volume-overload without changes in protein expressions of PPAR, and fatty acid utilization enzymes. Our data may provide a novel insight into the subcellular mechanisms for the pathological process of cardiac remodelling in response to mechanical stimuli. [source] New insights into the pathology of Parkinson's disease: does the peripheral autonomic system become central?EUROPEAN JOURNAL OF NEUROLOGY, Issue 2008A. Probst Recent studies in aged, neurologically unimpaired subjects have pointed to a specific induction site of the pathological process of Parkinson's disease (PD) in the region of the dorsal glossopharyngeus,vagus complex as well as in the anterior olfactory nucleus. From the lower brainstem, the disease process would then pursue an ascending course and involve more rostral brainstem areas, limbic structures, and eventually the cerebral cortex. One barrier to the acceptance of the caudal medullary structures as the induction site of PD pathology is that not all parts of the nervous system have been investigated for the presence of PD-associated lesions in cases of early asymptomatic PD. Using alpha-synuclein immunostaining, we investigated the brain, the sacral, and thoracic autonomic nuclei of the spinal cord as well as several components of the peripheral autonomic nervous system in a autopsy cohort of 98 neurologically unimpaired subjects aged 64 or more. Our data indicate that the autonomic nuclei of the spinal cord and the peripheral autonomic nervous system belong to the most constantly and earliest affected regions next to medullary structures and the olfactory nerves in neurologically unimpaired older individuals, thus providing a pathological basis for early premotor autonomic dysfunctions at a prodromal stage of PD. [source] Effect of vitamin E supplementation in patients with ataxia with vitamin E deficiencyEUROPEAN JOURNAL OF NEUROLOGY, Issue 5 2001S. Gabsi Ataxia with vitamin E (Vit E) defciency (AVED) is an autosomal recessive disorder caused by mutations of the , tocopherol transfer protein gene. The Friedreich ataxia phenotype is the most frequent clinical presentation. In AVED patients, serum Vit E levels are very low in the absence of intestinal malabsorption. As Vit E is a major antioxidant agent, Vit E deficiency is supposed to be responsible for the pathological process. Twenty-four AVED patients were fully investigated (electromyography, nerve conduction velocity (NVC) studies, somatosensory evoked potentials, cerebral computed tomography scan, sural nerve biopsy, genetic studies) and supplemented with Vit E (800 mg daily) during a 1-year period. Clinical evaluation was mainly based on the Ataxia Rating Scale (ARS) for cerebellar ataxia assessment and serum Vit E levels were monitored. Serum Vit E levels normalized and ARS scores decreased moderately but significantly suggesting clinical improvement. Better results were noted with mean disease duration , 15 years. Reflexes remained abolished and posterior column disturbances unchanged. Vitamin E supplementation in AVED patients stabilizes the neurological signs and can lead to mild improvement of cerebellar ataxia, especially in early stages of the disease. [source] Modulation of histamine H3 receptors in the brain of 6-hydroxydopamine-lesioned ratsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2000Oleg V. Anichtchik Abstract Parkinson's disease is a major neurological disorder that primarily affects the nigral dopaminergic cells. Nigral histamine innervation is altered in human postmortem Parkinson's disease brains. However, it is not known if the altered innervation is a consequence of dopamine deficiency. The aim of the present study was to investigate possible changes in the H3 receptor system in a well-characterized model of Parkinson's disease , the 6-hydroxydopamine (6-OHDA) lesioned rats. Histamine immunohistochemistry showed a minor increase of the fibre density index but we did not find any robust increase of histaminergic innervation in the ipsilateral substantia nigra on the lesioned side. In situ hybridization showed equal histidine decarboxylase mRNA expression on both sides in the posterior hypothalamus. H3 receptors were labelled with N-alpha-[3H]-methyl histamine dihydrochloride ([3H] NAMH). Upregulation of binding to H3 receptors was found in the substantia nigra and ventral aspects of striatum on the ipsilateral side. An increase of GTP-,-[35S] binding after H3 agonist activation was found in the striatum and substantia nigra on the lesioned side. In situ hybridization of H3 receptor mRNA demonstrated region-specific mRNA expression and an increase of H3 receptor mRNA in ipsilateral striatum. Thus, the histaminergic system is involved in the pathological process after 6-OHDA lesion of the rat brain at least through H3 receptor. On the later stages of the neurotoxic damage, less H3 receptors became functionally active. Increased H3 receptor mRNA expression and binding may, for example, modulate GABAergic neuronal activity in dopamine-depleted striatum. [source] The role of selective angiographic embolization of the musculo-skeletal system in haemophiliaHAEMOPHILIA, Issue 4 2009E. C. RODRIGUEZ-MERCHAN Summary., The incidence of haemarthrosis as a result of a spontaneous periarticular aneurysm in haemophilia is very low. In these circumstances, angiographic embolization might be considered as a promising therapeutic and coagulation factor saving option in joint bleeds not responding to replacement of coagulation factor to normal levels. Moreover, embolization should be considered as a possible treatment for postoperative pseudoaneurysms complicating total knee arthroplasty in haemophilia. However, the pathological process of aneurysmal bleeding and clotting factor replacement is entirely different. While embolization is the treatment of choice for some periarticular complications that may occur, it is by no means a panacea for all resistant periarticular bleeds in haemophilia or for postoperative bleeding which usually settles with clotting factor replacement. Another use of arterial embolization is for the treatment of haemophilic tumours of the pelvis, because they can act as a focus for infection and cause cutaneous fistulas. When they present perforations and infections of endogenous origin, their course is usually fatal. Suitable treatment has been investigated on numerous occasions, most of the literature agreeing that the only curative treatment is surgical resection. However, surgical resection after performing arterial embolization to reduce the vascularization of the pseudotumour is a good alternative, thereby reducing the size of the pseudotumour and the risk of bleeding complications during surgery. It is important to bear in mind that despite its efficacy, arterial embolization is an invasive procedure with a reported rate of complications up to 25% (16% minor, 7% serious, 2% death). [source] Cerebral ischemia/stroke and small ubiquitin-like modifier (SUMO) conjugation , a new target for therapeutic intervention?JOURNAL OF NEUROCHEMISTRY, Issue 3 2008Wei Yang Abstract Transient cerebral ischemia/stroke activates various post-translational protein modifications such as phosphorylation and ubiquitin conjugation that are believed to play a major role in the pathological process triggered by an interruption of blood supply and culminating in cell death. A new system of post-translational protein modification has been identified, termed as small ubiquitin-like modifier (SUMO) conjugation. Like ubiquitin, SUMO is conjugated to the lysine residue of target proteins in a complex process. This review summarizes observations from recent experiments focusing on the effect of cerebral ischemia on SUMO conjugation. Transient global and focal cerebral ischemia both induced a rapid, dramatic and long-lasting rise in levels of SUMO2/3 conjugation. After transient focal cerebral ischemia, SUMO conjugation was particularly prominent in neurons located at the border of the ischemic territory where SUMO-conjugated proteins translocated to the nucleus. Many SUMO conjugation target proteins are transcription factors and sumoylation has been shown to have a major impact on the activity, stability, and cellular localization of target proteins. The rise in levels of SUMO-conjugated proteins is therefore likely to have a major effect on the fate of post-ischemic neurons. The sumoylation process could provide an exciting new target for therapeutic intervention. [source] Subunits of the epithelial sodium channel family are differentially expressed in the retina of mice with ocular hypertensionJOURNAL OF NEUROCHEMISTRY, Issue 1 2005Frank M. Dyka Abstract Glaucoma is a prevalent cause of blindness, resulting in the apoptotic death of retinal ganglion cells and optic nerve degeneration. The disease is often associated with elevated intraocular pressure, however, molecular mechanisms involved in ganglion cell death are poorly understood. To identify proteins contributing to this pathological process, we analysed the retinal gene expression of DBA/2J mice that develop an elevated intraocular pressure by the age of 6 months with subsequent ganglion cell loss. In this study, we identified subunits of the epithelial sodium channel (ENaC) family that are specifically expressed under elevated intraocular pressure. Using reverse transcriptase polymerase chain reaction we observed a significant increase of ,-ENaC in the neuronal retina of DBA/2J mice when compared with control animals, while ,-ENaC and ,-ENaC were not detectable in this tissue. Specific immune sera to ENaC subunits showed up-regulation of ,-ENaC in synaptic and nuclear layers of the retina, and in the retinal pigment epithelium. Consistent with our polymerase chain reaction data, ,-ENaC was not detected by specific antibodies in the retina, while ,-ENaC was only present in the retinal pigment epithelium under ocular hypertension. Finally, the increase of ,-ENaC gene expression in the neuronal retina and the retinal pigment epithelium was not observed in other tissues of DBA/2J mice. Since the intraocular pressure is regulated by the transport of aqueous humour across epithelial structures of the eye that in turn is associated with ion flux, the specific up-regulation of ENaC proteins could serve as a protecting mechanism against elevated intraocular pressure. [source] Endoplasmic reticulum dysfunction , a common denominator for cell injury in acute and degenerative diseases of the brain?JOURNAL OF NEUROCHEMISTRY, Issue 4 2001Wulf Paschen Various physiological, biochemical and molecular biological disturbances have been put forward as mediators of neuronal cell injury in acute and chronic pathological states of the brain such as ischemia, epileptic seizures and Alzheimer's or Parkinson's disease. These include over-activation of glutamate receptors, a rise in cytoplasmic calcium activity and mitochondrial dysfunction. The possible involvement of the endoplasmic reticulum (ER) dysfunction in this process has been largely neglected until recently, although the ER plays a central role in important cell functions. Not only is the ER involved in the control of cellular calcium homeostasis, it is also the subcellular compartment in which the folding and processing of membrane and secretory proteins takes place. The fact that blocking of these processes is sufficient to cause cell damage indicates that they are crucial for normal cell functioning. This review presents evidence that ER function is disturbed in many acute and chronic diseases of the brain. The complex processes taken place in this subcellular compartment are however, affected in different ways in various disorders; whereas the ER-associated degradation of misfolded proteins is affected in Parkinson's disease, it is the unfolded protein response which is down-regulated in Alzheimer's disease and the ER calcium homeostasis that is disturbed in ischemia. Studying the consequences of the observed deteriorations of ER function and identifying the mechanisms causing ER dysfunction in these pathological states of the brain will help to elucidate whether neurodegeneration is indeed caused by these disturbances, and will help to fascilitate the search for drugs capable of blocking the pathological process directly at an early stage. [source] Melatonin attenuates isoproterenol-induced protein kinase A overactivation and tau hyperphosphorylation in rat brainJOURNAL OF PINEAL RESEARCH, Issue 1 2004Dan-Ling Wang Abstract:, Hyperphosphorylation of microtubule-associated protein tau at specific sites is a recognized pathological process in Alzheimer's disease (AD), and protein kinase A (PKA) is a crucial kinase in AD-like tau hyperphosphorylation. In the present study, isoproterenol (ISO) was injected bilaterally into hippocampus of rat brain; ISO is a specific PKA activator and it induces tau hyperphosphorylation. With this system, melatonin (MT) was shown to protect against ISO-induced tau hyperphosphorylation. We found that hippocampal injection of ISO (0.02 ,m) induced PKA overactivation and tau hyperphosphorylation at both paired helical filament (PHF)-1 and tau-1 sites. ISO injection also resulted in activation of superoxide dismutase (SOD) and elevation of malondialdehyde (MDA), parameters suggesting elevated oxidative stress. Preinfusion of MT intraperitoneally partially reversed ISO-induced tau hyperphosphorylation at the PHF-1 epitope (1 and 10 mg/kg continuously for 4 wk or 10 mg/kg for 1, 2 or 3 wk) and tau-1 epitope (10 mg/kg for 2 wk). Furthermore, MT (10 mg/kg for 2 wk) obviously antagonized ISO-induced PKA overactivation, as well as enhanced SOD activity and decreased the level of MDA. It is suggested from these data that ISO may induce abnormal hyperphosphorylation of tau through not only the activation of PKA but also because of the fact that it increases oxidative stress; MT may protect against ISO-induced tau hyperphosphorylation through suppression of both PKA overactivation and oxidative stress. [source] Psoriasis under the microscopeJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 2006BJ Cribier Abstract Histopathology is a major diagnostic tool in dermatology, particularly in psoriasiform diseases. Morphological studies showed that the initial event in psoriatic lesions is perivascular infiltrate, followed by dilatation of superficial papillary vessels. Proliferation of keratinocytes and neutrophil exocytosis are secondary events. Fully developed psoriasis has a very characteristic pattern, which includes elongation of rete ridges leading to regular acanthosis, oedema of the papillary dermis associated with tortuous dilated vessels, thinning of suprapapillar area, decreased thickness of granular layer, and exocytosis of neutrophils in the spinous layer (Kogoj's pustule) or in the cornified parakeratotic layer (Munro microabscesses). Pustular psoriasis is characterized by large or confluent intra-epidermal multilocular pustules. Whatever the clinical variant of psoriasis, common morphological signs suggest that it is basically a unique pathological process, with many possible presentations according to various factors such as age, size and localization of lesions, or therapy. Similar microscopic elementary lesions indicate that Hallopeau's acrodermatitis continua, Reiter's disease and geographical tongue are variants of psoriasis. Because of the many faces of the disease, psoriasis can resemble many other squamous or pustular disorders. Differential diagnosis by microscopic analysis is based on pattern analysis, PAS (Periodic Acid Schiff) staining to rule out fungal infection, and immunohistochemistry to characterize lymphocytic infiltrate. Psoriasis is one of the most common inflammatory skin diseases. In its characteristic presentation, psoriasis comprises well-circumscribed red scaly papules and plaques. In this form, the disease is generally easy to identify, especially when the elbows, knees and scalp are affected. Nevertheless, the term ,psoriasis' includes more clinical variants than any other inflammatory dermatosis: psoriasis vulgaris vs. pustular, localized vs. generalized, topographic variants, mucous membranes involvement, hair and nail lesions. Although some of these conditions might be extremely different from psoriasis vulgaris, common pathological findings can be identified in all of them. Microscopic analysis of psoriatic lesions may therefore help clinicians to make the diagnosis and to understand that, whatever the clinical presentation, signs and symptoms are mainly due to a unique pathological process. [source] Non-Hodgkin's lymphoma and auricular hypoplasia: associated with juvenile colloid milium or ligneous conjunctivitis?JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 3 2005A Kavak ABSTRACT The exact nature of amyloid-like hyaline material deposits in the skin is not well understood in some disorders. Three of those , ligneous conjunctivitis, ligneous periodontitis and colloid milium , have been rarely reported in a same patient. We report a case of mucosal and skin deposits of an amyloid-like homogeneous material associated with non-Hodgkin's lymphoma and congenital auricular hypoplasia. We discussed and reviewed the literature on these unique associations to determine whether these are the same pathological process. We also noted whether this case represents a new syndrome or a coincidental association. [source] QUANTITATIVE SENSORY TESTING AND SWEAT FUNCTION IN FRIEDREICH'S ATAXIA.JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 1 2000CORRELATION WITH CUTANEOUS INNERVATION To evaluate small fiber function in Friedreich's Ataxia (FA), we performed in 7 patients pin-prick, thermal thresholds, and sweat test. All tests were performed in four different sites: hand dorsum, anterior thigh, lateral distal leg, and foot dorsum. The same subjects underwent 3 mm punch skin biopsy from fingertip, anterior thigh, and lateral distal leg. We used a thin needle mounted on a calibrated nylon wire for the pin-prick test, and a Medoc 2001 TSA system for thermal threshold assessment. Sweat test was performed using a silicon mold after stimulation with pilocarpine by iontophoresis. Skin specimens, cut into 100-,m-thick sections, were double-stained using primary antibodies specific for collagen and nervous fibers and secondary antibodies labeled with Cy3 and Cy5 fluorophores. Tridimensional digitized images were obtained from z-series of 2-,m-thick optical sections acquired with a confocal microscope. We found in all patients in the more distal sites definite signs of functional impairment of the small fibers. These data correlated with the skin innervation morphological findings that showed, in the same sites, a sensible loss of small fibers regarding both the epidermal free endings and the subepidermal neural plexus. Less severe morphological abnormalities were found in the proximal sites. The large fiber neuropathy in FA is well documented. Our data show a length-dependent involvement of small fibers in the pathological process. [source] Plaque progression and regression in atherothrombosisJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 2007B. IBANEZ Summary., Atherosclerotic disease is a pathological process characterized by the deposition of lipid and other blood-borne material within the arterial wall. The deposition of these materials and the subsequent thickening of the wall may significantly compromise the vessel lumen. Atherosclerosis is a diffuse disease with focal clinical manifestations that are the consequence of thrombotic complications on disrupted atherosclerotic lesions. Until recently, atherosclerosis development was envisaged as an incessant progressing process; however, new evidence has shown that atherosclerotic plaque homeostasis is not necessarily a constantly progressing process. There are many data showing that atherosclerotic plaque formation can be slowed, stopped or even reversed. Comprehension of the underlying mechanisms involved in the homeostasis of atherosclerotic plaque (progression/regression) should allow the development of interventions enhancing the regression pathway. Novel imaging technology has allowed the accurate evaluation of plaque progression, vital in the assessment of the efficacy of interventions. In this review we discuss the processes involved in the formation and progression of atherosclerotic lesions, the triggers for plaque disruption, as well as new therapies. We also deal with the potential pathways of plaque regression, as well as tools for accurate serial atherosclerotic quantification. [source] Medicinal chemistry approaches for the treatment and prevention of Alzheimer's diseaseMEDICINAL RESEARCH REVIEWS, Issue 1 2003S.O. Bachurin Abstract Alzheimer's disease (AD) is the most common form of dementia, which is characterised by progressive deterioration of memory and higher cortical functions that ultimately result in total degradation of intellectual and mental activities. Modern strategies in the search of new therapeutic approaches are based on the morphological and biochemical characteristics of AD, and focused on following directions: agents that compensate the hypofunction of cholinergic system, agents that interfere with the metabolism of beta-amyloid peptide, agents that protect nerve cells from toxic metabolites formed in neurodegenerative processes, agents that activate other neurotransmitter systems that indirectly compensate for the deficit of cholinergic functions, agents that affect the process of the formation of neurofibrillary tangles, anti-inflammatory agents that prevent the negative response of nerve cells to the pathological process. The goal of the present review is the validation and an analysis from the point of view of medicinal chemistry of the principles of the directed search of drugs for the treatment and prevention of AD and related neurodegenerative disorders. It is based on systematization of the data on biochemical and structural similarities in the interaction between physiologically active compounds and their biological targets related to the development of such pathologies. The main emphasis is on cholinomimetic, anti-amyloid and anti-metabolic agents, using the data that were published during the last 3 to 4 years, as well as the results of clinical trials presented on corresponding websites. © 2002 Wiley Periodicals, Inc. Med Res Rev, 23, No. 1, 48,88, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/med.10026 [source] Towards metabolic mapping of the human retinaMICROSCOPY RESEARCH AND TECHNIQUE, Issue 5 2007D. Schweitzer Abstract Functional alterations are first signs of a starting pathological process. A device that measures parameter for the characterization of the metabolism at the human eye-ground would be a helpful tool for early diagnostics in stages when alterations are yet reversible. Measurements of blood flow and of oxygen saturation are necessary but not sufficient. The new technique of auto-fluorescence lifetime measurement (FLIM) opens in combination with selected excitation and emission ranges the possibility for metabolic mapping. FLIM not only adds an additional discrimination parameter to distinguish different fluorophores but also resolves different quenching states of the same fluorophore. Because of its high sensitivity and high temporal resolution, its capability to resolve multi-exponential decay functions, and its easy combination with laser scanner ophthalmoscopy, multi-dimensional time-correlated single photon counting was used for fundus imaging. An optimized set up for in vivo lifetime measurements at the human eye-ground will be explained. In this, the fundus fluorescence is excited at 446 or 468 nm and the time-resolved autofluorescence is detected in two spectral ranges between 510 and 560 nm as well as between 560 and 700 nm simultaneously. Exciting the fundus at 446 nm, several fluorescence maxima of lifetime t1 were detected between 100 and 220 ps in lifetime histograms of 40° fundus images. In contrast, excitation at 468 nm results in a single maximum of lifetime t1 = 190 ± 16 ps. Several fundus layers contribute to the fluorescence intensity in the short-wave emission range 510,560 nm. In contrast, the fluorescence intensity in the long-wave emission range between 560 and 700 nm is dominated by the fluorescence of lipofuscin in the retinal pigment epithelium. Comparing the lateral distribution of parameters of a tri-exponential model function in lifetime images of the fundus with the layered anatomical fundus structure, the shortest component (t1 = 190 ps) originates from the retinal pigment epithelium and the second lifetime (t2 = 1,000 ps) from the neural retina. The lifetime t3 , 5.5 ns might be influenced by the long decay of the fluorescence in the crystalline lens. In vitro analysis of the spectral properties of expected fluorophores under the condition of the living eye lightens the interpretation of in vivo measurements. Taking into account the transmission of the ocular media, the excitation of NADH is unlikely at the fundus. Microsc. Res. Tech., 2007. © 2007 Wiley-Liss, Inc. [source] When does Parkinson's disease begin?,MOVEMENT DISORDERS, Issue S2 2009Carles Gaig MD Abstract Pathological and neuroimaging studies have shown that in Parkinson's disease (PD) there is a "subclinical" or "premotor" period during which dopaminergic neurons in the substantia nigra (SN) degenerate but typical motor symptoms have not yet developed. Post-mortem studies based on nigral cell counts and evaluating dopamine levels in the striata, and imaging studies assessing the nigrostriatal pathway in vivo, have estimated that this time period could last 3 to 6 years. In addition, emerging evidence indicates that the neuropathological process of PD does not start in the SN but more likely elsewhere in the nervous system: in the lower brainstem and the olfactory bulb, or even more distant from the SN, such as in the peripheral autonomic nervous system. Patients with PD frequently can present non-motor symptoms, such as hyposmia or constipation, years before the development of classical motor signs. The physiopathology of these "premotor" symptoms, though still unclear, is currently thought to be related to early involvement by the pathological process underlying PD of non-dopaminergic lower brainstem structures or autonomic plexuses. However, the answer to the question "when does PD start" remains uncertain. Here, we review clinical, pathological, and neuroimaging data related to the onset of the pathological process of PD, and propose that its onset is non-motor and that non-motor symptoms could begin in many instances 10 and 20 years before onset of motor symptoms. The variable course of the disorder once the motor symptoms develop, suggests that the start and progression of premotor PD is also highly variable andgiven the heterogeneous nature of PD, may differ depending on the cause/s of the syndrome. When and where the neuropathological process develops in PD remains uncertain. © 2009 Movement Disorder Society [source] Stanley Fahn Lecture 2005: The staging procedure for the inclusion body pathology associated with sporadic Parkinson's disease reconsideredMOVEMENT DISORDERS, Issue 12 2006Heiko Braak MD Abstract The synucleinopathy known as sporadic Parkinson's disease (PD) is a multisystem disorder that severely damages predisposed nerve cell types in circumscribed regions of the human nervous system. A recent staging procedure for the inclusion body pathology associated with PD proposes that, in the brain, the pathological process (formation of proteinaceous intraneuronal Lewy bodies and Lewy neurites) begins at two sites and continues in a topographically predictable sequence in six stages, during which components of the olfactory, autonomic, limbic, and somatomotor systems become progressively involved. In stages 1 to 2, the Lewy body pathology is confined to the medulla oblongata/pontine tegmentum and anterior olfactory structures. In stages 3 to 4, the substantia nigra and other nuclei of the basal mid- and forebrain become the focus of initially subtle and, then, severe changes. During this phase, the illness probably becomes clinically manifest. In the final stages 5 to 6, the lesions appear in the neocortex. This cross-sectional study originally was performed on 168 autopsy cases using material from 69 incidental cases and 41 clinically diagnosed PD patients as well as 58 age- and gender-matched controls. Here, the staging hypothesis is critically reconsidered and discussed. © 2006 Movement Disorder Society [source] Activation of STAT3 and inhibitory effects of pioglitazone on STAT3 activity in a mouse model of SOD1-mutated amyotrophic lateral sclerosisNEUROPATHOLOGY, Issue 4 2010Noriyuki Shibata Signal transducer and activator of transcription-3 (STAT3) is a member of the proinflammatory transcription factor STAT family. Several studies have documented implications for neuroinflammation in amyotrophic lateral sclerosis (ALS). We recently demonstrated activation of STAT3 in spinal cords obtained at autopsy from sporadic ALS patients. To determine the involvement of STAT3 and effects of pioglitazone on STAT3 activity in familial ALS with superoxide dismutase-1 (SOD1) mutation, we performed immunoblot and immunohistochemical analyses of the active form of STAT3 (p-STAT3) in spinal cords from mice overexpressing mutant SOD1 (ALS mice) and nontransgenic littermates (control mice). Immunoblot analysis delineated significant increases in nuclear p-STAT3 levels in non-treated ALS mice as compared with pioglitazone-treated ALS mice and non-treated and pioglitazone-treated control mice. Immunohistochemical analysis revealed prominent p-STAT3 accumulations in the nucleus of motor neurons, reactive astrocytes and activated microglia in non-treated ALS mice but not pioglitazone-treated ALS mice and non-treated and pioglitazone-treated control mice. The present results provide in vivo evidence for increased phosphorylative activation and nuclear translocation of STAT3 in motor neurons and glia in mouse motor neuron disease, suggesting a common pathological process between sporadic and SOD1-mutated familial forms of ALS. Moreover, it is likely that pioglitazone may exert inhibitory effects on STAT3-mediated proinflammtory mechanisms in this disease. [source] Phosphorylated and cleaved TDP-43 in ALS, FTLD and other neurodegenerative disorders and in cellular models of TDP-43 proteinopathyNEUROPATHOLOGY, Issue 2 2010Tetsuaki Arai Transactivation response (TAR) DNA-binding protein of Mr 43 kDa (TDP-43) is a major component of the tau-negative and ubiquitin-positive inclusions that characterize amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration which is now referred to as FTLD-TDP. Concurrent TDP-43 pathology has been reported in a variety of other neurodegenerative disorders such as Alzheimer's disease, forming a group of TDP-43 proteinopathy. Accumulated TDP-43 is characterized by phosphorylation and fragmentation. There is a close relationship between the pathological subtypes of FTLD-TDP and the immunoblot pattern of the C-terminal fragments of phosphorylated TDP-43. These results suggest that proteolytic processing of accumulated TDP-43 may play an important role for the pathological process. In cultured cells, transfected C-terminal fragments of TDP-43 are more prone to form aggregates than full-length TDP-43. Transfecting the C-terminal fragment of TDP-43 harboring pathogenic mutations of TDP-43 gene identified in familial and sporadic ALS cases into cells enhanced the aggregate formation. Furthermore, we found that methylene blue and dimebon inhibit aggregation of TDP-43 in these cellular models. Understanding the mechanism of phosphorylation and truncation of TDP-43 and aggregate formation may be crucial for clarifying the pathogenesis of TDP-43 proteinopathy and for developing useful therapeutics. [source] Polyglutamine disease: Recent advances in the neuropathology of dentatorubral-pallidoluysian atrophyNEUROPATHOLOGY, Issue 4 2006Mitsunori Yamada Polyglutamine diseases are hereditary neurodegenerative disorders that are caused by the expansion of a CAG repeat in the causative genes. They comprise at least nine disorders, including DRPLA, HD, and Machado-Joseph disease. Initially, the discovery of neuronal intranuclear inclusions (NIIs) in human brains and in a murine model of HD provided a plausible hypothesis that the expression of expanded polyglutamine stretches leads to NII formation, resulting in neuronal cell death in selective brain regions characteristic to each disease. Recent studies, however, suggest that nuclear dysfunction, especially transcriptional abnormalities caused by the diffuse intranuclear accumulation of mutant proteins, plays a pivotal role in the development and progression of clinical symptoms. Polyglutamine diseases have a similarity with neuronal storage disease, and this pathological process might become a target for the establishment of an effective therapy for these diseases. [source] Review: Familial Parkinson's disease , genetics, clinical phenotype and neuropathology in relation to the common sporadic form of the diseaseNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 3 2008Carola Schiesling The identification of the first gene in familial Parkinson's disease (PD) only 10 years ago was a major step in the understanding of the molecular mechanisms in neurodegeneration. Alpha-synuclein aggregation was not only recognized as a key event in neurodegeneration in patients carrying mutations in this gene, but it turned out to be the most consistent marker to define Lewy body pathology also in non-heritable idiopathic PD (IPD). Subsequent comprehensive pathoanatomical studies of IPD brains led to a novel concept of an ascending pathological process in variable stages that are reflected by alpha-synuclein aggregation at specific predilection sites. To date, more than seven genes are known to cause familial PD. The fact that these genetic forms of Parkinsonism present with clinical features indistinguishable from IPD, but may display neuropathological features that are not consistent with IPD, underscores the need of a more differentiated approach to familial and sporadic forms of Parkinsonism. Indeed, in distinct populations, mutations in one single gene were found to cause the disease in up to 40% of patients formerly described as ,idiopathic' cases. These findings indicate that IPD, as defined by a late-onset disorder with no (apparent) genetic contribution, is part of a clinical syndrome that becomes more and more heterogeneous in terms of aetiology, with overlapping clinical and pathoanatomical features. Thus in the present review, we discuss clues from familial PD to our understanding of the molecular pathogenesis of neurodegeneration with special consideration of the variable clinical and neuropathological aspects. [source] Signal-Averaged Electrocardiographic Parameter Progression as a Marker of Increased Electrical Instability in Two Cases with an Overt Form of Arrhythmogenic Right Ventricular CardiomyopathyPACING AND CLINICAL ELECTROPHYSIOLOGY, Issue 3 2002BARBARA BAUCE BAUCE, B., et al.: Signal-Averaged Electrocardiographic Parameter Progression as a Marker of In-creased Electrical Instability in Two Cases with an Overt Form of Arrhythmogenic Right Ventricular Cardiomyopathy. In arrhythmogenic right ventricular cardiomyopathy (ARVC) the fibrofatty substitution of the RV myocardium constitutes the substrate for reentrant circuits, leading to the onset of ventricular arrhythmias. This pathological process also accounts for "delayed ventricular potentials" that could be recorded as late potentials using the signal-averaged ECG technique (SAECG). This study examined two patients affected by overt forms of ARVC who showed a worsening of the electrical instability associated with a fast progression of SAECG parameters, while all the other clinical findings remained unchanged. This suggests a possible role of SAECG parameter progression as a marker of increased electrical instability. [source] Outcome in adulthood of asymptomatic airway hyperresponsiveness in childhood: A longitudinal population studyPEDIATRIC PULMONOLOGY, Issue 3 2002Finn Rasmussen MD Abstract The clinical outcome of asymptomatic airway hyperresponsiveness (AHR) first detected in childhood is sparsely reported, with conflicting results. We used a birth cohort of 1,037 children followed to age 26 years to assess the clinical outcome of asymptomatic AHR to methacholine first documented in study members at age 9 years. Of 547 study members who denied wheezing symptoms ever at age 9 years, 41 (7.5%) showed AHR. Forty showed methacholine responsiveness, with a provocation concentration of methacholine that elicted a 20% drop in forced expired volume in 1 sec (PC20),,,8 mg/mL, and one had baseline airway obstruction with a bronchodilator response exceeding 10%. Of these 41 study members, 18 (44%), 11 (27%), and 4 (10%) maintained AHR in 1, 2, and 3 later assessments, respectively, while 23 (56%) manifested AHR only at age 9. Compared with asymptomatic study members without AHR, those with asymptomatic AHR at age 9 years were more likely to report asthma and wheeze at any subsequent assessment, were more likely to have high IgE levels and eosinophils at ages 11 and 21, and more often demonstrated positive responses to skin allergen testing at ages 13 and 21 years. Persistent AHR at later assessments increased these likelihoods further. In conclusion, asymptomatic children with AHR are more likely to develop asthma and atopy later in life compared with asymptomatic children without AHR. Persistent AHR, even though initially asymptomatic, was associated with an even greater increased risk of development of asthma. We suggest that rather than considering AHR as a marker of asthma, it should be regarded as a parallel pathological process that may lead to subsequent symptoms and clinical evidence of asthma. Pediatr Pulmonol. 2002; 34:164,171. © 2002 Wiley-Liss, Inc. [source] Proteomic profiling of PrP27-30-enriched preparations extracted from the brain of hamsters with experimental scrapiePROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 15 2009Alessandra Giorgi Abstract Transmissible spongiform encephalopathies (TSEs) are neurodegenerative disorders characterized by the accumulation in the CNS of a pathological conformer (PrPTSE) of the host-encoded cellular prion protein (PrPC). PrPTSE has a central role in the pathogenesis of the disease but other factors are likely involved in the pathological process. In this work we employed a multi-step proteomic approach for the identification of proteins that co-purify with the protease-resistant core of PrPTSE (PrP27-30) extracted from brains of hamsters with experimental scrapie. We identified ferritin, calcium/calmodulin-dependent protein kinase , type II, apolipoprotein E, and tubulin as the major components associated with PrP27-30 but also trace amounts of actin, cofilin, Hsp90,, the , subunit of the T-complex protein 1, glyceraldehyde 3-phosphate dehydrogenase, histones, and keratins. Whereas some of these proteins (tubulin and ferritin) are known to bind PrP, other proteins (calcium/calmodulin-dependent protein kinase , type II, Hsp90,) may associate with PrPTSE fibrils during disease. Apolipoprotein E and actin have been previously observed in association with PrPTSE, whereas cofilin and actin were shown to form abnormal rods in the brain of patients with Alzheimer disease. The roles of these proteins in the development of brain lesions are still unclear and further work is needed to explain their involvement in the pathogenesis of TSEs. [source] High-resolution biomarker discovery: Moving from large-scale proteome profiling to quantitative validation of lead candidatesPROTEOMICS - CLINICAL APPLICATIONS, Issue 10-11 2008Johannes A. Hewel Abstract Diverse proteomic techniques based on protein MS have been introduced to systematically characterize protein perturbations associated with disease. Progress in clinical proteomics is essential for personalized medicine, wherein treatments will be tailored to individual needs based on patient stratification using noninvasive disease monitoring procedures to reveal the most appropriate therapeutic targets. However, breakthroughs await the successful development and application of a robust proteomic pipeline capable of identifying and rigorously assessing the relevance of multiple candidate proteins as informative diagnostic and prognostic indicators or suitable drug targets involved in a pathological process. While steady progress has been made toward more comprehensive proteome profiling, the emphasis must now shift from in depth screening of reference samples to stringent quantitative validation of selected lead candidates in a broader clinical context. Here, we present an overview of the emerging proteomic strategies for high-throughput protein detection focused primarily on targeted MS/MS as the basis for biomarker verification in large clinical cohorts. We discuss the conceptual promise and practical pitfalls of these methods in terms of achieving higher dynamic range, higher throughput, and more reliable quantification, highlighting research avenues that merit additional inquiry. [source] Hind-limb paraparesis in a rat model for neurolathyrism associated with apoptosis and an impaired vascular endothelial growth factor system in the spinal cordTHE JOURNAL OF COMPARATIVE NEUROLOGY, Issue 6 2010Kuniko Kusama-Eguchi Abstract Neurolathyrism is a motor neuron disease characterized by lower limb paraparesis. It is associated with ingestion of a plant excitotoxin, ,-N-oxalyl-L-,,-diaminopropionic acid (L -,-ODAP), an agonist of ,-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate-type glutamatergic receptors. Previously, a limited model of neurolathyrism was reported for the rat. To improve upon the model, we stressed rat pups by separation from their mothers, followed by the subcutaneous L -,-ODAP treatment, resulting in a 4.6-fold higher incidence (14.0,15.6%) of the paraparesis compared with the prior study. The number and size of motor neurons in these rats were decreased only in the lumbar and sacral cord segments, at approximately 13,36 weeks after treatment. Only lumbar and sacral spinal cord tissue revealed pathological insults typical of physical and ischemic spinal cord injury in the surviving motor neurons. In addition, extensive but transient hemorrhage occurred in the ventral spinal cord parenchyma of the rat, and numerous TdT-mediated dUTP-biotin nick end-labeling (TUNEL)-positive cells were also observed. In parallel, vascular endothelial growth factor receptor (VEGFR)-2 (Flk-1) levels were significantly lowered in the lumbosacral spinal cord of the paraparetic rats compared with their controls, suggesting a failure of the VEGF system to protect neurons against L -,-ODAP toxicity. We propose, based on these data, a novel pathological process of motor neuron death induced by peripheral L -,-ODAP. For the first time, we present a model of the early molecular events that occur during chemically induced spinal cord injury, which can potentially be applied to other neurodegenerative disorders. J. Comp. Neurol. 518:928,942, 2010. © 2009 Wiley-Liss, Inc. [source] ORIGINAL ARTICLE: Leptin on Peritoneal Macrophages of Patients with EndometriosisAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 3 2010Meng-Hsing Wu Citation Wu M-H, Huang M-F, Chang F-M, Tsai S-J. Leptin on peritoneal macrophages of patients with endometriosis. Am J Reprod Immunol 2010; 63: 214,221 Problem, The expression of cyclooxygenase (COX)-2 is considered as a marker of macrophage activation and has been implicated in the development of endometriosis. Leptin is an immunomodulator, which may also affect the development of endometriosis. However, how leptin contributes to these pathological processes has not been completely understood. The aim of this study was to investigate the effects of leptin on peritoneal macrophages and its relationship with endometriosis. Methods of study, Peritoneal fluid from 60 women of reproductive age was obtained while they underwent laparoscopy. Forty patients had endometriosis and 20 patients did not have endometriosis. The concentration of leptin in the peritoneal fluid and prostaglandin F2, levels was measured by ELISA, and the other protein expression using Western blot when peritoneal macrophages were stimulated with leptin. Results, Concentration of leptin in peritoneal fluid was increased in patients with endometriosis compared with disease-free normal control. Functional leptin receptor was present in peritoneal macrophages. Treatment of peritoneal macrophages with leptin induced COX-2 expression. Production of prostaglandin F2, by peritoneal macrophages was increased after leptin stimulation in women with endometriosis. Conclusion, Elevated concentration of leptin in peritoneal fluid may contribute to the pathological process of endometriosis through activation of peritoneal macrophages. [source] Nontherapeutic Male Circumcision: Tackling the Difficult IssuesTHE JOURNAL OF SEXUAL MEDICINE, Issue 8 2009Caryn L. Perera BA (Lib & Info Mgt), Grad Cert EBP ABSTRACT Introduction., Male circumcision is the most commonly performed surgical procedure in the world. Circumcision may be performed to treat an underlying pathological process ("therapeutic circumcision"). However there may be religious, cultural, and social indications. Aim., This article addresses the religious, cultural, social, and ethical issues surrounding nontherapeutic male circumcision (NTMC). Main Outcome Measures., Any religious, social, cultural, or ethical issues relating to NTMC. Methods., Because of the absence of high level evidence, a concise literature review was undertaken to identify articles published between January 1990 and February 2009 summarizing current knowledge on NTMC. Results., There are complex religious, cultural, social, and prophylactic incentives for NTMC. The procedure may have associated clinical and psychosocial adverse events and raises such ethical issues as bodily integrity and consent. Because of the strength of the incentives for NTMC, there may be important implications in denying patients the procedure. Several important issues must be considered when introducing mass circumcision as a preventative strategy for HIV/AIDS. Conclusion., When assessing whether NTMC will benefit or harm a patient, clinicians must take his religious, cultural, and social circumstances into account. Males requiring mandatory religious or cultural NTMC are likely to suffer significant harm if they do not receive circumcision and should be considered separately to males in general. Perera CL, Bridgewater FHG, Thavaneswaran P, and Maddern GJ. Nontherapeutic male circumcision: Tackling the difficult issues. J Sex Med 2009;6:2237,2243. [source] Dopaminergic transplantation for parkinson's disease: Current status and future prospects,ANNALS OF NEUROLOGY, Issue 5 2009C. Warren Olanow MD, FRCPC Cell-based therapies that involve transplantation into the striatum of dopaminergic cells have attracted considerable interest as possible treatments for Parkinson's disease (PD). However, all double-blind, sham-controlled, studies have failed to meet their primary endpoints, and transplantation of dopamine cells derived from the fetal mesencephalon is associated with a potentially disabling form of dyskinesia that persists even after withdrawal of levodopa (off-medication dyskinesia). In addition, disability in advanced patients primarily results from features such as gait dysfunction, freezing, falling, and dementia, which are likely due to nondopaminergic pathology. These features are not adequately controlled with dopaminergic therapies and are thus unlikely to respond to dopaminergic grafts. More recently, implanted dopamine neurons have been found to contain Lewy bodies, suggesting that they are dysfunctional and may have been affected by the PD pathological process. Collectively, these findings do not bode well for the short-term future of cell-based dopaminergic therapies in PD. Ann Neurol 2009;66:591,596 [source] Gray matter atrophy in multiple sclerosis: A longitudinal studyANNALS OF NEUROLOGY, Issue 3 2008Elizabeth Fisher Ph.D. Objective To determine gray matter (GM) atrophy rates in multiple sclerosis (MS) patients at all stages of disease, and to identify predictors and clinical correlates of GM atrophy. Methods MS patients and healthy control subjects were observed over 4 years with standardized magnetic resonance imaging (MRI) and neurological examinations. Whole-brain, GM, and white matter atrophy rates were calculated. Subjects were categorized by disease status and disability progression to determine the clinical significance of atrophy. MRI predictors of atrophy were determined through multiple regression. Results Subjects included 17 healthy control subjects, 7 patients with clinically isolated syndromes, 36 patients with relapsing-remitting MS (RRMS), and 27 patients with secondary progressive MS (SPMS). Expressed as fold increase from control subjects, GM atrophy rate increased with disease stage, from 3.4-fold normal in clinically isolated syndromes patients converting to RRMS to 14-fold normal in SPMS. In contrast, white matter atrophy rates were constant across all MS disease stages at approximately 3-fold normal. GM atrophy correlated with disability. MRI measures of focal and diffuse tissue damage accounted for 62% of the variance in GM atrophy in RRMS, but there were no significant predictors of GM atrophy in SPMS. Interpretation Gray matter tissue damage dominates the pathological process as MS progresses, and underlies neurological disabillity. Imaging correlates of gray matter atrophy indicate that mechanisms differ in RRMS and SPMS. These findings demonstrate the clinical relevance of gray matter atrophy in MS, and underscore the need to understand its causes. Ann Neurol 2008 [source] | |||||||||||||||||||||||||||||||||||||