Mouse models of alpha-synucleinopathy and Lewy pathology. Alpha-synuclein expression in transgenic mice.
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Adenine↗
Biomedical subjects
S Barbieri
Publications and source records attributed to S Barbieri.
Non-motor effects of deep brain stimulation of the subthalamic nucleus in Parkinson's disease: preliminary physiological results.
Although deep brain stimulation (DBS) is a clinically effective therapy for patients with advanced Parkinson's disease (PD), its physiological effects on the brain and possible actions on non-motor functional systems remain largely unknown. This study evaluated the effects of DBS of the subthalamic nucleus (STN) on neurophysiological variables and on cardiovascular physiology. Nine patients affected by PD undergoing chronic DBS of the STN have been studied. We performed electroencephalography (EEG), somatosensory (SEPs) and visual evoked potentials (VEPs), exteroceptive masseteric silent period and sympathetic skin response (SSR) studies with DBS ON and OFF. To assess the effects of stimulation on the cardiovascular system the tilt test and plasma renin activity were studied. When we turned the DBS OFF, both SEP N20 and the VEP P100 component increased significantly in amplitude whereas the SSR decreased in amplitude and increased in latency. Although plasma renin activity tended to increase with DBS OFF, its modification induced by postural changes and blood pressure values did not significantly differ with DBS ON and OFF. We conclude that DBS of the STN in PD, besides inducing a clinical improvement, induces several non-motor effects.
Afferent Pathways↗
Decreased EMG inhibition following electrical stimulation over muscle tendons in myopathies.
OBJECTIVE: To assess the central EMG inhibitory action of tendon afferent input in muscle diseases. METHODS: The EMG inhibition elicited by electrical stimulation over muscle tendons was tested in 13 healthy voluntary subjects and 8 patients who had a primary muscle disease with a mild force deficit. Electrical stimuli were delivered to the tendon of the extensor carpi radialis muscle at the wrist during tonic voluntary isometric contraction at 50% of the maximum EMG level. The EMG signal was recorded by surface electrodes over the extensor carpi radialis muscle. RESULTS: The prestimulus background EMG level was reduced in 7 out 8 of the patients. Both groups had the same phases of EMG modulation following tendon stimulation (TE1, TI1, TE2) and their latency and amplitude did not differ significantly. Conversely, the area of TI1 was significantly larger (i.e. the inhibition decreased) in patients ([mean+/-SD] absolute area: controls=4.1+/-1.6 mVms, patients=6.9+/-2.9 mVms, P<0.05). CONCLUSIONS: In muscle dysfunction there are serial 'upstream' changes of central inhibitory systems, probably to maximize the residual muscle power of the affected muscle.
Adolescent↗
Neuropathology in mice expressing human alpha-synuclein.
The presynaptic protein alpha-synuclein is a prime suspect for contributing to Lewy pathology and clinical aspects of diseases, including Parkinson's disease, dementia with Lewy bodies, and a Lewy body variant of Alzheimer's disease. alpha-Synuclein accumulates in Lewy bodies and Lewy neurites, and two missense mutations (A53T and A30P) in the alpha-synuclein gene are genetically linked to rare familial forms of Parkinson's disease. Under control of mouse Thy1 regulatory sequences, expression of A53T mutant human alpha-synuclein in the nervous system of transgenic mice generated animals with neuronal alpha-synucleinopathy, features strikingly similar to those observed in human brains with Lewy pathology, neuronal degeneration, and motor defects, despite a lack of transgene expression in dopaminergic neurons of the substantia nigra pars compacta. Neurons in brainstem and motor neurons appeared particularly vulnerable. Motor neuron pathology included axonal damage and denervation of neuromuscular junctions in several muscles examined, suggesting that alpha-synuclein interfered with a universal mechanism of synapse maintenance. Thy1 transgene expression of wild-type human alpha-synuclein resulted in similar pathological changes, thus supporting a central role for mutant and wild-type alpha-synuclein in familial and idiotypic forms of diseases with neuronal alpha-synucleinopathy and Lewy pathology. These mouse models provide a means to address fundamental aspects of alpha-synucleinopathy and test therapeutic strategies.
Animals↗
gamma-hydroxybutyric acid for alcohol-sensitive myoclonus with dystonia.
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Adult↗
Postcontraction depression of reciprocal inhibition in human forearm muscles.
We tested whether a preceding muscle contraction changes reciprocal inhibition (RI) between forearm antagonists. RI was studied in 14 healthy subjects by assessing changes in the H reflex (evoked by median-nerve stimulation) in forearm flexor muscles after conditioning radial-nerve stimulation at 0- and 20-ms intervals. The maximum sizes of the M wave (M(max)) and H reflex (H(max)) were also measured. After a long-lasting maximum voluntary handgrip contraction (mean +/- SEM: 3.9 +/- 0.6 min) of ipsilateral forearm muscles, M(max) and H(max) were unchanged but RI was diminished. After contraction of the contralateral homologous muscles and after contraction elicited by ipsilateral muscle stimulation, RI remained unchanged. These results show that a preceding maximum voluntary contraction (lasting 30 s or more) reduces the activity of the spinal inhibitory interneurons mediating RI. This finding may imply the need to reinterpret results from RI studies in normal subjects and in patients with movement disorders.
Adult↗
Mouse models of alpha-synucleinopathy and Lewy pathology.
The discovery of two missense mutations (A53T and A30P) in the gene encoding the presynaptic protein alpha-synuclein (alphaSN) that are genetically linked to rare familial forms of Parkinson's disease and its accumulation in Lewy bodies and Lewy neurites has triggered several attempts to generate transgenic mice overexpressing human alphaSN. Analogous to a successful strategy for the production of transgenic animal models for Alzheimer's disease we generated mice expressing wildtype and the A53T mutant of human alphaSN in the nervous system under control of mouse Thy1 regulatory sequences. These animals develop neuronal alpha-synucleinopathy, striking features of Lewy pathology, neuronal degeneration and motor defects. Neurons in brainstem and motor neurons appeared particularly vulnerable. Motor neuron pathology included axonal damage and denervation of neuromuscular junctions, suggesting that alphaSN may interfere with a universal mechanism of synapse maintenance. Thy1-transgene expression of wildtype human alphaSN resulted in comparable pathological changes thus supporting a central role for mutant and wildtype alphaSN in familial and idiopathic forms of diseases with neuronal alpha-synucleinopathy and Lewy pathology. The mouse models provide means to address fundamental aspects of alpha-synucleinopathy and to test therapeutic strategies.
Amino Acid Substitution↗
Limited value of zinc protoporphyrin as a marker of iron status in chronic hemodialysis patients.
BACKGROUND: In an attempt to find new parameters able to evaluate the actual iron availability by bone marrow cells, zinc protoporphyrin (ZnPP), a metabolic intermediate generated in the red blood cell by the incorporation of zinc instead of iron, has been proposed. ZnPP is a good marker of iron-deficiency anemia in non-uremic people, as red blood cell ZnPP concentration rises specifically (except for lead intoxication) in this condition. Existing data on ZnPP as a marker of iron deficiency in uremic patients comes mainly from cross sectional studies on chronic hemodialysis and has produced conflicting results. SUBJECTS AND METHODS: Therefore, we prospectively studied 42 HID patients, 28-88 years old, 13-346 months of dialysis age, beginning from a period of maximal iron deficiency, due to the lack of parenteral iron compounds (T0) up to the end of more than one year of follow-up with continuous parenteral iron supplementation (T4). ZnPP, hemoglobin, transferrin saturation and ferritin were serially determined before and after six weeks (T1), four months (T2), seven months (T3) and 14 months (T4) of parenteral iron supplementation at a maintenance dose of 0.5-1 mg/kg/week. RESULTS: In comparison with baseline values (95+/-37 micromol/mol heme) there were no significant changes in ZnPP levels at T1 and T2 despite a continuous increase in both transferrin saturation and ferritin values, while ZnPP significantly decreased at T4 (63+/-37 micromol/mol heme, p<0.001). There was no correlation between ZnPP and both transferrin saturation and ferritin at any time during the study, the same was true for ZnPP and zinc and lead serum concentration, fibrinogen and reactive C protein levels at T1 and T4, respectively. At T4, only 2/10 patients who still showed ZnPP levels >80 micromol/mol heme had absolute or functional iron deficiency, when the percentage of hypochromic red cells were measured. CONCLUSION: We conclude that ZnPP untimely parallels a change in iron balance in only a proportion of uremic people, in as much as confounding factors, such as chronic inflammation and uremia in itself may obscure its relationship with iron status. Therefore, ZnPP cannot be assumed to be a first-line diagnostic marker of iron balance in uremic patients.
Adult↗
[Relationship between risk profiles, prognosis, and outcome of patients with acute renal failure treated with dialysis].
BACKGROUND: The paradox of the increased mortality in the patients with acute renal failure (ARF) although submitted to better cares and newer renal replacement therapies (RRT) has recently prompted to the use of quantitative individual severity scores (ISS) calculating for each patient an individual death probability (DP) in correlation with the risk covariates found before the start of RRT; beside the clinical use, the ISS allow an evaluation of the effect of strategies and modalities of treatments as quantitative additive factors eventually added or subtracted to the base-line individual background of risk. The ideal index should be chosen on the basis of its precocity (origin just at the start of therapy), sensitivity (true positive against false positive results), universality (independence from the development set) and discriminative power (the capability to discern patients potentially treatable from those with an unchangeable prognosis). Indexes already validated in their development set should be used and studied into a different set ("evaluation set"). METHODS: The aim of this study has been: to evaluate a literature index (ATN-ISS, Liaño, developed prospectively in a remote set) in the local (A) environment on 340 patients with ARF successively treated with dialysis (mostly hemo-filtration) studied retrospectively along a 4 year period in our regional hospital and compare its performances with a local index (PDTOR) developed by logistic analysis in the same pool; the fitness of both tests to the real outcome has been evaluated by the Limeshow test and by ROC curves; to compare both indexes in a remote environment (B) of a dialytic pool of 345 patients extracted by a group of 25721 patients treated by 25 Italian ICU (Archidia Study group). The responses of the two indexes have been compared even with the index (SAPSII) prospectively generated at the admittance in the ICU by the Archidia Group. RESULTS: In the local set (A) TOR-ISS fits well with the outcomes (Limeshow test C2 = N.S.) as expected being evaluated in its own "development" set, while ATN-ISS significantly underestimates deaths, perhaps working on a retrospectively built data-base, that could contain fewer risk elements than necessary. (B) In the remote set, ATN-ISS fits very well, while TOR-ISS significantly overestimates expected deaths, for its retrospective origin or for a real lower death incidence compared to that of its development set. SAPSII shows no correlation at all with the outcome because its calculation is often well before (10 days on average) than the actual start of dialytic treatment. CONCLUSIONS: In conclusion ATN-ISS, an index built prospectively on a large cohort of patients, fits correctly in a remote prospectively built evaluation set. Retrospective built indexes or data-base don't allow a correct ISS evaluation while ICU indexes (SAPSII, APACHE), generated at the admittance in the ICU should not be used for ARF patients submitted to dialysis.
Acute Kidney Injury↗
How to save money for erythropoietin therapy by changing from 'roller coaster' to continuous iron supplementation.
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Aged↗
A tentative interpretation of electromyographic regional differences in bulbar- and limb-onset ALS.
Electromyography (EMG) could be useful in defining regional motor neuron vulnerability in ALS. We performed EMG in 36 sporadic ALS patients (9 with bulbar-onset and 27 with limb-onset symptoms). Active denervation was more frequent in limb than in corresponding paraspinal muscles, in the thoracic paraspinal, and in the bulbo-cervical muscles in patients with bulbar-onset symptoms. These results are consistent with a regional motor neuron vulnerability along with a nerve length-dependent liability.
Adult↗
Deterioration of multifocal motor neuropathy after plasma exchange.
We report a patient with motor neuropathy in whom plasma exchange (PE) was followed by a pronounced clinical worsening with the appearance of conduction blocks in previously clinically unaffected motor nerves, leading to the diagnosis of multifocal motor neuropathy (MMN). This report highlights the different response to therapy of MMN and chronic inflammatory demyelinating polyneuropathy (CIDP) because not only steroids but also PE, which is often effective in CIDP, do not improve and at times may even worsen MMN.
Humans↗
Fc epsilonRI-deficient mice infected with Schistosoma mansoni mount normal Th2-type responses while displaying enhanced liver pathology.
The IgE/Fc epsilonRI interaction is postulated to play an important role in resistance to helminths both at the level of anti-parasitic effector cell function and in the initiation of Th2 responses through IL-4 produced by Fc epsilonRI+ non-B, non-T (NBNT) cells. To formally evaluate the role of IgE/Fc epsilonRI signaling in the host response to helminths we studied Schistosoma mansoni infection in Fc epsilonRI knockout (KO) mice. Infected wild-type (wt) and KO animals showed comparable adult worm and tissue egg burdens, arguing against a role for Fc epsilonRI interactions in host resistance. Significantly, NBNT cells from infected KO, in contrast to wt animals, did not secrete IL-4 when stimulated with anti-IgE Ab or soluble parasite Ag. Nevertheless, serum IgE levels and Th2 cytokine production profiles were comparable in both strains of mice, demonstrating that the Ag-dependent stimulation of IL-4 secretion by NBNT cells is not essential for helminth-induced Th2 differentiation. However, when stimulated with low Ag doses, splenocytes from infected Fc epsilonRI-deficient mice produced less IL-4 in vitro than similar cultures from infected wt animals, an effect attributable to their defective NBNT cell function. Moreover, infected KO mice showed enhanced egg granuloma formation and hepatic fibrosis, revealing that the IgE/Fc epsilonRI interaction, while not essential for Th2 response development or resistance to primary infection, plays a significant role in down-regulating host pathology.
Animals↗
Impaired generation of bone marrow B lymphocytes in mice deficient in C/EBPbeta.
CAAT/enhancer binding proteins (C/EBP) are a family of transcription factors that mediates adipocyte differentiation and the regulation of genes expressed in immune responses and inflammation, such as interleukin-6 (IL-6), IL-8, and granulocyte colony-stimulating factor (G-CSF). We investigated the role of C/EBPbeta (NF-IL6) in the generation of bone marrow B lymphocytes by taking advantage of C/EBPbeta-/- mice. We found that the expansion of bone marrow (BM) B lymphocytes was impaired in long-term lymphoid cultures from C/EBPbeta-/- mice. Consistent with this finding, the number of BM B cells was decreased in C/EBPbeta-/- mice. Both the levels of IL-7 gene expression and bioactive IL-7 from BM stromal cells were decreased in C/EBPbeta-/- mice. Furthermore, the proliferative responsiveness of BM B-cell precursors to IL-7 was also reduced as compared to wild-type mice, indicating that C/EBPbeta is required for the generation of BM B cells induced by IL-7. Accordingly, IL-7 stimulates the C/EBPbeta DNA-binding activity of normal BM pre-B lymphocytes as well as of 70Z/3 pre-B cells. These results point to C/EBPbeta as a critical signaling molecule in BM B lymphopoiesis.
Animals↗
Erroneous evaluation of conduction block due to anomalous innervation of the extremities.
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Action Potentials↗
Criteria for early detection of conduction block in multifocal motor neuropathy (MMN): a study based on control populations and follow-up of MMN patients.
Motor conduction block (MCB) has been used as the main diagnostic criterion in multifocal motor neuropathy (MMN). Nonetheless, no agreed definition of block currently exists; the proposed required percent decrement of proximal compound muscle action potential (CMAP) amplitude varies from > 20% to > 50%. The aim of this work was to evaluate, through a follow-up study of patients with MMN, the behaviour of MCB over time. The percent decrement and temporal dispersion of proximal CMAP have also been calculated in normal controls and in patients affected by amyotrophic lateral sclerosis (ALS). The results show that MCB in patients with MMN is a dynamic entity which greatly varies over time and that a > 50% CMAP amplitued reduction may well be preceded by a smaller decrement that is nonetheless indicative of focal myelin damage in the appropriate clinical context. This datum and the results obtained in the control group and in patients with ALS suggest that a reappraisal of the diagnostic criteria for MCB, in cases with clinical and electrophysiological data strongly indicative of MMN, should be considered. Since MMN is a treatable disorder, the use of the proposed less restrictive criteria for the identification of MCB could allow for a promp and more effective treatment.
Adolescent↗
Long term effect of intravenous immunoglobulins and oral cyclophosphamide in multifocal motor neuropathy.
OBJECTIVES: To report the long term effect of the combined treatment with high dose intravenous immunoglobulins (i.v.Ig) and oral cyclophosphamide (CTX) in patients with multifocal motor neuropathy, and to determine whether the association of oral CTX in these patients may help to delay and, possibly, suspend i.v.Ig infusions. METHODS: Six patients with multifocal motor neuropathy responding to an initial course of i.v.Ig (0.4 g/kg/day for five consecutive days) were followed up for 37 to 61 (mean 47) months. All patients were subsequently treated with periodic i.v.Ig infusions (0.4 g/kg/day for two days at clinical worsening) and oral CTX (1-3 mg/kg/day). Improvement was assessed using the Rankin disability scale, a functional impairment scale for upper and lower limbs, and the MRC rating scale on the 20 most affected muscles. Electrophysiological and antiglycolipid antibody studies were performed before treatment, then yearly during follow up. RESULTS: All patients improved during treatment and, by the end of follow up or before worsening after therapy suspension, the median Rankin (P=0.0335) and upper (P=0.0015) and lower limb (P=0.0301) impairment scores and the mean MRC (P=0.0561) score were improved. By that time the number of nerves with partial motor conduction block was reduced (P=0.0197) and antiglycolipid antibody titres had decreased in all but one patient. All patients required periodic i.v.Ig infusions to maintain improvement but, after three to seven months of oral CTX, the interval between i.v.Ig infusions could be progressively prolonged until, in three patients, both treatments could be stopped for up to two years before clinical worsening. The main complications, both related to oral CTX, were haemorrhagic cystitis in two patients and persistent amenorrhea in one patient. CONCLUSIONS: I.v.Ig can induce and maintain improvement in multifocal motor neuropathy but does not eradicate the disease. Oral CTX may help to induce a sustained remission but it is not devoid of side effects and might therefore be reserved for patients with multifocal motor neuropathy who require frequent i.v.Ig infusions to maintain improvement.
Administration, Oral↗
A role for CD4+ NK1.1+ T lymphocytes as major histocompatibility complex class II independent helper cells in the generation of CD8+ effector function against intracellular infection.
Major histocompatibility complex (MHC) class II (A beta) knockout mice were vaccinated with ts-4, an attenuated mutant strain of Toxoplasma gondii, which in normal animals induces strong T cell immunity mediated by interferon gamma (IFN-gamma). After challenge with the lethal parasite strain RH, the knockout mice displayed decreased resistance consistent with absence of CD4+ effectors. Nevertheless, these animals generated CD8+ lymphocyte effectors capable of mediating partial protection through IFN-gamma secretion. Moreover, in vivo neutralization experiments indicated that the development of resistance in knockout mice depends on CD4+ cells as well as interleukin 2 (IL-2). The identity of the IL-2-producing protective cell population was further characterized as CD4+, NK1.1+ by in vitro depletion studies and reverse transcriptase-PCR analysis of fluorescence-activated cell sorter (FACS)-purified CD4+ NK1.1+ T lymphocytes. These results demonstrate that in the absence of conventional MHC class II-restricted CD4+ T lymphocytes, CD8 priming persists and mediates partial protective immunity to T. gondii. Moreover, the data argue that CD4+, NK1.1+ cells, previously implicated in the initiation of T helper cell 2 (Th2) responses through their production of IL-4, can also play a role as alternative IL-2-secreting helper cells in Th1-mediated host resistance to infection.
Animals↗