Publications by authors named "Patricia L Musolino"

13 Publications

  • Page 1 of 1

Cerebrovascular Disease Progression in Patients With Arg179 Pathogenic Variants.

Neurology 2021 01 16;96(4):e538-e552. Epub 2020 Nov 16.

From the Departments of Neurology (A.L., S.L.S., P.L.M.) and Radiology (J.B.P., J.K.-K., P.C.), Massachusetts General Hospital, Harvard Medical School, Boston; Department of Internal Medicine (E.R., D.M.M.), McGovern Medical School, University of Texas Health Science Center at Houston; Department of Neuroradiology (A.L., M.C.), Goethe University, Frankfurt am Main, Germany; andDepartment of Neurosurgery (E.S.), Boston Children's Hospital, Harvard Medical School, Boston, MA.

Objective: To establish progression of imaging biomarkers of stroke, arterial steno-occlusive disease, and white matter injury in patients with smooth muscle dysfunction syndrome caused by mutations in the gene, we analyzed 113 cerebral MRI scans from a retrospective cohort of 27 patients with Arg179 pathogenic variants.

Methods: Systematic quantifications of arterial ischemic strokes and white matter lesions were performed on baseline and follow-up scans using planimetric methods. Critical stenosis and arterial vessel diameters were quantified applying manual and semiautomated methods to cerebral magnetic resonance angiograms. We then assessed correlations between arterial abnormalities and parenchymal injury.

Results: We found characteristic patterns of acute white matter ischemic injury and progressive internal carotid artery stenosis during infancy. Longitudinal analysis of patients older than 1.2 years showed stable white matter hyperintensities but increased number of cystic-like lesions over time. Progressive narrowing of the terminal internal carotid artery occurred in 80% of patients and correlated with the number of critical stenoses in cerebral arteries and arterial ischemic infarctions. Arterial ischemic strokes occurred in same territories affected by critical stenosis.

Conclusions: We found characteristic, early, and progressive cerebrovascular abnormalities in patients with Arg179 pathogenic variants. Our longitudinal data suggest that while steno-occlusive disease progresses over time and is associated with arterial ischemic infarctions and cystic-like white matter lesions, white matter hyperintensities can remain stable over long periods. The evaluated metrics will enable diagnosis in early infancy and be used to monitor disease progression, guide timing of stroke preventive interventions, and assess response to current and future therapies.
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http://dx.doi.org/10.1212/WNL.0000000000011210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905785PMC
January 2021

Clinical Diffusion Mismatch to Select Pediatric Patients for Embolectomy 6 to 24 Hours After Stroke: An Analysis of the Save ChildS Study.

Neurology 2021 01 3;96(3):e343-e351. Epub 2020 Nov 3.

From the Department of Neuroradiology (P.B.S., M.-N.P., A.B.), Clinic for Radiology & Nuclear Medicine, University Hospital Basel, Switzerland; Department of Diagnostic and Interventional Neuroradiology (P.B.S., U.H., G.B., J.F.), University Medical Center Hamburg-Eppendorf, Hamburg; Departments of Pediatrics (R.S.), and Neurology (J.M.), University Hospital of Muenster; Department of Neuroradiology (R.C.), Alfried-Krupp Hospital, Essen; Department of Neuroradiology (H.H., E.H.), Klinikum Stuttgart, Germany; Department of Neuroradiology (A.G.), Medical University of Innsbruck, Austria; Department for Diagnostic and Interventional Neuroradiology (F.D.), University of Munich (LMU), Campus Grosshadern; Department of Neuroradiology (O.N., M.W.), RWTH Aachen University; Diagnostic and Interventional Neuroradiology (G.B.), Eberhard Karls University Tuebingen; Department of Radiology and Neuroradiology (A.W.), University Hospital Knappschaftskrankenhaus Bochum Langendreer; Department of Neuroradiology (D.K.), University Hospital Carl Gustav Carus, Dresden7; Department of Neuroradiology (U.Y.), Saarland University Hospital, Homburg, Germany; ASST Valcamonica (A.M.), Ospedale di Esine, UOSD Neurologia, Esine, Italy; Division of Neuroradiology and Musculoskeletal Radiology (W.M.), Department of Biomedical Imaging and Image-Guided Therapy, and Department of Biomedical Imaging and Image-Guided Therapy (R.N.), Division of Cardiovascular and Interventional Radiology, Medical University of Vienna, Austria; Department of Radiology and Neuroradiology (U.J.-K.), University Hospital of Schleswig-Holstein, Kiel; Section of Neuroradiology (M.B.), University of Ulm, Guenzburg; Department for Neuroradiology (S.S.), University Hospital Leipzig; Department of Neuroradiology (O.B.), University Hospital of Magdeburg; Department of Diagnostic and Interventional Neuroradiology (F.G.), Hannover Medical School, Germany; Institute of Neuroradiology (J.T.), Kepler University Hospital, Johannes Kepler University Linz, Austria; Institute of Neuroradiology (B.T.), University Hospital Duesseldorf; Department of Neuroradiology at Heidelberg University Hospital (M.M.); Department of Radiology (C.W.), University Hospital Regensburg; Department of Neuroradiology (P.S., A. Kemmling), University Hospital of Luebeck, Germany; Department of Neurology (P.L.M.), Massachusetts General Hospital, Harvard Medical School, Boston; Division of Child Neurology (S.L.), Department of Neurology, Stanford University, CA; Department of Neuroradiology (M.S.), University Hospital of Cologne; Department of Diagnostic and Interventional Radiology and Neuroradiology (A.R.), University Hospital Essen, University of Duisburg-Essen; Institute of Epidemiology and Social Medicine (A. Karch, N.R.), University of Muenster; and Department of Radiology, University of Munich (LMU) (M.W.), Campus Grosshadern, Germany.

Objective: To determine whether thrombectomy is safe in children up to 24 hours after onset of symptoms when selected by mismatch between clinical deficit and infarct.

Methods: A secondary analysis of the Save ChildS Study (January 2000-December 2018) was performed, including all pediatric patients (<18 years) diagnosed with arterial ischemic stroke who underwent endovascular recanalization at 27 European and United States stroke centers. Patients were included if they had a relevant mismatch between clinical deficit and infarct.

Results: Twenty children with a median age of 10.5 (interquartile range [IQR] 7-14.6) years were included. Of those, 7 were male (35%), and median time from onset to thrombectomy was 9.8 (IQR 7.8-16.2) hours. Neurologic outcome improved from a median Pediatric NIH Stroke Scale score of 12.0 (IQR 8.8-20.3) at admission to 2.0 (IQR 1.2-6.8) at day 7. Median modified Rankin Scale (mRS) score was 1.0 (IQR 0-1.6) at 3 months and 0.0 (IQR 0-1.0) at 24 months. One patient developed transient peri-interventional vasospasm; no other complications were observed. A comparison of the mRS score to the mRS score in the DAWN and DEFUSE 3 trials revealed a higher proportion of good outcomes in the pediatric compared to the adult study population.

Conclusions: Thrombectomy in pediatric ischemic stroke in an extended time window of up to 24 hours after onset of symptoms seems safe and neurologic outcomes are generally good if patients are selected by a mismatch between clinical deficit and infarct.

Classification Of Evidence: This study provides Class IV evidence that for children with acute ischemic stroke with a mismatch between clinical deficit and infarct size, thrombectomy is safe.
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http://dx.doi.org/10.1212/WNL.0000000000011107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884981PMC
January 2021

Clinical and radiographic course of arrested cerebral adrenoleukodystrophy.

Neurology 2020 06 1;94(24):e2499-e2507. Epub 2020 Jun 1.

From the Department of Neurology (E.J.M., P.L.M., R.S., F.S.E.) and Department of Radiology (P.A.C.), Division of Neuroradiology, Harvard Medical School, Massachusetts General Hospital, Boston; Department of Pediatrics (E.J.M.), Division of Child Neurology, Weill Cornell Medical College, New York-Presbyterian Hospital, NY; and Department of Pediatric Neurology (S.v.d.S., M.E.), Emma Children's Hospital, Amsterdam University Medical Center, the Netherlands.

Objective: To gain insight into the natural history of arrested cerebral adrenoleukodystrophy (CALD) by quantifying the change in Neurologic Function Score (NFS) and Loes Score (LS) over time in patients whose cerebral lesions spontaneously stopped progressing.

Methods: We retrospectively reviewed a series of 22 patients with arrested CALD followed longitudinally over a median time of 2.4 years (0.7-17.0 years). Primary outcomes were change in radiographic disease burden (measured by LS) and clinical symptoms (measured by NFS) between patients who never developed a contrast-enhancing lesion (gadolinium enhancement (GdE)- subgroup) and those who did (GdE+ subgroup). Secondary analyses comparing patterns of neuroanatomic involvement and lesion number, and prevalence estimates, were performed.

Results: Cerebral lesions were first detected at a median age of 23.3 years (8.0-67.6 years) with an initial LS of 4 (0.5-9). NFS was 0.5 (0-6). Overall change in NFS or LS per year did not differ between subgroups. No patients who remained GdE- converted to a progressive CALD phenotype. The presence of contrast enhancement was associated with disease progression ( = 0.559, < 0.001). Four patients (18.2%) underwent step-wise progression, followed by spontaneous resolution of contrast enhancement and rearrest of disease. Three patients (13.6%) converted to progressive CALD. Nineteen patients (86.4%) had arrested CALD at the most recent follow-up. The prevalence of arrested CALD is 12.4%.

Conclusion: Arrested CALD lesions can begin in childhood, and patients are often asymptomatic early in disease. The majority of patients remain stable. However, clinical and MRI surveillance is recommended because a minority of patients undergo step-wise progression or conversion to progressive CALD.
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http://dx.doi.org/10.1212/WNL.0000000000009626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455338PMC
June 2020

MRI brain lesions in asymptomatic boys with X-linked adrenoleukodystrophy.

Neurology 2019 04 22;92(15):e1698-e1708. Epub 2019 Mar 22.

From the Department of Radiology, Division of Neuroradiology (A.P.L., P.A.C.), Department of Neurology (E.J.M., R.A.-B., A.L., P.L.M., F.S.E.), and Department of Biostatistics (D.H.), Harvard Medical School, Massachusetts General Hospital, Boston; and Department of Pediatrics, Division of Child Neurology (E.J.M.), Weill Cornell Medical College, New York-Presbyterian Hospital, New York.

Objective: To describe the brain MRI findings in asymptomatic patients with childhood cerebral adrenoleukodystrophy (CCALD).

Methods: We retrospectively reviewed a series of biochemically or genetically confirmed cases of adrenoleukodystrophy followed at our institution between 2001 and 2015. We identified and analyzed 219 brain MRIs from 47 asymptomatic boys (median age 6.0 years). Patient age, MRI scan, and brain lesion characteristics (e.g., contrast enhancement, volume, and Loes score) were recorded. The rate of lesion growth was estimated using a linear mixed effect model.

Results: Sixty percent of patients (28/47) showed brain lesions (median Loes score of 3.0 points; range 0.5-11). Seventy-nine percent of patients with CCALD (22/28) had contrast enhancement on first lesional or subsequent MRI. Lesion progression (Loes increase of ≥0.5 point) was seen in 50% of patients (14/28). The rate of lesion growth (mL/mo) was faster in younger patients ( = -0.745; < 0.0001). Older patients (median age 14.4 y/o) tended to undergo spontaneous arrest of disease. Early lesions grew 46× faster when still limited to the splenium, genu of the corpus callosum, or the brainstem ( = 0.001).

Conclusion: We provide a description of CCALD lesion development in a cohort of asymptomatic boys. Understanding the early stages of CCALD is crucial to optimize treatments for children diagnosed by newborn screening.
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http://dx.doi.org/10.1212/WNL.0000000000007294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511088PMC
April 2019

ABCD1 dysfunction alters white matter microvascular perfusion.

Brain 2017 Dec;140(12):3139-3152

Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.

Cerebral X-linked adrenoleukodystrophy is a devastating neurodegenerative disorder caused by mutations in the ABCD1 gene, which lead to a rapidly progressive cerebral inflammatory demyelination in up to 60% of affected males. Selective brain endothelial dysfunction and increased permeability of the blood-brain barrier suggest that white matter microvascular dysfunction contributes to the conversion to cerebral disease. Applying a vascular model to conventional dynamic susceptibility contrast magnetic resonance perfusion imaging, we demonstrate that lack of ABCD1 function causes increased capillary flow heterogeneity in asymptomatic hemizygotes predominantly in the white matter regions and developmental stages with the highest probability for conversion to cerebral disease. In subjects with ongoing inflammatory demyelination we observed a sequence of increased capillary flow heterogeneity followed by blood-brain barrier permeability changes in the perilesional white matter, which predicts lesion progression. These white matter microvascular alterations normalize within 1 year after treatment with haematopoietic stem cell transplantation. For the first time in vivo, our studies unveil a model to assess how ABCD1 alters white matter microvascular function and explores its potential as an earlier biomarker for monitoring disease progression and response to treatment.
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http://dx.doi.org/10.1093/brain/awx262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841142PMC
December 2017

Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy.

N Engl J Med 2017 10 4;377(17):1630-1638. Epub 2017 Oct 4.

From Massachusetts General Hospital and Harvard Medical School (F.E., P.L.M.), Dana-Farber and Boston Children's Cancer and Blood Disorders Center (C. Duncan, M.A., C. Dansereau, D.A.W.), and Boston Children's Hospital, Harvard Medical School, and Harvard Stem-Cell Institute (D.A.W.), Boston, and Bluebird Bio, Cambridge (A.M.P., E.S., T.O., D.D.) - all in Massachusetts; University of Minnesota Children's Hospital, Minneapolis (P.J.O., T.C.L., W.P.M., G.V.R.); University of California, Los Angeles, Los Angeles (S.D.O., R.S., A.J.S.); University College London Great Ormond Street Hospital Institute of Child Health and Great Ormond Street Hospital NHS Trust, London (A.J.T., H.B.G., P.G.); Pediatric Neurology Department, Hôpital Bicêtre-Hôpitaux Universitaires Paris Sud, Le Kremlin Bicêtre, France (C.S., P.A.); Fundacion Investigar, Buenos Aires (H.A.); and Women's and Children's Hospital, North Adelaide, SA, Australia (D.B., N.J.C.S.).

Background: In X-linked adrenoleukodystrophy, mutations in ABCD1 lead to loss of function of the ALD protein. Cerebral adrenoleukodystrophy is characterized by demyelination and neurodegeneration. Disease progression, which leads to loss of neurologic function and death, can be halted only with allogeneic hematopoietic stem-cell transplantation.

Methods: We enrolled boys with cerebral adrenoleukodystrophy in a single-group, open-label, phase 2-3 safety and efficacy study. Patients were required to have early-stage disease and gadolinium enhancement on magnetic resonance imaging (MRI) at screening. The investigational therapy involved infusion of autologous CD34+ cells transduced with the elivaldogene tavalentivec (Lenti-D) lentiviral vector. In this interim analysis, patients were assessed for the occurrence of graft-versus-host disease, death, and major functional disabilities, as well as changes in neurologic function and in the extent of lesions on MRI. The primary end point was being alive and having no major functional disability at 24 months after infusion.

Results: A total of 17 boys received Lenti-D gene therapy. At the time of the interim analysis, the median follow-up was 29.4 months (range, 21.6 to 42.0). All the patients had gene-marked cells after engraftment, with no evidence of preferential integration near known oncogenes or clonal outgrowth. Measurable ALD protein was observed in all the patients. No treatment-related death or graft-versus-host disease had been reported; 15 of the 17 patients (88%) were alive and free of major functional disability, with minimal clinical symptoms. One patient, who had had rapid neurologic deterioration, had died from disease progression. Another patient, who had had evidence of disease progression on MRI, had withdrawn from the study to undergo allogeneic stem-cell transplantation and later died from transplantation-related complications.

Conclusions: Early results of this study suggest that Lenti-D gene therapy may be a safe and effective alternative to allogeneic stem-cell transplantation in boys with early-stage cerebral adrenoleukodystrophy. Additional follow-up is needed to fully assess the duration of response and long-term safety. (Funded by Bluebird Bio and others; STARBEAM ClinicalTrials.gov number, NCT01896102 ; ClinicalTrialsRegister.eu number, 2011-001953-10 .).
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http://dx.doi.org/10.1056/NEJMoa1700554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5708849PMC
October 2017

Diffuse microvascular dysfunction and loss of white matter integrity predict poor outcomes in patients with acute ischemic stroke.

J Cereb Blood Flow Metab 2018 01 8;38(1):75-86. Epub 2017 May 8.

1 J. Philip Kistler Stroke Research Center, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

We sought to investigate the relationship between blood-brain barrier (BBB) permeability and microstructural white matter integrity, and their potential impact on long-term functional outcomes in patients with acute ischemic stroke (AIS). We studied 184 AIS subjects with perfusion-weighted MRI (PWI) performed <9 h from last known well time. White matter hyperintensity (WMH), acute infarct, and PWI-derived mean transit time lesion volumes were calculated. Mean BBB leakage rates (K2 coefficient) and mean diffusivity values were measured in contralesional normal-appearing white matter (NAWM). Plasma matrix metalloproteinase-2 (MMP-2) levels were studied at baseline and 48 h. Admission stroke severity was evaluated using the NIH Stroke Scale (NIHSS). Modified Rankin Scale (mRS) was obtained at 90-days post-stroke. We found that higher mean K2 and diffusivity values correlated with age, elevated baseline MMP-2 levels, greater NIHSS and worse 90-day mRS (all p < 0.05). In multivariable analysis, WMH volume was associated with mean K2 ( p = 0.0007) and diffusivity ( p = 0.006) values in contralesional NAWM. In summary, WMH severity measured on brain MRI of AIS patients is associated with metrics of increased BBB permeability and abnormal white matter microstructural integrity. In future studies, these MRI markers of diffuse cerebral microvascular dysfunction may improve prediction of cerebral tissue infarction and functional post-stroke outcomes.
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http://dx.doi.org/10.1177/0271678X17706449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5757442PMC
January 2018

Leptomeningeal transthyretin-type amyloidosis presenting as acute hydrocephalus and subarachnoid hemorrhage.

J Clin Neurosci 2016 Jul 16;29:203-5. Epub 2016 Feb 16.

Department of Neurology, Massachusetts General Hospital, 55 Fruit Street, WACC 835, Boston, MA 02118, USA.

We present a report of a 47-year-old woman with developmental delay who presented with subarachnoid hemorrhage and acute hydrocephalus. She did not have an aneurysm, but there was symmetric calcification and gadolinium-enhancement of the meninges within the Sylvian fissure. Biopsy and genetic testing confirmed transthyretin-type amyloidosis. It is important to consider such rare causes in atypical presentations of non-aneurysmal subarachnoid hemorrhage.
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http://dx.doi.org/10.1016/j.jocn.2015.12.017DOI Listing
July 2016

Brain endothelial dysfunction in cerebral adrenoleukodystrophy.

Brain 2015 Nov 15;138(Pt 11):3206-20. Epub 2015 Sep 15.

1 Department of Neurology, Massachusetts General Hospital, Boston, MA, USA 2 Center for Rare Neurological Diseases, Massachusetts General Hospital, Boston, MA, USA.

See Aubourg (doi:10.1093/awv271) for a scientific commentary on this article.X-linked adrenoleukodystrophy is caused by mutations in the ABCD1 gene leading to accumulation of very long chain fatty acids. Its most severe neurological manifestation is cerebral adrenoleukodystrophy. Here we demonstrate that progressive inflammatory demyelination in cerebral adrenoleukodystrophy coincides with blood-brain barrier dysfunction, increased MMP9 expression, and changes in endothelial tight junction proteins as well as adhesion molecules. ABCD1, but not its closest homologue ABCD2, is highly expressed in human brain microvascular endothelial cells, far exceeding its expression in the systemic vasculature. Silencing of ABCD1 in human brain microvascular endothelial cells causes accumulation of very long chain fatty acids, but much later than the immediate upregulation of adhesion molecules and decrease in tight junction proteins. This results in greater adhesion and transmigration of monocytes across the endothelium. PCR-array screening of human brain microvascular endothelial cells after ABCD1 silencing revealed downregulation of both mRNA and protein levels of the transcription factor c-MYC (encoded by MYC). Interestingly, MYC silencing mimicked the effects of ABCD1 silencing on CLDN5 and ICAM1 without decreasing the levels of ABCD1 protein itself. Together, these data demonstrate that ABCD1 deficiency induces significant alterations in brain endothelium via c-MYC and may thereby contribute to the increased trafficking of leucocytes across the blood-brain barrier as seen in cerebral adrenouleukodystrophy.
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http://dx.doi.org/10.1093/brain/awv250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4731416PMC
November 2015

Hematopoietic stem cell transplantation in the leukodystrophies: a systematic review of the literature.

Neuropediatrics 2014 Jun 23;45(3):169-74. Epub 2014 Jan 23.

Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, United States.

Objective: The objective of this study is to systematically review the literature on worldwide numbers of leukodystrophy patients undergoing hematopoietic stem cell transplantation (HSCT) as well as the safety and efficacy of the procedure in this patient population.

Materials And Methods: A PubMed and EMBASE search up to June 2012 was conducted with a manual search of references from relevant articles. Selected studies were evaluated using internationally accepted criteria. The effect estimates of HSCT upon survival in early-stage disease versus late-stage disease were compared.

Results: One hundred and fifty-two studies qualified for inclusion and reported on a total of 689 patients. Study quality ranged from poor to good; no study was rated excellent. Small sample sizes limited most studies. Meta-analysis in a subset of larger studies indicates that transplantation in earlier stages of disease fairs better than in the late stages. Beyond survival, little longitudinal data on functional outcome is reported and neurological outcome is sparse.

Conclusion: Further studies are needed to determine the neurological outcome following HSCT in the leukodystrophies. HSCT in the early stages of cerebral disease is still recommended for select leukodystrophies.
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http://dx.doi.org/10.1055/s-0033-1364179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157669PMC
June 2014

Signaling cascade of insulin-induced stimulation of L-dopa uptake in renal proximal tubule cells.

Am J Physiol Cell Physiol 2008 Dec 8;295(6):C1602-9. Epub 2008 Oct 8.

Centro de Investigaciones Endocrinológicas, Consejos Nacional de Investigaciones Cientificas y Tecnicas, Buenos Aires, Argentina.

The inward l-dihydroxyphenylalanine (L-dopa) transport supplies renal proximal tubule cells (PTCs) with the precursor for dopamine synthesis. We have previously described insulin-induced stimulation of L-dopa uptake into PTCs. In the present paper we examined insulin-related signaling pathways involved in the increase of l-dopa transport into isolated rat PTCs. Insulin (50-500 microU/ml) increased L-dopa uptake by PTCs, reaching the maximal increment (60% over the control) at 200 microU/ml. At this concentration, insulin also increased insulin receptor tyrosine phosphorylation. Both effects were abrogated by the tyrosine kinase inhibitor genistein (5 microM). In line, inhibition of the protein tyrosine phosphatase by pervanadate (0.2-100 microM) caused a concentration-dependent increase in both the uptake of L-dopa (up to 400%) and protein tyrosine phosphorylation. A synergistic effect between pervanadate and insulin on L-dopa uptake was observed only when threshold (0.2 microM), but not maximal (5 microM), concentrations of pervanadate were assayed. Insulin-induced stimulation of L-dopa uptake was also abolished by inhibition of phosphatidylinositol 3-kinase (PI3K; 100 nM wortmannin, and 25 microM LY-294002) and protein kinase C (PKC; 1 microM RO-318220). Insulin-induced activation of PKC-zeta was confirmed in vitro by its translocation from the cytosol to the membrane fraction, and in vivo by immunohistochemistry studies. Insulin caused a wortmannin-sensitive increase in Akt/protein kinase B (Akt/PKB) phosphorylation and a dose-dependent translocation of Akt/PKB to the membrane fraction. Our findings suggest that insulin activates PKC-zeta, and Akt/PKB downstream of PI3K, and that these pathways contribute to the insulin-induced increase of L-dopa uptake into PTCs.
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http://dx.doi.org/10.1152/ajpcell.00090.2008DOI Listing
December 2008

Nerve degeneration is prevented by a single intraneural apotransferrin injection into colchicine-injured sciatic nerves in the rat.

Brain Res 2006 Oct 28;1117(1):80-91. Epub 2006 Sep 28.

Faculty of Biomedical Sciences, Austral University, Av. Pte. Perón 1500, B1629AHJ Pilar, Prov. Buenos Aires, Argentina.

In this work, we have immunohistochemically analyzed the effects of single injections of apotransferrin (aTf) on the expression of myelin (myelin basic proteins [MBPs]) and axonal (protein gene product 9.5 [PGP 9.5] and beta(III)-tubulin [beta(III)-tub]) proteins in colchicine-injected and crushed sciatic nerves of adult rats. A protein redistribution was seen in the distal stump of injured nerves, with the appearance of MBP- and PGP 9.5-immunoreactive (IR) clusters which occurred earlier in crushed nerves (3 days post-injury [PI]) as compared to colchicine-injected nerves (7 days PI). beta(III)-tub-IR clusters appeared at 1 day PI preceding the PGP 9.5- and MBP-IR clusters in colchicine-injected nerves. With image analysis, the peak of clustering formation was found at 14 days PI for MBP and at 3 days PI for beta(III)-tub in colchicine-injected nerves. At 28 days of survival, the protein distribution patterns were almost normal. The intraneural application of aTf, at different concentrations (0.0005 mg/ml, 0.005 mg/ml, 0.05 mg/ml, 0.5 mg/ml), prevented nerve degeneration produced by colchicine, with the appearance of only a small number of MBP- and beta(III)-tub-IR clusters. However, aTf was not able to prevent clustering formation when the nerve was crushed, a kind of injury that also involves necrosis and blood flow alterations. The results suggest that aTf could prevent the colchicine effects by stabilizing the cytoskeleton proteins of the nerve fibers, avoiding the disruption of the axonal transport and thus the myelin degeneration. Transferrin is proposed as a complementary therapeutic avenue for treatment of cytotoxic nerve injuries.
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http://dx.doi.org/10.1016/j.brainres.2006.02.045DOI Listing
October 2006

Normal anatomy of the developing fetal brain. Ex vivo anatomical-magnetic resonance imaging correlation.

J Neurol Sci 2006 Dec 14;250(1-2):20-6. Epub 2006 Aug 14.

Science and Technology Department, (UBACYT) Buenos Aires University, Paraguay 2155, Buenos Aires, Argentina.

Fetal brain Magnetic Resonance Imaging (MRI) is a new technique of growing interest, with a high potential to detect prenatal central nervous system abnormalities. This requires an accurate knowledge of the normal morphological sequence of brain development. In this paper we studied the cortical development of post-mortem normal fetal brains, correlating MRI estimations of fetal age with in vitro anatomical and anthropometric measurements. Ten post-mortem fetal heads were submitted to MRI. Maturational state of sulci and gyri and gray-white matter differentiation were analysed in the MRIs and by dissection of the brains. The findings were correlated with the previously estimated ages of the fetuses, which varied between 17 and 38 weeks. Consistency between methods was assessed employing intraclass correlation coefficient and Bland-Altman plots, with a 95% confidence interval. Estimations of fetal age obtained by MRI were very similar to those achieved by anthropometric measurements or by considering anatomical parameters. Gyral development proved to be more precise than gray-white matter differentiation for this purpose. Fetal MRI proved to be as reliable as the macroscopic anatomical examination for depicting normal cortical developmental sequence and age, suggesting that this technique may be a suitable option for achieving precise information about the morphology of human brains along the gestational period.
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http://dx.doi.org/10.1016/j.jns.2006.06.020DOI Listing
December 2006