131 research outputs found

    Pregnancies and associated events in women receiving Enzyme Replacement Therapy for late onset Glycogen Storage Disease Type II (Pompe disease)

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    AIM: Glycogen storage disease type II (GSD II or Pompe disease; OMIM; 232 300) is a rare autosomal recessive lysosomal storage disorder resulting from deficiency of α-glucosidase and accumulation of glycogen in muscle. Clinical symptoms include weakness of skeletal and respiratory muscles and, in infants, cardiomyopathy. Patients with GSD II receive infusions of recombinant α-glucosidase (enzyme replacement therapy; ERT), which slow the progression of the disease. ERT is given to male and female patients of all ages but as yet little is documented on the effects of continuing ERT during pregnancy. The aim of this case series was therefore to ascertain the pregnancy outcomes of women with GSD II on ERT and to describe adverse events associated with pregnancy, delivery and therapy. METHODS: The medical records of eight women attending the Royal Free Hospital Lysosomal Storage Disorders Unit were reviewed. Four of the eight women had seven pregnancies over a period of 8 years. RESULTS: In this series GSD II was associated with interventional deliveries but normal neonates. Cessation of ERT in early pregnancy resulted in deterioration of maternal symptoms and emergence of allergic reactions on restarting ERT. CONCLUSION: Individualized care plans are required to ensure the best neonatal and maternal outcomes. Consideration should be given to the potential benefits to mother and fetus of continuing ERT during pregnancy

    Modeling the interaction between tubuloglomerular feedback and myogenic mechanisms in the control of glomerular mechanics

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    Introduction: Mechanical stresses and strains exerted on the glomerular cells have emerged as potentially influential factors in the progression of glomerular disease. Renal autoregulation, the feedback process by which the afferent arteriole changes in diameter in response to changes in blood pressure, is assumed to control glomerular mechanical stresses exerted on the glomerular capillaries. However, it is unclear how the two major mechanisms of renal autoregulation, the afferent arteriole myogenic mechanism and tubuloglomerular feedback (TGF), each contribute to the maintenance of glomerular mechanical homeostasis.Methods: In this study, we made a mathematical model of renal autoregulation and combined this model with an anatomically accurate model of glomerular blood flow and filtration, developed previously by us. We parameterized the renal autoregulation model based on data from previous literature, and we found evidence for an increased myogenic mechanism sensitivity when TGF is operant, as has been reported previously. We examined the mechanical effects of each autoregulatory mechanism (the myogenic, TGF and modified myogenic) by simulating blood flow through the glomerular capillary network with and without each mechanism operant.Results: Our model results indicate that the myogenic mechanism plays a central role in maintaining glomerular mechanical homeostasis, by providing the most protection to the glomerular capillaries. However, at higher perfusion pressures, the modulation of the myogenic mechanism sensitivity by TGF is crucial for the maintenance of glomerular mechanical homeostasis. Overall, a loss of renal autoregulation increases mechanical strain by up to twofold in the capillaries branching off the afferent arteriole. This further corroborates our previous simulation studies, that have identified glomerular capillaries nearest to the afferent arteriole as the most prone to mechanical injury in cases of disturbed glomerular hemodynamics.Discussion: Renal autoregulation is a complex process by which multiple feedback mechanisms interact to control blood flow and filtration in the glomerulus. Importantly, our study indicates that another function of renal autoregulation is control of the mechanical stresses on the glomerular cells, which indicates that loss or inhibition of renal autoregulation may have a mechanical effect that may contribute to glomerular injury in diseases such as hypertension or diabetes. This study highlights the utility of mathematical models in integrating data from previous experimental studies, estimating variables that are difficult to measure experimentally (i.e. mechanical stresses in microvascular networks) and testing hypotheses that are historically difficult or impossible to measure

    Basal ganglia and cerebral cortical distribution of dopamine D1- and D2-receptors in neonatal and adult cat brain

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    Quantitative receptor autoradiography was performed on neonatal and adult cat brains. Serial sections through the basal ganglia were assayed for D1- and D2-dopamine receptors and acetylcholinesterase (AChE) staining. The neonatal basal ganglia revealed patches of increased D1-receptor density that frequently overlapped with patches of increased AChE staining, while the D2-receptor distribution was more homogeneous. The adult basal ganglia revealed a mild amount of heterogeneity for both the D1- and D2-receptors, varying from 10 to 25%, with little correspondence to the marked heterogeneity seen with AChE staining. A distinct laminar distribution of the D1-receptor, without significant D2 binding, was seen in the cerebral cortex.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26835/1/0000395.pd

    Clinical prodromes of neurodegeneration in Anderson-Fabry disease

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    To estimate the prevalence of prodromal clinical features of neurodegeneration in patients with Anderson-Fabry disease (AFD) in comparison to age-matched controls

    Iodine-125 and fluorine-18 labeled aryl-1,4-dialkylpiperazines: Potential radiopharmaceuticals for in vivo study of the dopamine uptake system

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    A series of fluorine-18 and iodine-125 labeled aryl-1,4-dialkylpiperazine analogs, derivatives of GBR 12935, were synthesized as radiotracers for positron emission tomography or single photon emission computerized tomography imaging of the brain based on their affinity for the presynaptic dopamine reuptake system. High specific activity fluorine-18 tracers were prepared by nucleophilic aromatic substitution reactions; iodine-125 tracers were prepared by isotopic exchange reactions. In vitro competitive binding studies demonstrated that iodine substitution is tolerated in the 4-position of the phenyl ring of the phenalkylpiperazine group. In vivo regional brain biodistribution studies in mice indicated no selectivity of the radioiodinated ligands for the dopamine reuptake site, with striatum/cerebellum concentration ratios of 1. Similar negative results with the new fluorine-18 derivatives demonstrated that in vivo selectivity for the dopamine reuptake site appears to be critically dependent on the carbon chain length between the piperazine ring and the solitary aromatic ring. These studies suggest that development of new radiopharmaceuticals based on the GBR 12935 structure cannot be based solely on considerations of in vitro binding affinities.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30090/1/0000461.pd

    Transcriptional Activation of REST by Sp1 in Huntington's Disease Models

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    In Huntington's disease (HD), mutant huntingtin (mHtt) disrupts the normal transcriptional program of disease neurons by altering the function of several gene expression regulators such as Sp1. REST (Repressor Element-1 Silencing Transcription Factor), a key regulator of neuronal differentiation, is also aberrantly activated in HD by a mechanism that remains unclear. Here, we show that the level of REST mRNA is increased in HD mice and in NG108 cells differentiated into neuronal-like cells and expressing a toxic mHtt fragment. Using luciferase reporter gene assay, we delimited the REST promoter regions essential for mHtt-mediated REST upregulation and found that they contain Sp factor binding sites. We provide evidence that Sp1 and Sp3 bind REST promoter and interplay to fine-tune REST transcription. In undifferentiated NG108 cells, Sp1 and Sp3 have antagonistic effect, Sp1 acting as an activator and Sp3 as a repressor. Upon neuronal differentiation, we show that the amount and ratio of Sp1/Sp3 proteins decline, as does REST expression, and that the transcriptional role of Sp3 shifts toward a weak activator. Therefore, our results provide new molecular information to the transcriptional regulation of REST during neuronal differentiation. Importantly, specific knockdown of Sp1 abolishes REST upregulation in NG108 neuronal-like cells expressing mHtt. Our data together with earlier reports suggest that mHtt triggers a pathogenic cascade involving Sp1 activation, which leads to REST upregulation and repression of neuronal genes

    Role of Synucleins in Alzheimer’s Disease

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    Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common causes of dementia and movement disorders in the elderly. While progressive accumulation of oligomeric amyloid-β protein (Aβ) has been identified as one of the central toxic events in AD leading to synaptic dysfunction, accumulation of α-synuclein (α-syn) resulting in the formation of oligomers has been linked to PD. Most of the studies in AD have been focused on investigating the role of Aβ and Tau; however, recent studies suggest that α-syn might also play a role in the pathogenesis of AD. For example, fragments of α-syn can associate with amyloid plaques and Aβ promotes the aggregation of α-syn in vivo and worsens the deficits in α-syn tg mice. Moreover, α-syn has also been shown to accumulate in limbic regions in AD, Down’s syndrome, and familial AD cases. Aβ and α-syn might directly interact under pathological conditions leading to the formation of toxic oligomers and nanopores that increase intracellular calcium. The interactions between Aβ and α-syn might also result in oxidative stress, lysosomal leakage, and mitochondrial dysfunction. Thus, better understanding the steps involved in the process of Aβ and α-syn aggregation is important in order to develop intervention strategies that might prevent or reverse the accumulation of toxic proteins in AD

    Parkinson’s disease mouse models in translational research

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    Animal models with high predictive power are a prerequisite for translational research. The closer the similarity of a model to Parkinson’s disease (PD), the higher is the predictive value for clinical trials. An ideal PD model should present behavioral signs and pathology that resemble the human disease. The increasing understanding of PD stratification and etiology, however, complicates the choice of adequate animal models for preclinical studies. An ultimate mouse model, relevant to address all PD-related questions, is yet to be developed. However, many of the existing models are useful in answering specific questions. An appropriate model should be chosen after considering both the context of the research and the model properties. This review addresses the validity, strengths, and limitations of current PD mouse models for translational research

    Excitatory amino acidergic pathways and receptors in the basal ganglia

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    The striatum receives the majority of excitatory amino acidergic input to the basal ganglia from neocortical and allocortical sources. The subthalamic nucleus and the substantia nigra also receive excitatory amino acidergic inputs from neocortex. The subthalamic nucleus, which has prominent projections to the pallidum and nigra, is the only known intrinsic excitatory amino acidergic component of the basal ganglia. Possible excitatory amino acidergic inputs reach the basal ganglia from the intralaminar thalamic nuclei and the pedunculo-pontine nucleus. The striatum is richly endowed with all subtypes of excitatory amino acid receptors and these appear to be inhomogeneously distributed within the striatal complex. The non-striatal nuclei contain lesser levels of excitatory amino acid receptors and the relative proportion of these receptors varies between nuclei. The presence of high densities of excitatory amino acid receptors is a phylogenetically conserved feature of the striatum and its non-mammalian homologues. In Huntington's disease, there is substantial depletion of α -amino-3-hydroxy-5-methylisoxazole-4-propionic acid, N-methyl-D-aspartate, and kainate receptors within the striatum. In Parkinson's disease substantia nigra, there is significant loss of N-methyl-D-aspartate and α -amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41734/1/726_2004_Article_BF00814003.pd
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