What is Parkinsons Disease

The Parkinson's-Reversing Breakthrough

The Parkinson's Breakthrough Program entails the most effective and natural strategies people can use to heal the root cause of Parkinson's Disease. It is a digital manual aimed at showing the users the most effective method for overcoming Parkinson's without high-priced prescription drugs riddled with harmful side effects.The program was not created to be a quick fix. In fact, like different programs, it is tasking. Yet, you will not have to spend a lot of time dealing with it. The system requires your full attention, perseverance, and discipline. For the period of its usage, you will have the opportunity to use to eat some food ingredients that will detoxify you.The methods employed in this book are natural ones that have been proven by many specialists. The users will be privy to what to do and what not to do to treat the underlying root cause of their Parkinson's and the way they can reverse the symptoms naturally and effectively. The system comes with bonus E-books- Lessons from The Miracle Doctors, Mind Control in the USA', and 10 Deadly Health Myths of The 21st Century. The book is in a digital format (PDF) and has been created at a very affordable price. Read more here...

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Results in the VTA and Substantia Nigra

Using Western blotting, Nestler and colleagues found increased GluRl levels in the VTA of rats killed 16-18 h after discontinuation of repeated cocaine, morphine, ethanol, or stress paradigms (12,13). Increased GluR1 was not observed in the substantia nigra after repeated cocaine or morphine treatment (12). The substantia nigra was not examined in stress studies (12), but after repeated ethanol administration, there was a greater increase in GluR1 in the substantia nigra than in the VTA (13). Repeated cocaine also increased NR1 in VTA but had no effect on GluR2, NR2A B, or GluR6 7 (12). Churchill et al. (14) treated rats with saline or cocaine for 7 d (15 mg kg on d 1 and 7, 30 mg kg on d 2-6), measuring locomotor activity after the first and last injections those rats that showed > 20 increase in locomotor activity were defined as sensitized. Then, protein levels of glutamate receptor subunits were determined by Western blotting 24 h or 3 wk after daily injections were...

Proposed Diagnostic Criteria for Parkinsons Disease

Group A Characteristic of Parkinson's disease iii. Documentation of a lesion or condition associated with parkinsonism and plausibly connected to the patient's symptom (e.g., focal brain lesion or recent neuroleptic exposure). II. Possible Parkinson's disease C. Either substantial and sustained response to levodopa or a dopamine agonist has been documented Or Patient has not had an adequate trial of levodopa or a dopamine agonist. III. Probable Parkinson's disease C. Substantial and sustained response to levodopa or a dopamine agonist has been documented. IV. Definite Parkinson's disease A. All criteria for possible or probable Parkinson's disease are met And Adapted with permission from Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson's disease. Arch Neurol 1999 56 33-39.

Differential Diagnosis of Parkinsonism

Parkinson's disease is a progressive neurological disease with the following clinical characteristics. Asymmetric findings Levodopa response dyskinesia Lewy bodies The clinical heterogeneity of Parkinson's disease makes it difficult to differentiate it from other parkinsonian disorders based on the clinical criteria alone. The pathological examination may prove the diagnosis of Parkinson's disease wrong in 10 -15 of patients. Pathologically, Lewy bodies are present in pigmented neurons of the substantia nigra and other central nervous system areas. There is a therapeutic response to levodopa, which tends to support the diagnosis of Parkinson's disease (in over 77 of patients the response is good or excellent), but the drug cannot be used to differentiate reliably between Parkinson's disease from other parkinsonian disorders.

Twin Studies to Investigate the Cause of Parkinsons Disease

An example of the use of investigations in twins to understand more about a disease is provided by recent work in Parkinson's disease. Parkinson's disease (PD) is a progressive neurodegenerative disease causing slowness, tremor, and problems with walking and balance. PD is rare before age fifty but becomes more common thereafter, with increasing age. The cause of PD has long been debated. Both genetic and environmental causes have been suggested, but neither has been definitively shown. Researchers turned to studies in twins to determine the relative contribution of genes and environment to the disease. The first studies identified twin pairs by recruiting through physicians and PD patient organizations. Studies in the United States, the United Kingdom, and Germany identified 103 pairs, of which only thirteen were concordant for PD. In Finland, forty-two twins with PD were identified by records linkage, but among these was only one concordant pair a DZ pair. No study had convincingly...

Genes And Parkinsonism

Parkinsonism is a syndrome of rest tremor, rigidity, bradykinesia, loss of postural reflexes, and the freezing phenomenon.1-1-1 Most often, it is a manifestation of Parkinson's disease (PD), which is characterized neuro-pathologically by brainstem Lewy bodies. Recent epide-miological and molecular data suggest that this is not one disorder, but is comprised of at least several disorders with genetic, environmental, or mixed etiologies. Genes play a complex role in PD. Most twin studies, which are powerful tools in dissecting genetic from environmental contributions to the disease, have discounted a genetic influence in PD. However, it is difficult to draw solid conclusions from them because of methodological short-comings. 2 The largest of them, an unselected population-based cross-sectional twin study, has shown similar concordance for PD in monozygotic (MZ) and dizygotic (DZ) twin pairs with onset > 50 years, but a striking concordance in MZ pairs with onset < 50 years. 3 This...

Gender Differences In Pd And Clinical Endpoints

Anesthetic agents have also been investigated for gender-based differences in PD and clinical responses (212). Females have 20-30 greater sensitivity to the muscle relaxant effects of vecuronium, pancuronium, and rocuronium (100,101) compared with men in terms of doses. The exact reason for the gender differences in the sensitivity is still unclear. The authors (107) incline to the PK differences (diverse distribution) as the likely explanation. Again, proper PK-PD modeling might help in indentifying the reason for gender diversities in this case. Many psychotropic medications also appear to exhibit gender-mediated differences in PD (43,218-220). Women show greater improvement in psychotic symptoms and more severe side-effects with typical antipsychotic agents than do men (221). For example, women appear to need much lower doses of fluspirilene than men to treat schizophrenia (222). The gender differences in the antipsychotic treatment responses may be at least partially a result of...

Parkinsons Disease and Parkinsonian Syndromes

The majority of patients with PD or parkinsonian syndromes-in particular, multiple system atrophy (MSA)-complains of gastrointestinal and pelvic organ dysfunction. Stocchi et al 26 reported a similar occurrence of altered bowel frequency and defecation in PD and MSA patients. Gastrointestinal symptoms in PD include gastroparesis and constipation as a result of decreased bowel movement frequency and defecation difficulty. In all patients, these disorders became manifest or worsened after the onset of neurologic symptoms. The most striking features of bowel dysfunction in PD patients were constipation and difficulty in expulsion 27 . The prevalence of constipation in PD patients is high more than 50 suffer from moderate to severe constipation 27, 28 . PD patients are reported to have prolonged colorectal transit time and paradoxical contraction of the PR muscle on defecation 29, 30 . Difficulty in defecation is a very common symptom in PD, occurring in 67-94 of patients constipation is...

Parkinsons Disease Pd

Parkinson Disease Nervous System

The symptoms of 'the shaking palsy' were first described by James Parkinson in 1817. The disease most usually appears in the sixth decade of life though it may occur earlier. If the symptoms have not appeared by the age of 70 they are unlikely to do so. It is relatively common, affecting some 200 individuals per 100000. defect in the neurological control of movement. It has been known since the end of the nineteenth century that the control centres affected are deep in the brain stem and basal ganglia. The principal sites involved are the substantia nigra, corpus striatum, globus pallidus, subthalamic nucleus and thalamus. Most important is the pathway from the substantia nigra to the corpus striatum. As is only to be expected (think of the ice dancer or trapeze artiste) the 'wiring' responsible for so subtle a function as behavioural movement involves numerous feedback and feedforward loops (Figure 21.8). Furthermore, at least four neurochemical systems play a part dopaminergic,...

Parkinsons Disease

Albanese A, Diagnostic criteria for Parkinson's disease. Neurol Sci, 2003 24 S23-S26. Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson's disease. Arch Neurol 1999 56 33-39. Hedera P, Lerner AJ, Castellani R, Friedland RP. Concurrence of Alzheimer's disease, Parkinson's disease, diffuse Lewy body disease, and amyotrophic lateral sclerosis. J Neurol Sci 1995 128 219-224. Riley DE, Chelimsky TC. Autonomic nervous system testing may not distinguish multiple system atrophy from Parkinson's disease. J Neurol Neurosurg Psychiatry 2003 74 56-60.

Biomedical and Health Research

Hallen (Ed.), Human Genome Analysis Vol. 24. S.S. Baig (Ed.), Cancer Research Supported under BIOMED 1 Vol. 25. N.J. Gooderham (Ed.), Drug Metabolism Towards the Next Millennium Vol. 26. P. Jenner (Ed.), A Molecular Biology Approach to Parkinson's Disease Vol. 27. P.A. Frey and D.B. Northrop (Eds.), Enzymatic Mechanisms Vol. 28. A.M.N. Gardner and R.H. Fox, The Venous System in Health and Disease Vol. 29. G. Pawelec (Ed.), EUCAMBIS Immunology and Ageing in Europe Vol. 30. J.-F. Stoltz, M. Singh and P. Riha, Hemorheology in Practice Vol. 31. B.J. Njio, A. Stenvik, R.S. Ireland and B. Prahl-Andersen (Eds.), EURO-QUAL Vol. 32. B.J. Njio, B. Prahl-Andersen, G. ter Heege, A. Stenvik and R.S. Ireland (Eds.), Quality of Orthodontic

Role of the VTA in Behavioral Sensitization

Recently, we have shown that AMPA receptor supersensitivity can also be demonstrated in microdialysis experiments, by monitoring the ability of intra-VTA AMPA to activate VTA DA neurons and thus increase DA levels in the ipsilateral NAc. Using dual-probe microdialysis, we found that intra-VTA administration of a low dose of AMPA produced significantly greater DA efflux in the NAc of amphetamine-treated rats (11). This augmented response was transient (present 3 but not 10-14 d after the last injection) and specific for AMPA, as intra-VTA NMDA administration produced a trend toward increased NAc DA levels that did not differ between groups. Thus, both microdialysis and in vivo electrophysiological data suggest an enhancement of AMPA receptor transmission onto VTA DA neurons during the early phase of drug withdrawal. An increase in glutamate receptor expression would provide a simple explanation for such findings. For this and other reasons, a number of studies have...

Clinical Versus Pathological Dimensions of AD

A large body of evidence now points to the fact that the pathology of AD may represent an insidious process developing over as many as 15 to 20 years before there are any clinical manifestations (83-89). While there is ongoing discussion over which pathological marker (i.e, tangle burden, plaque count, synaptic loss) is most closely linked to dementia severity (90-95), there is no debate over the fact that overt clinical manifestations of the disease occur after the presence of significant neuropathological abnormality. In this regard, AD is similar to Parkinson's disease, in which 50-60 of the pigmented neurons in the substantia nigra pars compacta must be lost before the patient shows definite clinical signs (96).

Regulation of Adult Neurogenesis and Gliogenesis by Abused Substances

In contrast to decreased cell division after dopamine stimulation, dopamine depletion increases progenitor proliferation. Reduction of Dj 2 receptor tone with the antagonist haloperidol increases dentate granule cell proliferation in the gerbil hippocampus (38). Similarly, a single or repeated injection of the neurotoxin (MPTP), known to selectively damage dopaminergic terminals in the dorsal striatum and cell bodies in the substantia nigra, causes a robust proliferative response in striatal and nigral regions of adult mice (14,39). Nearly all newly generated cells in the striatum, but not in the nigra, rapidly differentiate into astrocytes, whereas no neurogenesis is seen in the two affected areas even 60 d after cell birth (14). Strong striatal astrogenesis after dopaminergic insult implies the participation of astroglia in dopamine repair. The unexpected lack of striatal and nigral neurogenesis after a long period of survival may be related to the extent of MPTP damage to midbrain...

Functional Roles of Adult Neural Progenitor Cells

Under pathophysiological conditions, inducible cytogenesis can play dual roles in a given pathophysiological process. First, cytogenesis can be provoked to process aberrant functions. For example, the neurons that are formed through normal ongoing neurogenesis do not send processes to the CA3 region of the hippocampus (44,45). However, epilepsy-induced neurogenesis sends axon collaterals back onto the dentate gyrus that forms recurrent collaterals contributing to enhanced local activity for epilepsy (44). Second and more significantly, cytogenesis can be stimulated to repair (rescue or compensate) for cell loss in chronic neurodegenerative diseases, such as Parkinson's disease. In this case, repopulation of missing cells by increased endogenous neurogenesis in the diseased site could be an ideal self-repair. The newborn cells after

Host Range and Virus Propagation

Natural infection with BDV has originally been shown to occur in horses, sheep, cattle and rabbits. Recently, cats, ostriches and various zoo ruminants have been identified as natural hosts. Reports on infection of other species, such as goat, deer and donkey, are rare, and BDV etiology has not been proven unequivocally, although such cases seem likely in view of the extremely broad experimental host spectrum of the virus. During recent years it has been proposed that BDV or a closely related virus might also be involved in infections of humans. There was a prevalence of seropositive reactions in patients with psychiatric disorders from Germany, the USA and Japan. The specificity of this reaction could be substantiated when a BDV-specific protein translated by RNAs which had been derived from a BDV-specific cDNA clone was used for the assay. Recently, the presence of virus-specific nucleic acid has been demonstrated in postmortem brain samples of schizophrenic patients and patients...

Pleiotropic Effects Of Creatine

Capacity for intracellular ATP and ADP concentrations, one could explain at least part of the Cr-dependent protection of cells from various stressors, especially the neuroprotective effects of Cr (see chapters 8-11 Stockler et al., 2007 Schulze and Battini, 2007 Tarnopolsky, 2007 Klein and Ferrante, 2007), by the classical beneficial effects of Cr in improving the cellular energy state. Cr supplementation mediates remarkable neuroprotection in experimental animal models of amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Parkinson's disease, and traumatic brain and spinal cord injury (see chapters 10 and 11 herein Tarnopolsky, 2007 Klein and Ferrante, 2007). Prophylactic Cr administration also mediates neuroprotection in cerebral ischemia in mice (Adcock et al., 2002 Prass et al., 2007 Zhu et al., 2004). Transgenic mice expressing high levels of BB-CK in liver cells, which normally express only very low levels of this enzyme, show a high degree of resistance to tumour...

Dementia With Lewy Bodies

Combining both features of a primary degenerative dementia and an akinetic-rigid, parkinsonian syndrome with prominent behavioral features, dementia with Lewy bodies (DLB) illustrates some of the shortcomings of current nosological schemata. Lewy bodies are the pathological hallmark of Parkinson's disease, where they are primarily restricted to substantia nigra and pigmented brainstem nuclei. However, the presence of Lewy bodies in the cerebral cortex coupled with behavioral symptoms, such as visual hallucinations, led to the recognition of DLB as a distinct syndrome. Complicating this assessment is the presence of AD pathology in about 50 of autopsies of clinically diagnosed cases of DLB, leading to the concept of a Lewy body variant of AD. A number of diagnostic criteria have been proposed and are summarized in Table 46. A number of studies, utilizing varying proportions of DLB cases have reported validity, and reliability of the clinical criteria of DLB, often in relation to...

Assessing the Value of Candidate Tests The Problem of No Gold Standard

Currently, cross-sectional designs are most commonly used to assess the accuracy of a proposed diagnostic marker. In one form of this research strategy, test results on a group of patients with a clinical diagnosis of AD are compared to test results on a group of matched, nondemented control subjects. In a related approach, test results of patients with probable AD are compared to test results of patients who carry a different clinical diagnosis such as mul-tiinfarct dementia or Parkinson's disease. This assessment strategy makes the most sense if the proposed test is being used to delineate a clinical dementia of the Alzheimer's type from clinical dementia of another etiology. The utility of this kind of approach in the evaluation of markers of underlying AD pathology is much less clear. Cross-sectional designs for evaluating the accuracy of a biological assay to identify underlying AD pathology are inherently flawed because of the difficulty of selecting an age appropriate sample of...

Role of Inflammation in Neurodegenerative Disorders

Previously, the brain has been considered an immune privileged environment partly owing to the existence of the brain-blood barrier. However, inflammatory responses in the brain have been increasingly associated with pathogenesis of several degenerative neurological disorders including Parkinson's disease (PD), Alzheimer's disease, AIDS dementia, and amyotrophic lateral sclerosis (ALS, 32-34).

Biology Of Microglia

These areas are concentrated around the subven-tricular zones where active neurogenesis occurs. These ameboid tissue macrophages then migrate throughout the entire brain parenchyma and differentiate into resident microglial cells. In the mature CNS, microglia are ubiquitously present as highly ramified cells (resting microglia) 5,6 . They respond to changes in the CNS microenvironment in a variety of disorders with or without the participation of the systemic monocytes. Although in degenerative disorders such as AD and Parkinson's disease there is little evidence to support recruitment of monocytes from the periphery, in infectious and autoimmune diseases such as HIVE and multiple sclerosis (MS) and in stroke, there is frank infiltration of monocyte-derived macrophages as well as other inflammatory cells. Even in these diseases in which monocytes are known to contribute significantly to the disease process, studies using sensitive markers of...

Microglial Activation Part of the Etiology of PD

The hallmark of PD is the progressive degeneration of the nigrostriatal dopaminergic system involving the loss of dopaminergic neurons in the substantia nigra and their fibers in the striatum. Sufficient damage to the dopaminergic pathways, over time, eventually leads to disorders in movement regulation. It has now been recognized that microglial activation is involved in the neurodegenerative process of PD (55-58). Furthermore, epidemiological studies appear to suggest that microglial activation, as a consequence of exposure to infectious agents and environmental toxins and occurrence of early-life traumatic brain injuries, may play a role in the early stage of the pathogenetic process of PD (59-64). Some of the important clues in favor of the hypothesis that microglial activation will result in dopaminergic neurodegeneration have come from experiments with neuron-glia cultures stimulated with the bacterial endotoxin LPS. Indeed, LPS neurotoxicity requires the presence of glia, and...

Ageing of the normal brain

A modest loss of brain volume occurs in normal ageing. In men, total brain volume at 60 is 10 less than at 25 years (Murphy et al 1992). This change affects cortical and subcortical white matter rather than grey matter (Guttmann et al 1998, Peters et al 1994) and is associated with myelin pathology in vertical fibres traversing deeper layers of the cortex. This myelin pathology will slow nerve conduction in association pathways, and may lead to functional deficits in reaction time and working memory (Peters 1996, Peters et al 1994, 2000). In the rhesus monkey, neurons of prefrontal cortex and substantia nigra show severe dendritic pathology, with loss of organelles, vacuolation of cytoplasm, membranous whorls and dense inclusion bodies (Siddiqi & Peters 1999, Peters et al 1998). There is a reduction of 30 60 in the density of apical synapses on pyramidal cells in prefrontal cortex. These changes correlate with age-related cognitive impairment (Peters et al 1996, 1998).

Therapeutical Approaches for HCM Are Symptom Oriented

A-cardiac actin (a-cAct), TNNT2, TNNI3, and TNNC1 for the cardiac troponins T, I, and C (cTnT, cTnl, and cTnC), and TPM1 for a-tropomyosin (a-TM). MYBPC3 encodes the cardiac myosin-binding protein C (cMyBP-C), TTN encodes titin, and CRP3 encodes the muscle LIM protein (MLP), which is a Z-disc protein stabilizing the contractile apparatus. Recently, a mutation in the promoter region of the phospholamban gene (PLN) has been reported. 8 Patients presenting FHC associated with the Wolff-Parkinson-White syndrome plus ventricular preexcitation exhibited mutations in PRKAG2, encoding the g2-regulatory subunit of AMP-activated protein kinase (AMPK), a metabolic protein.

Sensorimotor Examination

The sensorimotor neurological examination does not contribute to making a diagnosis of dementia per se. However, the pattern of neurological abnormalities often point to likely underlying diseases that may be contributing to the dementing process. For example, a clinician should look for evidence of upper motor neuron signs (e.g., hemiparesis, asymmetric deep tendon reflexes, extensor plantar responses) that would suggest the possibility of stroke or structural lesion. Extrapyramidal signs would raise the question of Parkinson's disease, progressive supranuclear palsy, or Lewy body dementia. Abnormalities of gait may be associated with cerebrovascular disease, Parkinson's disease, and normal pressure hydrocephalus. Dysarthria would alert the clinician to possible extrapyramidal disorders, bilateral strokes, de-myelinating disease, and motor neuron disease. Sensory abnormalities (e.g., peripheral neuropathy) may be associated with B12, other vitamin deficiency states, thyroid disease,...

Research Models of PD

Disturbance Gradual loss of TH-immunoreactive, dopaminergic neurons in the substantia nigra pars compacta Reduced level of striatal terminal DA, its metabolites and uptake transporter clinically responsive to DA prodrug, l-DOPA model should exhibit as many of the phenotypic features of the disease as possible. These features should include (1) persistent depletion of close to 80 of the striatal DA and its metabolites, (2) pronounced reduction of striatal sites for DA uptake, (3) significant (near 50 ) loss of substantia nigral cells, (4) marked deficit in the animal's motor performance, and (5) formation and accumulation of inclusion bodies in nigral neurons. There are several existing experimental models of PD, which have been developed and characterized for specific purposes and used in studies that examine certain symptomatology of PD or for determining the underlying mechanisms. These models include the unilateral 6-hydroxydopamine lesion rat produced by the chemical-induced...

Therapeutic Opportunities

Neuronal cell death in most neurodegenerative disorders, as well as in traumatic brain injury and spinal-cord damage, exhibits most of the hallmarks of apoptosis (reviewed in refs. 83-85). Limiting the extent of caspase activation in the target neuronal population may be therapeutically relevant in slowing the progression of Alzheimer's, Parkinson's, ALS, and Huntington's diseases, as well as in retinal degenerations and in the injured central nervous system (CNS) (see Chapter 14). Given that the IAPs have been demonstrated to suppress apoptosis initiated by virtually every trigger tested to date in tissue-culture cells (reviewed in ref. 23), their utility has been explored in in vivo model systems. Stereotactic injection of adenoviral expression vectors has been used to determine the protective effect of NAIP and XIAP in the rat hippocampus in the four-vessel occlusion global ischemia model. Suppression of caspase activation shortly after the ischemic event, as well as long-term...

Conditionspecific Measures for Fecal Incontinence

Three instruments have dominated measurement of HRQoL in FI. The Gastrointestinal Quality of Life Index (GIQLI) 11 , the Manchester Health Questionnaire 12 , and the FIQL scale 13 . Each of these instruments has been used successfully in the assessment of QoL associated with treatment for with FI. A number of other instruments have also been developed, but their utilization has not been as wide spread. This is in part due to the very specific nature of the instrument, e.g., QoL in a Parkinson's disease population 14 , clinical community epidemiology 15,16 , or children 17 .

Dose Selection for Phase II

In addition to examining dose or concentration response information from studies specifically designed to provide it, the entire database should be examined for possible desirable or undesirable PD effects that could be related to dose or concentration. If possible have an estimate from Phase I studies of the smallest dose that could provide any benefit. If quantifiable, select reasonable PD parameters to measure in Phase II in order to gain further information on the variability in PD and an early understanding of the influence of disease state on PD effects in Phase II. In addition, information about the relationship between PD and the proposed efficacy endpoint can be gathered in Phase II if not already known. The careful selection of PD endpoints or biomarkers are invaluable in understanding the dose or exposure response data as the development progresses from Phase I to II and reduces the likelihood of a failed Phase III study or a Phase III study where all doses rest on the...

Pathology and Histopathology

Experimental studies in mice and hamsters infected with WNV and SLEV have provided a substantial pool of information concerning the pathology of infection within the central nervous system. Prominent features seen by microscopy include neuronal necrosis, neuronophagia and perivascular cuffing, with infiltrations of mononuclear cells and the formation of microgleal nodules. In St Louis encephalitis, lesions may be found in the substantia nigra, the basal ganglia, brainstem, thalamus, spinal cord and cerebellum the cerebral cortex is usually less heavily damaged. In hamsters infected with SLEV, other organs such as the liver and heart may show extensive damage, but such lesions are rare in human St Louis encephalitis infections. Interstitial myocarditis has been reported in humans and horses infected with WNV, and the same virus has also been responsible for a small number of cases of fatal hepatitis in humans, with the development of lesions very similar to those seen in the liver of...

Psychiatric Disorders

Upon treatment with antipsychotic drugs, adverse reactions are more likely to be seen in PMs for CYP2D6. In addition, the costs for treatment of patients are higher and estimates have been made that costs 4000-6000 more per year to treat patients of the variant UM and PM phenotypes. 9 Parkinsonism-like side effects are

Synaptic Transmission

There are many other neurotransmitters. Many hormones serve this function, including epinephrin (adrenaline), ADH, oxytocin, insulin, and glucagon. The amino acids glycine, glutamine, and aspartic acid are neurotransmitters, as are the gases carbon monoxide and nitric oxide. A group of compounds called endorphins modifies the effect of neurotrans-mitters and may be involved in mood and pain reduction. They are similar in structure to morphine. It is thought that exercise produces a natural release of endorphins. Dopamine is a central nervous system neurotransmitter that can be inhibitory or excitatory, depending on the receptor. A decline in dopamine production produces Parkinson's disease, in which the inhibitory action of dopamine is missing. As a result, the neurons that control muscle tone become overstimulated. All movement requires overcoming the tension of the opposing muscle. Dopamine cannot cross the blood-brain barrier, but the drug L-dopa can, and it is converted to...

PET Imaging of Labeled Fatty Acid Incorporation into the Human Brain

Positron emission tomography (PET) has been used to quantify local glucose metabolism and blood flow in the human brain and to image brain receptor densities (Rapoport, 1995). However, to date, PET has not been employed successfully in humans to image signal transduction beyond the receptor, the downstream process by which neurotransmitters and drugs are closely linked to cognition and behavior (Cooper et al., 1996). In view of our results on dopaminergic and cholinergic signaling in normal and lesioned rodents (see Section 3.3.), a PET method for in vivo imaging of FA incorporation into the human brain might be of use for examining disrupted signaling in Alzheimer and Parkinson disease.

EncephalitisDRG cew 020

Complications from encephalitis can be short term or lifelong. Bronchial pneumonia and respiratory tract infections may complicate the course of encephalitis. Patients may go into a coma and experience all the complications of immobility, such as contractures and pressure ulcers. Other complications include epilepsy, parkinsonism, behavioral and personality changes, and mental retardation. A comatose state may last for days, weeks, or months after the acute infectious state.

Evolution Of The Histidylbenzylglycinamide Series

Ble potency reportedby Brown and Goldstein (8). Presumably because ofthe high degree ofhydrophobicity ofPD 083176, this inhibitor proved to be cell-impermeable and incapable of inhibiting cellular farnesylation at concentrations as high as 250 pM. A drug discovery effort focusing on the development of truncated analogs of PD 083176 was initiated in part because of the excellent potency of PD 083176 against FTase coupled with a reasonable degree of selectivity for this enzyme. (PD 083176 inhibits purified geranylgeranyl-transferase I (GGTase I) with an IC50 of 1.25 pM.) Microinjection experiments provided further impetus for pursuit of the PD 083176 series Xenopus oocytes injected with PD 083176 exhibited only a 32 maturation frequency in response to insulin, an event dependent on Ras function (9). In contrast, insulin treatment elicited a 68 positive response in the dimethyl sulfoxide (DMSO)-treated control group. These experiments provided evidence that members ofthe PD 083176 series...

Pathological Diagnostic Criteria Ruling Out Other Pathology

Pathological diagnosis of AD is often complicated by the presence of other pathology. In a subpopulation of pathologically confirmed cases of AD, abundant pathology characteristic of other neurodegenerative disorders, such as Parkinson's disease, are also present, allowing simultaneous diagnosis of both diseases in the same individual (1,2,56,57). Additional complications are presented by the presence of dementing disorders, which are relatively more dif

Biological Evaluation Of The Histidylbenzylglycinamides

Table 1 summarizes the biological properties ofthe key compounds that led to the synthesis of PD 169451. Efforts to improve the cellular permeability of this chemical series resulted in PD 152440, which inhibited cellular farnesylation at 5 yM, but proved to be nonselective against FTase relative to other prenylation enzymes (see Fig. 3). Because an increasing number ofliterature reports indicated that K-Ras was an efficient substrate for geranylgeranylation when challenged with an FTI, we proceeded with the in vivo evaluation of PD 152440 despite its lack of selectivity. Treatment of H-ras transfected Replacement of the O-benzyl group of PD 152440 with a phenyl ring resulted in PD 161956, which accomplished both increased potency (active against cellular farnesyla-tion at 0.1 .M) as well as a 50-fold gain in selectivity against FTase relative to GGTase I. Although PD 161956 gave the first indication ofin vivo antitumor activity for this chemical series, the degree ofactivity was...

The Neurological Continuum

Phenotypical continuum that includes some neurological signs even in patients with type I. Among the earliest anecdotal reports were those of parkinsonism that is marked by early onset, aggressive progression, and refractoriness to conventional anti-Parkinson therapy in patients with very mild type I Gaucher disease. 6

Insulin like Growth Factor IGFI

IGF-I is a polypeptide showing high similarity to insulin. Two different forms are distinguished IGF-I and IGF-II. IGF-I circulates in blood in the form of IGF-binding protein (IGF-BP), probably inhibiting activity of free IGF. IGF-I is a pivotal growth factor secreted as a result of stimulation by human growth hormone. Both in vivo and in vitro studies indicate its anti-apoptotic and anti-inflammatory properties (Goes et al., 1996 Sukhanov et al., 2007 Sun et al., 2010). There are reports that IGF-I has protective actions in ischaemic rat kidney due to inhibition of inflammatory cytokine production (Goes et al., 1996) and anti-apoptotic in Parkinson disease via inhibition of GSK-3P signalling pathway (Sun et al., 2010). IGF-I exerts its protective actions also in central nervous system and cardiomyocytes (Sun et al., 2010). In premature babies a small concentration of IGF-I is a risk factor of retinopathy of prematurity (Perez-Munuzuri et al., 2010). IGF-I deficiency after birth may...

Plants Affecting The Dopaminergic Neurotransmission

In normal physiological conditions, the dopaminergic neurons of the substancia nigra control the cholinergic output but if they do not, as is the case in Parkinsonism, the skeletal muscles experience tremors, rigidity, and akynesia. L-DOPA given by mouth is effective in restoring the ability to initiate movements and is the most effective treatment for this condition however, high doses are needed that produce nausea, vomiting, and hypotension. Because of the side effects associated with L-DOPA treatment, a number of dopamine receptor agonists have been tried including apomor-phine, and ergolines such as bromocriptine. Another alternative to treat Parkinsonism is the use of anticholinergic agents, such as crude extract of Atropa belladona L. (Solanaceae) and, more recently, anticholinergic alkaloids and their derivatives, which attenuate the tremor and relieve the muscular rigidity but are better to be used sparingly in elderly, as these these induce heavy nervous side effects. In...

Epidemiology and Diagnosis

In the history it is important, as well as asking about LUTS, to exclude any other co-morbidities that could be contributing to the presentation. It is important to exclude neurological disorders, including cerebrovas-cular events, multiple sclerosis (MS), spinal cord injury (SCI), pelvic or perineal trauma, Parkinson's disease, multisystem atrophy (MSA), and motor neuron disease (MND), and consider if they are taking any drugs that could contribute to dysfunctional voiding (anticholin-ergics, antidepressants, anesthetic agents, analgesics). Also, it is important to assess the patient's general medical state to ensure that they are not going to come to any harm as a result of any therapy instigated.

Bromocriptine Parlodel

Additionally, Parlodel is also prescribed to treat a wide variety of other medical conditions that are not related to fertility or women's health at all. Examples include Parkinson's disease, which is a neurological condition, and acromegaly, which is a rare condition where the body produces too much growth hormone.

Modeling And Simulations For Clinical Trial Designs

The technique of population PK and PD modeling is assumption-dense and depends on a clear understanding of the known PK behavior of a drug, the disease pathophysiology and biological framework within the context of drug action, and sound computational and statistical principles. The process of model building starts from pooling all available PK information from clinical studies to develop a structural population PK model. This would encompass, for example, all Phase I IIa studies to support dose regimen and trial design for Phase IIb. The next step, usually, is to determine which covariates of interest (e.g., age, gender, food, formulation, disease, creatinine clearance, BMI, and so on) may influence PK parameters of interest, for example, the clearance and or volume of distribution, such that a covariate-adjusted model is developed. Integration of the structural PK model with PD endpoint is then performed, wherein the endpoint may be a biomarker or surrogate for efficacy or for...

Use knowledge and experience to effectively drive and direct discovery

For every 50 entering preclinical development), even starting with a recombinant human protein with known activity is no guarantee of clinical and market success. For example, at Amgen, GDNF (glial-derived neurotrophic factor) has been demonstrated in vitro cell cultures to arrest death of or heal the brain cells associated with Parkinson disease and even dramatically improved the signs of parkinsonism in primate animal models. However, GDNF was a failure in human trials without significant improvement in the clinical signs and symptoms of the disease. Alternatively, an unexpected adverse effect from such a protein, which may very closely resemble the natural protein, can occur to stop its development. For example, a thrombopoietic factor for platelet disorders was found and was quite active but for some unknown reason produced antibodies against the not only the protein but also against the naturally occurring thrombopoietin, which was a life-threatening complication.

Newcastle Disease Virus iParamyxoviridae

Identification of viruses or virus-like agents (prions) in a variety of chronic neurological diseases has led to speculation of a viral etiology for multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, schizophrenia and other illnesses. Experimental evidence for viruses in these chronic diseases is still tenuous.

Neurological Abnormalities

Ing dysfunction include CVEs, cauda equina syndrome or spinal cord compression, Parkinson's disease, Shy-Drager syndrome (multisystem atrophy), multiple sclerosis (MS), and motor neuron disease (MND). Spinal cord injury also causes long-term voiding dysfunction, but rarely AUR. Most patients are, however, managed with an in-dwelling catheter after the initial injury, until the period of spinal shock has passed when a better idea of long-term bladder function can be ascertained.

Corticobasal Degeneration

First described in the 1960s, corticobasal degeneration is also known as cortical-basal ganglionic degeneration. It typically comes on as an asymmetric parkinsonian syndrome, most often in the sixth decade or later. Long considered a rare disorder, the description of additional cases and case series in recent years has widened the clinical spectrum. Cortical manifestations of corticobasal degeneration include not only dementia and alien limb sign, but also apraxia and cortical sensory loss. The basal ganglionic component includes parkinsonism and limb dystonia. There may be postural tremor and a focal reflex myoclonus. Dementia may be the presenting sign. Not all patients exhibit the alien limb sign throughout the clinical course.

Proposed Research Criteria for Corticobasal Degeneration

Early dementia, early vertical gaze palsy, rest tremor, severe autonomic disturbances, sustained responsiveness to levodopa, lesions on imaging studies indicating another pathological condition. Movement disorders akinetic rigid syndrome-levodopa resistant, and limb dystonia and reflex focal myoclonus. (Adapted with permission from Litvan I, Bhatia KP, Burn DJ, et al. SIC task force appraisal of clinical diagnostic criteria for Parkinsonian disorders. Mov Dis 2003 18 467-486, and from John Wiley and Sons.)

Multiplesystem Atrophy

Multiple-system atrophy is a progressive disorder with features of parkinsonism, cerebellar, autonomic, urinary, and corticospinal dysfunction. It is of unknown etiology. It most commonly affects middle-aged individuals, and both genders are affected equally. Disease course is variable and median survival from first symptoms is about 9 years. The parkinsonian features are usually unresponsive to levodopa therapy. There may be gait and limb ataxia, orthostatic hypotension, erectile dysfunction, constipation, and decreased sweating. Whereas multiple-system atrophy is a distinct neuropathological entity, the consensus diagnostic criteria depend on specific clinical features. Pathologically, glial cytoplasmic inclusions and degeneration are found throughout the basal ganglia, substantia nigra, brainstem autonomic nuclei, and Purkinje cells of the cerebellum.

Diagnostic Categories of Multiple System Atrophy

Possible MSA one criterion plus two features from seperate domains. When the criterion is Parkinsonism, a poor levodopa response qualifies as one feature (hence only one additional future is required). II. Probable MSA criterion for autonomic failure urinary dysfunction, plus poor levodopa-responsive Parkinsonism or cerebellar dysfunction.

Exclusion Criteria for the Diagnosis of MSA

AIn practice, multiple-system atrophy is most frequently confused with Parkinson's disease or progressive supranuclear palsy (PSP). Mild limitation of upward gaze alone is nonspecific, whereas a prominent (> 50 ) limitation of upward gaze of any limitation of downward gaze suggests PSP. Before the onset of vertical gaze limitation, a clinically obvious slowing of voluntary vertical saccades is usually easily detectable in PSP and assists in the early differentiation of these two disorders.

Serotonin 5hydroxytryptamine 5ht

Subjection of brain sections to this technique reveals that serotonin is localised in the mid-brain, the pineal gland, the substantia nigra and raphe nuclei of brain stem, and the hypothalamus. It can be detected in the varicosities (see Chapter 1) of fibres coursing up to the cerebral

Beth Levant 1 Introduction

The central nervous system (CNS) dopamine system plays an important role in mediating the reinforcing effects of drugs of abuse (1). In addition, dopamine receptors have been the principal target of drugs employed in the treatment of neuropsychiatry disorders such as schizophrenia and Parkinson's disease. Until 1990, the dopamine receptor population in the brain and periphery was believed to consist of two subtypes, Dj and D2, which were distinguished by their pharmacology and coupling to signal transduction systems (for review see ref. 2). Dj and D2 receptors exhibit similar distributions in brain with the highest densities in the striatum (for review see ref. 3). A number of selective radioli-gands have been synthesized and extensively used to characterize the classical dopamine receptor subtypes. These radioligands include the D1-selective ligands 3H SCH 23390 and 125I SCH 23982. D2 receptor-selective ligands include the antagonists 3H spiperone, 3H YM 09151-2, and 125I...

Progressive Supranuclear Palsy

First described by Steele, Richardson, and Olzweski in 1964, progressive supranuclear palsy (PSP) is also known by its acronym. The original descriptions focused on the parkinsonian movement disorder with progressive eye movement abnormality and frequent falls. Dementia also occurs as part of the clinical expression of PSP. PSP is almost never familial in nature. More recent investigations have tended to widen the scope of the clinical spectrum, and clinical overlaps occur, particularly with corti-cobasal degeneration. PSP may be misdiagnosed as PD or vascular dementia. False-negative diagnoses confirmed pathologically may include not only corticobasal degeneration but also multiple-system atrophy, central nervous system Whipple's disease, diffuse Lewy body disease, subcortical gliosis, and prion diseases.

Introduction Fatty Acids And Neuronal Excitability

In addition to their role in brain development, fatty acids also exert important modu-latory effects on neuronal excitability (Ordway, et al., 1991) and receptor-mediated signaling pathways (Hwang & Rhee, 1999). Fatty acids can either increase or decrease the firing of neurons, modulate neurotransmitter release, or alter synaptic responses (Meves, 1994 Bazan et al., 1996 McGahon et al., 1999 Leaf et al., 1999b). PUFAs have been shown to reduce neuronal sodium and calcium currents (Vreugdenhil et al., 1996) and inhibit or activate potassium channels (Poling et al., 1996 Keros & McBain, 1997 Horimoto et al., 1997). The PUFA docosahexaenoic acid (DHA) facilitates excitatory synaptic transmission mediated by W-methyl-D-aspartate (NMDA)-type glutamate receptors (Nishikawa et al., 1994). DHA also alters inhibitory neurotransmission in some neuron types (e.g., substantia nigra) by reducing responses to the inhibitory transmitter y-amino-butyric acid (GABA) (Hamano et al., 1996). It is...

National Institute of Neurological Disorders and Stroke and Society for Progressive Supranuclear Palsy Clinical

Symmetric akinesia or rigidity, proximal more than distal abnormal neck posture, especially retrocollis poor or absent response of parkinsonism to levodopa early dysphagia and dysarthria early onset of cognitive impairment including more than two of apathy, impairment in abstract thought, decreased verbal fluency, utilization or imitation behavior, or frontal release signs (Adapted with permission from Litvan I, Bhatia KP, Burn DJ, et al. SIC task force appraisal of clinical diagnostic criteria for Parkinsonian disorders. Mov Dis 2003 18 467-486.)

Diagnostic Classification

Fewer studies have examined the ability of functional imaging to differentiate AD from other dementias. Similar patterns of temporoparietal hypome-tabolism hypoperfusion have been reported in Parkinson's disease with dementia (PDD) (49-51). The overlap between AD and PDD may reflect the high incidence of Alzheimer's pathology found in patients with PDD (52). Two recent studies (53-54) demonstrated a distinct pattern of reduced occipital glucose metabolism in patients suspected to have dementia with Lewy bodies (DLB) as compared with AD. Parkinson's disease without dementia shows a metabolic pattern similar to normals (55).

Compression within the Spiral Groove of the Humerus

Lesions of the radial nerve occur most commonly in this region. The lesions are usually due to displaced fractures of the humeral shaft after inebriated sleep, during which the arm is allowed to hang off the bed or bench (Saturday night palsy), during general anesthesia, or from callus formation due to an old humeral fracture. There may be a familial history, or underlying diseases such as alcoholism, lead and arsenic poisoning, diabetes mellitus, polyarteritis nodosa, serum sickness, or advanced Parkinsonism.

Risk Taking and Substance Abuse

Diagram of the dopaminergic-basal ganglia systems. The substantia nigra sends dopaminergic neurons to the putamen and caudate. The ventral tegmental area sends dopaminergic neurons to the ventral striatum and to the cortex. Figure 9.1. Diagram of the dopaminergic-basal ganglia systems. The substantia nigra sends dopaminergic neurons to the putamen and caudate. The ventral tegmental area sends dopaminergic neurons to the ventral striatum and to the cortex. Dulawa, Grandy, Low, Paulus, and Geyer (1999) reviewed and summarized the reports that demonstrated reward is related to an increase in the activity of the neurotransmitter dopamine. They also reviewed the evidence that in animals, dopamine modulates the degree of exploratory behaviors. Patients with Parkinson's disease have reduced production of dopamine, and patients with Parkinson's disease report diminished responses to novelty. Some, but not all, studies have even reported that polymorphisms of the human dopamine D4...

Multiple System Atrophy

Multiple system atrophy (MSA) is characterized clinically by a combination of parkinsonian, pyramidal, cerebellar, and autonomic symptoms. In contrast to Parkinson's disease, rest tremor is usually absent, and the findings are relatively symmetric. The autonomic symptoms are disabling and help differentiate MSA from other parkinsonian disorders. The pathological features include cell loss and gliosis in the striatum, substantia nigra, locus ceruleus, inferior olives, pontine nuclei, dorsal vagal nuclei, Purkinje cells of the cerebellum, and Onuf's nucleus of the caudal spinal cord. Neurochemically, low levels of dopamine in the substantia nigra and striatum have been shown in postmortem studies. Putaminal T2 hypointensity Oculomotor deficit Levodopa response Lewy bodies Gait disturbance Dysarthria dysphagia Putaminal T2 hypointensity Levodopa dyskinesia Lewy bodies

Dominantly Inherited PD

Golbe et al. 7 described the first large kindred of autosomal dominant PD with autopsy verification in 1990 and later reported a clinical genetic analysis of 60 individuals in five generations. The kindred originated from Contursi, a hill town in the Salerno province of the southcentral region of Italy. There was severe neuronal loss and Lewy bodies in the substantia nigra, typical of PD. Mean age at onset was 46.5 years 15 years younger than that of PD in the community and the disease had a rapid course, averaging 9.7 years from onset to death. Contrary to observations in the initial report of the pedigree, rest tremor was frequent, present in 58.1 . Most of the affected individuals responded well to levodopa and exhibited its usual motor complications. Most also developed cognitive impairment toward the end of the illness. At the time, a number of other pedigrees of dominantly inherited parkinsonism had been described, some with clinical and neuropathological features similar to...

What Do Genes In Autosomal Dominant Pd Tell Us About Pathogenesis

Autosomal recessive parkinsonism, which have occurred in parallel with the finding of dominant genes and are outside the scope of this article. The subject has been recently reviewed. 26,27 Derangements in protein handling seem to be central in the pathogenesis of PD (Fig. 1). a-Synuclein is a small protein characterized by imperfect repeats (KTKEGV) distributed through most its amino-terminal half of the polypeptide that also includes a hydrophobic middle region and an acidic carboxy-terminal region. Its function is not established but it is believed to modulate synaptic vesicle turnover and synaptic plasticity. In vitro, it polymerizes into 10-nm fibrils, which are a major component of nigral Lewy bodies and Lewy neurites in PD and other forms of parkinsonism. It is unfolded in its native state but becomes structured on binding to lipid membranes. In the unfolded form, it is degraded by proteosomes in a ubiquitin-independent manner. In diseases where it aggregates, it forms a...

Diffuse Lewy Body Disease

Diffuse Lewy body disease (DLBD) is considered to be a variant or overlapping condition lying between Alzheimer's disease and Parkinson's disease. Clinical differentiation may therefore be difficult. In most patients with DLBD, however, psychosis and dementia are often found to precede parkinsonism (gait disturbance, rigidity, and resting tremor). The differentiation between DLBD and other parkinsonian syndromes, especially progressive supranuclear palsy, is particularly difficult when a patient with parkinsonism and dementia is also found to have oculomotor deficit. Neuroimaging studies, including magnetic resonance imaging (MRI) and positron-emission tomography (PET) scanning, cannot reliably differentiate between Parkinson's disease, Alzheimer's disease, and DLBD. Immunocytochemical staining techniques using antibodies against ubiquitin have improved the identification of Lewy bodies. More than 30 of patients with Alzheimer's disease have Lewy bodies in the cortex and substantia...

Mean LOS 63 days Description Medical Degenerative Nervous System Disorders

Parkinsonism is a clinical condition that is characterized by the following gradual slowing of voluntary movement (bradykinesia) muscular rigidity stooped posture distinctive gait with 698 Parkinson's Disease short, accelerating steps diminished facial expression and resting tremor. Parkinson's disease occurs with progressive parkinsonism in the absence of a toxic or known etiology and is a progressively degenerative disease of the substantia nigra and basal ganglia. Parkinson's disease is also called paralysis agitans. Degeneration of the substantia nigra in the basal ganglia of the midbrain leads to depletion of the neurotransmitter dopamine, which is normally produced and stored in this location. Dopamine promotes smooth, purposeful movements and modulation of motor function. Depletion of dopamine leads to impairment of the extrapyramidal tracts and consequent loss of movement coordination.

Discharge And Home Healthcare Guidelines

Be sure the patient or caregiver understands all medications, including the dosage, route, action, and adverse reactions. Avoid the use of alcohol, reserpine, pyridoxine, and phenothiazine while taking levodopa. In general, recommend massage and relaxation techniques, and reinforce exercises recommended by the physical therapist. Several techniques facilitate mobility and enhance safety in Parkinson's disease patients. Instruct the patient to try the following strategies (1) To assist in maintaining balance, concentrate on taking larger steps with feet apart, keeping back straight and swinging the arms (2) to overcome akinesia, tape the frozen leg to initiate movement (3) to reduce tremors, hold objects (coins, keys, or purse) in the hand (4) to obtain partial control of tremors when seated, grasp chair arms (5) to reduce rigidity before exercise, take a warm bath (6) to initiate movement, rock back and forth (7) to prevent spine flexion, periodically lie prone and avoid using a neck...

Fecal Incontinence in Disease Mainly Affecting the Brain

Loss of control of the ascending and descending pathways induced by lesions in the CNS may present with urinary and fecal incontinence. Any supraspinal lesion of brain, brainstem, and spinal cord rostral to the sacral Onufs nucleus-including cerebrovascular disease, hydrocephalus, intrinsic or extrinsic tumors, traumatic head injury, multiple sclerosis, Parkinson's disease (PD) and other neurodegenerative diseases, and spinal cord injury (SCI)-may affect voiding and fecal continence.

General considerations

Note *Pergolide and cabergoline are ergoline dopamine agonists. Recently, an increased risk of valvular fibrosis during treatment with these substances has been reported in patients with Parkinson's disease 69 . Therefore, the use of this group of dopamine agonists is considered today as a third line treatment option. recommended and all causes of secondary RLS, such as iron deficiency, should be excluded. The treatment of RLS is guided by clinical symptoms, and it usually results in improvement of RLS and the RLS-related sleep disturbances. Dopaminergic agents (in particular the dopamine agonists ropinirole, pramipexole, and rotigotine) are considered to be the treatment of choice in RLS and PLMD however, their exact mechanism of action is not understood 65,66 (see also Table 8.5). The dosage of dopamine agonists used in RLS is usually much lower than in the treatment of Parkinson's disease. Contrary to the treatment of Parkinson's disease, medication is usually given only in the...

Disinfection of the Transfer Set during a Change

The use of Amuchina 50 solution versus povidone-iodine 10 solution for transfer set change in PD patients was first described by Cabralda et al. 23 . No episode of peritonitis occurred related to transfer set change using povidone-iodine or Amuchina 50 . The soaking time with Amuchina 50 was 2 min and the nursing time was 5 min compared to 10 min soaking time and 20 min nursing time for povidone-iodine. Transfer set change used 20-30 ml of Amuchina solution compared to 120 ml povidone-iodine. The procedures for using sodium hypochlorite or povidone-iodine as disinfectants during transfer set replacement are included in table 1.

Possible Mitochondrial DNA Markers

Mitochondrial tRNA 4336G variants Possible association with AD and Parkinson's disease Possible association with AD Somatic mitochondrial 4977 nt deletions a1-ACT, a antichymotrypsin AD, Alzheimer disease ApoE, apolipoprotein E APP, amyloid precursor protein CYP2D, cytochrome P4502D variant Dx, diagnostic EOFAD, early onset familial Alzheimer disease FTDP-17, frontotemporal dementia and Parkinsonism linked to chromosome 17 Gm allotype, marker on IgG heavy chains HLA, human leukocyte antigens LOAD, late onset Alzheimer disease LOFAD, late onset familial Alzheimer disease LRP, an apolipoprotein E receptor PREDT, predictive PS-1 and PS-2, presenilin 1 and 2 rRNA, ribosomal RNA Rx, treatment SDAT, senile dementia of the Alzheimer type SP, specificity ST, sensitivity. information about diagnostic accuracy from ref. 321. & family history of Parkinson disease & family history of Parkinson disease

Pglycoprotein Gene Polymorphisms And Their Implications In Drug Therapy And Disease

An association was reported between the response of epilepsy patients to drug treatment and the C3435T polymorphism in the MDR1 gene.228 Patients with seizures that were not controlled by drugs were more likely to be homozygous for the C-variant allele, which is associated with higher Pgp transport function, suggesting that the drugs have a lower efficiency of penetration across the blood-brain barrier in this group. However, two later studies failed to confirm these results.229'230 The anti-Parkinson drug budipine is exported actively out of the brain by Pgp in mice,231 and Parkinson's disease susceptibility has been linked to Pgp polymorphisms in Chinese populations, where a MDR1 haplotype containing the SNPs 2677T and 3435T was found to protect against the disease.232

The Complexity Of Cell Death In Neurodegeneration

Early in the field of cell death, two distinct forms of cell death were noted necrotic, or bursting of the cell membrane, and apoptotic, wherein the cell membrane remains intact and the nuclear material is digested in a methodical manner. However, morphological analyses of both human tissue and animal models of neuronal diseases have indicated a wide range of neuronal cell-death capabilities. Although some similarities to other model systems exist, an alarming amount of disparity appears to be uniquely neuronal. Additionally, many of the biochemical processes observed in non-neuronal systems is paralleled in neuronal systems, but the morphological outcome can be vastly different. Here, we will limit the discussion of neurodegenerative diseases to the morphological, biochemical, and molecular aspects of cerebral ischemia, Parkinson's disease, and Huntington's disease as diverse examples of the different modalities of cell death in the adult nervous system. PARKINSON'S DISEASE...

Pk Differences Between Males And Females

Although the FDA mandated in 1998 that new drug applications must include data on safety and effectiveness by gender, a 2001 U.S. General Accounting Office investigation revealed that over one-third of the FDA-approved drugs in the preceding two years failed to provide such gender-specific information (36). Although women may be increasingly represented in clinical trials, failure to analyze gender-related differences in PK, side-effects, and efficacy limits the generalizability of such data to women. The importance of studying gender-based differences in PK, PD, and efficacy safety is demonstrated by the increasing data on gender-related variation in basic processes involved in linking drug administration to clinical response. Gender-based differences in the major processes that contribute to interindividual PK variability (bioavailabil-ity, distribution, metabolism, and elimination) are theorized to stem from variations between men and women in factors such as body weight (BW),...

Reaction of Catechol OMethyltransferase

The steady-state kinetic studies show that the action of soluble COMT follows an ordered binding mechanism (fig. 15-7B). SAM binds first, followed by Mg2+ and then the methyl acceptor (Lotta et al., 1995). COMT is a drug target, primarily to depress its activity against l-DOPA, which is the leading therapeutic agent prescribed for Parkinson's Disease. Very potent, slow-binding inhibitors bind with Mg2+-dependence (Bonifacio et al., 2002). The most efficacious inhibitors can suppress the tissue activity of COMT by more than 75 when administered to mice.

The Frontal Lobes and Aging

The reason why older people have a propensity to get stuck in set or be mentally rigid is unclear, but there at least two possibilities. As I mentioned earlier, neurons communicate by giving off chemicals called neurotransmitters. One of the major neurotransmitters that appears to decrease with aging is dopamine. For example, Volkow et al. (2000) who with functional imaging (PET) found that with aging there was a decrease of dopamine and a decrease of frontal lobe activation. The cells that give off dopamine are found in the midbrain and from the midbrain travel to both the basal ganglia and the cerebral cortex (see Figure 9.1). Patients with Parkinson's disease have a reduced level of dopamine, and they also have evidence for frontal lobe dysfunction (Green et al., 2002). For example, patients with Parkinson's disease often perform poorly on tests such as the Wisconsin Card Sorting Test, frequently getting stuck in set, and thus the reduced creativity seen with aging might be related...

Restless Legs Syndrome

Restless legs syndrome (RLS) features nocturnal involuntary limb movements that can cause insomnia because of frequent sleep disruption, and often affects bed partners because of frequent myoclonic-type jerking. It generally begins in early adulthood and affects from 2 to 5 of the population. RLS may run in families, with susceptibility genes identified on chromosomes 12q and 14q. RLS has also been associated with Parkinson's disease, pregnancy, end-stage renal disease, iron deficiency anemia, peripheral neuropathy, and diabetes.

Applications of Microarray Analysis

Microarrays are new enough that their applications are still being developed. Microarray expression analysis can be used to help study complex, multigenic diseases such as Parkinson's disease (PD). The great challenge in understanding the genetics of such disorders is identifying susceptibility genes, which are genes that increase a person's risk of developing the dis-linkage analysis exami- ease. Frequently, the first step in discovering a susceptibility gene is linkage analysis. This technique can identify regions of a chromosome that harbor such a gene, but the regions that are identified are frequently very disease genes large, containing hundreds of genes. Screening through all of these genes Brain tissue can be collected through anatomical donations from patients with Parkinson's disease and from unaffected individuals, for example. Regions of the brain that are especially affected in Parkinson's patients can be compared to the same regions from unaffected individuals. Genes...

Cellular Circuits Of The Cerebellum

FIGURE 1 Comparison of connections of the basal ganglia (A) and cerebellum (B). The basal ganglia and the cerebellum have many commonalties and influence motor function in similar ways. Excitatory input from broad areas of the cerebral cortex drive spiney neurons in the neostriatal region of the basal ganglia (A) and also relay nuclei in the pons, which then excite Purkinje cells of the cerebellar cortex (B). Both spiney neurons and Purkinje cells release y-aminobutyric acid (GABA) to inhibit relay neurons in the globus pallidus substantia nigra (A) or in the deep cerebellar nuclei (B). In turn, these relay nuclei project to the thalamus, where they modulate thalamic inputs to specific motor areas of the cerebral cortex.

Viral Heparin Binding Complement Inhibitors A Recurring Theme

The amino acid sequence of VCP predicts 4 putative heparin binding sites based on conserved surface exposed K R-X-K R motifs and a net overall positive charge (Smith, Mullin, Parkinson, Shchelkunov, Totmenin, Loparev, Srisatjaluk, Reynolds, Keeling, Justus, Barlow and Kotwal 2000). However, only two of these binding sites (one at the C-terminal end and the other at K64, R65, R66 in CCP1 combined with the CCP 1-2 linker region) had realistic heparin-binding potential based on the solved X-ray crystal structure and modeling based on fibroblast growth factor in complex with heparin (Murthy et al. 2001). Eventually the X-ray crystallographic structure for VCP bound to heparin was solved (Ganesh et al. 2004) and only found the binding site in CCP4 occupied. Binding to heparin did not alter the conformation of CCP1-3, but induced a 29.5 degree rotation of the CCP3-4 hinge region. Whether or not the heparin-induced change in CCP4 position, relative to the rest of VCP, is important to...

The Neuroprotective Role Of Creatine

Abstract Significant progress has been made in identifying neuroprotective agents and their translation to patients with neurological disorders. While the direct causative pathways of neurodegeneration remain unclear, they are under great clinical and experimental investigation. There are a number of interrelated pathogenic mechanisms triggering molecular events that lead to neuronal death. One putative mechanism reported to play a prominent role in the pathogenesis of neurological diseases is impaired energy metabolism. If reduced energy stores play a role in neuronal loss, then therapeutic strategies that buffer intracellular energy levels may prevent or impede the neurodegenerative process. Recent studies suggest that impaired energy production promotes neurological disease onset and progression. Sustained ATP levels are critical to cellular homeostasis and may have both direct and indirect influence on pathogenic mechanisms associated with neurological disorders. Creatine is a...

Other Cerebrospinal Fluid Abnormalities in Alzheimer Disease

Ferritin increased compared to Parkinson's patients and controls 195 dementia levels correlate negatively with stage of severity of AD IL-1 increased in sporadic AD and in de novo Parkinson's patients 28 IL-6 significantly decreased in early onset AD increased in sporadic 417 AD and in de novo Parkinson's patients increased in AD, AIDS 28 Indicators of mitochondrial function lactate significantly increased 314 succinate, fumarate and glutamine significantly decreased Neurotransmitters and their metabolites Nitrate levels decreased in AD, Parkinson's and multiple systems 196

Neurodegenerative disorders

Various neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, other dementias of varied causes, and multiple system atrophy, all commonly have sleep disruption and EDS as manifestations 58-60 . Patients with neuromuscular disorders or peripheral neuropathies have an increased incidence of sleep-related breathing disorders (central or obstructive apnea), pain, and PLMS, and may develop EDS as a result of disrupted sleep from these associated conditions 61 . Patients with myotonic dystrophy often suffer from EDS, even in the absence of sleep-related breathing disorders 62 .

Intracranial Self Stimulation

Intracranial self-stimulation is a behavioral paradigm whereby subjects carry out an operant task to receive direct electrical stimulation of specific regions of their brains (19). Stimulation of the regions including the mesencephalic dopaminergic cell bodies or of the lateral hypothalamus that includes the ascending dopaminergic pathways are both reinforcing in this paradigm. It is believed that dopamine is involved in the reinforcing properties of this behavior, as it can be abolished by selective lesion of dopaminergic neurons (20). To investigate further the role of dopamine, fast-scan cyclic voltammetry was used to monitor dopamine in terminal regions during intracranial self-stimulation of the ventral tegmental area substantia nigra.

Pathophysiological and Behavioral Aspects

Further studies investigating pathophysiological mechanisms of FI is of crucial importance because progress will have an impact on both diagnostic and therapeutic strategies. Due to the possible multifactorial origin of FI and the existence of different clinical presentations, basic research into the influence played by each of the numerous factors involved in continence control can be of help 2 . Future studies must consider that the traditional assumption that women younger than 65 years of age are at maximum risk of FI because of obstetric trauma to anal sphincters or pudendal neuropathy is not true 3 . Prevalence of FI in men has been certainly underestimated. Also, other causative factors, different than those secondary to childbirth, have to be of primary interest, these being neuropathies (diabetes, multiple sclerosis, Parkinson's disease, spinal cord injury, systemic sclerosis, myotonic dystrophy, amyloidosis) and conditions related to idiopathic FI. Moreover, conditions...

Clinical Presentation

Neurological manifestations of Wilson disease typically develop later in life, most often in the third decade, but may also occur in children. The spectrum of symptoms range widely from discrete tremor, dysarthria, and lack of motor coordination to severe pseudobulbar palsy. Because of affection of the basal ganglia clinical signs of Parkinson disease such as micrographia, hypersalivation, hypomimia, and rigid dystonia may occur. Psychiatric manifestations include behavioral changes and deteriora

Basic Protocol Searching Omim Over The Internet

Consider the case where one wants to retrieve all of the entries involving the SNCA gene in Parkinson's disease. Within the text box to the right, one would simply type SNCA GENE AND PARKINSON DIS At the time of this writing, the query returns two entries in this case one for Parkinson Disease, Familial, Type 1 ( 601508), the second for Synuclein, Alpha (*163890), as shown in Figure 1.2.1. The search would produce two entries regardless of the order of the search terms. The numbers above each description are the OMIM accession numbers for these entries their significance is described below (see Understanding the Database Record). NCBI's Genes and Diseases. NCBI's Genes and Diseases database is an extremely useful database for physicians, researchers and scientists alike. This database is part of an ongoing effort to map and characterize diseases caused by the mutation in one gene or a result of mutations in several genes such as asthma and diabetes. The Genes and Disease site linked...

Huntingtons Disease Chorea Hd

It has been found that in many cases agents such as l-dopa aggravate the symptoms whilst drugs that block dopaminergic synapses, for instance haloperidol, or inhibit dopamine synthesis, for example reserpine, are able to reduce the symptoms. It seems, therefore, that the symptoms of HD are the consequence of an excess of dopamine. We shall see in Section 21.9 that parkinsonism is, in contrast, due to lack of dopamine. The choreas are thus often regarded as inverse parkinsonisms.

Medicinal Sapindaceae

Sapindus Mukorossi Gaertn

The main mechanism of action of caffeine occurs via the blockade of adenosine receptors in the CNS. Adenosine is an autacoid, which is involved in the modulation of behavior, oxygenation of cells, and dilatation of cerebral and coronary blood vessels and indirectly inhibits the release of dopamine. The blockade of adenosine receptors by caffeine increases the activity of dopamine, which is implicated in the effects of caffeine (91). The question that arises from this observation is to know whether or not adenosine antagonists hold potential for the treatment of Parkinsonism, and further study on the adenosine receptor antagonists from medicinal plants should be encouraged. A possible source for such agents could be the medicinal flora of Asia and the Pacific, among which is the family Sapindaceae.

Edmund A Bermudez Md Mph and Ming Hui Chen MD MMSc

Stress Echocardiography Protocol

Stress echocardiography is indicated in the diagnosis of coronary artery disease in those with an intermediate likelihood of coronary artery disease and an abnormal electrocardiogram (Fig. 1, Table 1). Those individuals with left bundle branch block, Wolff-Parkinson-White syndrome, left ventricular hypertrophy, digoxin use, or more than 1 mm ST segment depression on electrocardiogram should undergo imaging with stress as interpretation of ST segments are an unreliable marker of ischemia in these settings. If the patient is able to exercise, treadmill stress, or bicycle stress (supine or upright) should be performed. When this is not feasible, dobutamine stress may be used. In the United States, vasodilator stress is an uncommon modality for stress echocardiography.

Neurotransmitters And Neuromodulators

Complexity of synaptic structure of the brain. Infelicity of 'telephone exchange' image. Fuzzy distinction between neurotransmitters and neuromodulators. Ionotropic and metabotropic responses, punctate and diffusional transmission. Criteria for neurotransmitters. Neurotransmitters Acetylcholine synthesis - localisation - pharmacology - reuptake - feedback control - pre- and postsynaptic AChRs. Amino acids excitatory (glutamate, aspartate) -synthesis - wide distribution - NMDA - reuptake inhibitory (GABA, glycine) - synthesis -ubiquity - reuptake. Serotonin (5-HT) synthesis - localisation - varicosities - classes of receptor - feedback control - reuptake - inactivation - pharmacology. Catecholamines dopamine synthesis - localisation - wide distribution (varicosities) - mood control dopamine - classes of receptor - feedback control - reuptake - inactivation - pharmacology - Parkinsonism nor-adrenaline - classes of receptor - feedback control - reuptake - inactivation - pharmacology...

Current Clinical Neurology

Attarian, 2006 Psychiatry for Neurologists, edited by Dilip V. Jeste and Joseph H. Friedman, 2006 Status Epilepticus A Clinical Perspective, edited by Frank W. Drislane, 2005 Thrombolytic Therapy for Acute Stroke, Second Edition, edited by Patrick D. Lyden, 2005 Parkinson's Disease and Nonmotor Dysfunction, edited by Ronald F. Pfeiffer Robert H. Paul, Ronald Cohen, Brian R. Ott, and Stephen Salloway, 2005 Atypical Parkinsonian Disorders Clinical and Research Aspects, edited by Irene Litvan, 2005 Handbook of Neurocritical Care, edited by Anish Bhardwaj, Marek A. Mirski, and Michael Benatar, 2003 Surgical Treatment of Parkinson's Disease and Other Movement Disorders, edited by

The Chronic Mouse MPTPProbenecid Model

Initial motor deficit (rotarod performance) is detected at 3 wk and deteriorated further 6 mo after treatment. Decrease of TH-immunoreactivity in the substantia nigra, associated with significant loss of substantia nigra neurons Persistent reduction in the levels of striatal terminal DA, its metabolites and uptake Murine inclusion bodies immunoreactive to a-synuclein and ubiquitin contain lipofuscin and lysosomal structures. Morphologically, these inclusion bodies resemble those detected in the cortex of PD. striatal levels remain low. The loss of DA neurons in the substantia nigra 6 mo after treatment is estimated to be at least 60 . The first sign of motor deficit in chronic MPTP probenecid treated mice as evidenced by the rotarod performance test is detected at 3 wk and persists for at least 6 mo after treatment (40).

The Nigrostriatal Pathway

It projects from the substantia nigra to the caudate and putamen, and its effects are mediated by the neurotransmitter dopamine. In essence, dopamine facilitates the motor loop in two ways. First, it provides tonic, excitatory drive to the direct (stimulatory) pathway through the neostriatum, and, second, it inhibits the indirect (inhibitory) pathway. The additive effects of this pathway provide an excitatory bias to the basal ganglia loop and allow the overall level of cortical activity to funnel through the motor loop and provide positive feedback to motor areas. Yurek DM, Sladek JR, Jr. Dopamine cell replacement Parkinson's disease. Annu Rev Neurosci 1990 13 415-440. FIGURE 5 Effects of Parkinson's disease, Huntington's chorea, and hemiballismus on output of the basal ganglia motor loop. (A) In the hypokinetic condition of Parkinson's disease, cells of the substantia nigra degenerate. In the absence of the nigrostriatal pathway, there is increased inhibitory control of...

The Acute and Subacute Mouse MPTP Model

Initial increase followed by decrease of motor activity. The activity returns to normal within a week. No long-term motor deficit Initial decrease, but later returning to normal of TH-immunoreactivity in the substantia nigra. No long-term loss of nigral cells Reduced level of striatal terminal DA, its metabolites and uptake these levels return to normal after extended survival period. No evidence of detecting the formation of a-synuclein- and ubiquitin-containing inclusion bodies survival times are extended, the neurotoxic effects of MPTP in mice are reversed gradually (40-43). A loss of tyrosine hydroxylase (TH)-immunoreactive cells in the substantia nigra has been shown in some studies (34,44,45) but not in others (41,42). Behaviorally, the motor response to subacute MPTP is quite variable. In general, MPTP causes a transient hyperactivity immediately after injection, followed by some decrease in activity, but the activity returns to normal after 5-7 d (46). Despite the evidence for...

Diagnostic Criteria for Essential Tremor

Medications, alcohol, Parkinsonism, dystonia, other basal ganglionic discoders, and hyperthyroidism are not potential etiological factors. 2. Use of medications, alcohol, Parkinsonism, dystonia, other basal ganglionic disorders, and hyperthyroidism are nor potential etiological factors.

Neuroses Psychoses And The Mindbrain Dichotomy

First of all let us subdivide the term 'mental illness' into two neurological ('organic') and psychological (or 'functional'). This subdivision is by no means clear cut. Taking the neurological category first, we find it is often useful to subdivide it further into conditions that have a clear anatomical substratum (e.g. multiple sclerosis, parkinsonism) and those where that substratum is more subtle (e.g. depression, schizophrenia). Turning to the second category (the psychological) we find that it is also customarily divided into two the neuroses and the psychoses. Again the basis of this subdivision is far from clear cut. It is generally held that in the neuroses (such as depression) the sufferer shares the same 'world' as the rest of us but sees it through whatever is the opposite of rose-tinted spectacles. In psychotic conditions (e.g. schizophrenia) the patient seems to live in a different world altogether. He or she seems to be overcome with delusions and hallucinations. On...

Creatine Supplementation In Neurodegenerative Disorders

Parkinson's Disease Parkinson's disease (PD) is characterized by chronic progressive neurodegeneration of brainstem neurons, particularly dopaminergic neurons in the substantia nigra pars compacta, and the loss of their projection axon terminals in the neostriatum. This loss of dopaminergic neurons is associated with a slow onset of clinical symptoms associated with motor disability. There is a direct correlation between disease progression, neuronal loss, and motor dysfunction (Bernheimer et al., 1973 Damier et al., 1999). Abnormal movements are characterized by both akinesia and bradykinesia, resting tremor, rigidity, and gait abnormalities with postural instability and difficulty in initiating movement. The presence of symptoms in PD can be correlated with the loss of dopaminergic neurons when depletion reaches 60 , and with dopamine depletion in the striatum by 60 to 80 (Bernheimer et al., 1973). Although, recent imaging studies show that much less dopamine depletion may be...

Clinical Uses Of Electrical Stimulation

Electrical stimulation of neuron clusters deep inside the brain also known as deep brain stimulation (DBS) is now used to inactivate the subthalamic nucleus, which is overactive in Parkinson's disease. A multielectrode lead is implanted into the ventrointermediate nucleus of the thalamus. The lead is connected to a pulse generator that is surgically implanted under the skin in the upper chest. When the patient passes a magnet over the pulse generator, the device delivers high-frequency pulse trains to the subthalamic nucleus to block the tremor.

Differential Regulation of Key Signaling Molecules in Innate Immunity and Human Diseases

Differential splicing events in human cells give rise to two additional IRAK-1 variants, IRAK-1b and IRAK-1c. IRAK-1b derives from alternative splicing and deletion of 90bp within exon 12, which yields an in-frame deletion of 30 amino acids (residues 514-543) (Jensen and Whitehead 2001). IRAK-1c is due to alternative splicing and deletion of exon 11 and part of exon 12 (Rao, Nguyen, Ngo and Fung-Leung 2005). IRAK-1b exists in minute amount (less then 1 of IRAK-1) in most human cells and tissues with unknown function. On the other hand, the full length IRAK-1 and IRAK-1c are abundantly expressed in human leukocytes and most tissues (Rao et al. 2005 Su et al. 2007). In contrast to IRAK-1, both IRAK-1b and IRAK-1c are stable and do not undergo covalent modification following various stimulations (Li et al. 2000 Jensen et al. 2001 Su et al. 2007). Overexpression of IRAK-1c blocks IL-1P induced MAP kinase activation, suggesting that IRAK-1c may serve as a negative regulator of...

Dementia Associated with Sensorimotor Signs

Degenerative diseases with extrapyramidal features (e.g., Parkinson's disease, Huntington's disease, progressive supranuclear palsy, and Wilson's disease) Motor neuron disease with frontotemporal dementia Patients with multiple sclerosis often suffer from cognitive, emotional, and behavioral problems that tend to add to their disability and problems functioning at home and work (122-124). Dementia has been reported in up to a third of patients with Parkinson's disease (125-128). Some patients have coexisting Alzheimer's pathology, which probably accounts for their decline in mental state functioning. Others present with a disruption of frontal networks (subcortical dementia syndrome) with bradyphrenia, impaired activation, and forgetfulness. These difficulties may reflect diminished dopamine availability to caudate nucleus and prefrontal regions. Medications and coexisting depression also may play an important role. Huntington's disease, progressive supranuclear palsy, and Wilson's...

Guidelines For Understanding Results

Figure 1.2.9 shows the allelic variants for SNCA, both of which cause Parkinson's Disease. The first one is caused by a change in the alanine at position 53 to threonine (represented as snca, ala53thr in the first line of the description). The second one is caused by a change in the alanine at position 30 to proline (shown as snca, ala30prc> ). The corresponding text for each entry gives all known information about the genetics and clinical implications of that particular mutation.

The Msr System and Age Related Diseases

It is now established that in age-related diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and cataractogenesis, oxidized proteins accumulate 85-87 . Furthermore, methionine oxidation has been observed in neurodegenerative diseases despite high expression of the MsrA protein in the cerebellum and neurons of rat brain 67 . Indeed, Gabbita et al. 88 revealed a decrease in MsrA activity in all brain regions studied in an Alzheimer patient compared with control subjects. This decrease in MsrA activity was accompanied by an increase in brain protein carbonyl levels. In Parkinson's disease, it was shown that a-synuclein oxidation plays a critical role in the disease. a-synuclein contains four methionines that are all solvent-exposed. It was shown that oxidation of these methion-ine residues inhibited its fibrillation and could thus be an important factor in Parkinson's disease if Msr activity is impaired during this pathology 89 . However, it was shown that...

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