Publications by authors named "Jorge Santos Silva"

22 Publications

  • Page 1 of 1

Factors associated with one year mortality in ill patients with proximal femoral fractures treated non operatively.

Injury 2021 Jul 1;52 Suppl 3:S60-S64. Epub 2021 Jun 1.

Trauma Service, Instituto de Ortopedia e Traumatologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, SP, Brazil. Electronic address:

Introduction: Non-operative treatment is an exceptional indication for the treatment of proximal femur fracture. The aim of the study was to analyze the mortality rate in one year and associated factors in severely ill patients submitted to non-operative treatment.

Methods: It was included 28 patients treated from August 2014 to September 2019. Eighteen (64.3%) patients were female and 10 (35.7%) were male. The mean age was 78.7 ± 11.9 years old. The main outcome evaluated was the mortality rate in one year. It was also evaluated the correlation with gender, age, personal habits, number of comorbidities and Charlson Comorbidity Index (CCI).

Results: The functional result was assessed with WOMAC score via telephone call. The mortality rate in one year was 42.8% without statistical positive correlation with any of the studied parameters. Patients with three or more comorbidities didn't have a higher mortality rate comparing to survived patients (83.3% vs 81.3%). The CCI also didn't show any correlation with high mortality (6.9 vs 7.1). The functional result of the survived patients was poor (78.2 points WOMAC).

Conclusion: The conclusion is that the mortality rate in one year of ill patients with hip fractures treated non-operatively is 42.8% without correlation with age, gender of number of comorbidities, and the functional result of the survived patients is poor.
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http://dx.doi.org/10.1016/j.injury.2021.04.059DOI Listing
July 2021

Intramedullary Steinmann pin nailing of the ulna: an option for the damage control orthopedics treatment of forearm fractures in open injuries in polytraumatized patients - A description of the technique and presentation of a case series.

Injury 2021 Jul 1;52 Suppl 3:S33-S37. Epub 2021 Jun 1.

Instituto de Ortopedia e Traumatologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, SP, Brazil. Electronic address:

Introduction: Forearm shaft fracture is common in young adult patients and associated with soft tissue and organ injuries. In open fractures in polytrauma patients, damage control orthopaedics (DCO) is well indicated. The aim of this study is to describe intramedullary Steinmann pin fixation of the ulna as a DCO procedure for the forearm and present a case series.

Description Of The Technique: A 3.0 mm Steinmann pin is inserted retrograde in the ulna proximal fragment through the fracture site using the open wound as the approach. With direct visualization of the reduction, the pin is advanced into the distal fragment. The reduction of the longitudinal axis and shortening is thus achieved.

Patients And Methods: This method was used for all open fractures of forearm both-bone fractures in polytrauma patients undergoing DCO from 2014 to 2019. The alignment and length of the ulna were evaluated radiographically after pin fixation and before and after definitive fixation. Differences in the need for secondary procedures and infection rate between DCO and definitive fixation were also evaluated.

Results: There were 30 males (85.7%) with an average age of 32.9 ± 12.0 years and a mean ISS (Injury Severity Score) of 29.4 (range, 18.0-41.0). The most common associated injuries were thoracic trauma (62.8%) and head trauma (45.7%). In the radius and ulna, 51.4% and 60.0% of fractures, respectively, were multifragmentary (types B and C). Gustilo type IIIA represented 77.1% of the injuries. Pin fixation achieved good alignment and length in all cases. The mean time between DCO and definitive fixation was 12.0 days, and no secondary procedure was needed, nor any case developed either superficial or deep infection. The conversion from DCO to definitive fixation was considered easy in all cases.

Conclusion: Intramedullary Steinmann pin fixation of the ulna is a viable option for DCO for forearm both-bone fractures in open fractures in polytrauma patients.
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http://dx.doi.org/10.1016/j.injury.2021.05.033DOI Listing
July 2021

A RETROSPECTIVE CASE-SERIES ON THE USE OF S53P4 BIOACTIVE GLASS FOR THE ADJUNCTIVE TREATMENT OF SEPTIC DIAPHYSEAL NON-UNION.

Acta Ortop Bras 2019 Sep-Oct;27(5):273-275

Universidade de São Paulo, Hospital das Clínicas - HCFMUSP, Faculdade de Medicina, Instituto de Ortopedia e Traumatologia, Reconstruction and Lengthening Group, São Paulo, SP, Brazil.

Objective: Non-union and persistence of infection at a fracture site for long periods are always described as a challenge to orthopedists, especially in cases of severe compound fractures with comminution and segmental bone loss. This is a case series of septic non-unions, using S53P4 bioactive glass for adjunctive treatment, using internal syntheses or external fixators. The objective is to retrospectively evaluate the results of the use of S53P4 bioglass for the adjunctive treatment of septic non-unions.

Methods: We reviewed 18 patients with septic non-unions. The patients were preoperatively classified using the Non-union Scoring System (NUSS) and union outcomes were assessed by the modified radiographic union scale in tibial (RUST) fractures. Of the 18 patients treated, six underwent internal osteosynthesis and 12 were treated with external fixators in combination with bioactive glass grafting.

Results: The patients had a mean NUSS score of 56.6 (standard deviation of 7.6) and fracture union was achieved according to the RUST score in 17 of 18 cases (94.4%), with a mean value of 10.2 (standard deviation of 1.0). One patient was lost to follow-up. Reevaluation using the modified RUST score was 12.3 (SD = 1.0), maintaining union of 17/18.

Conclusion: The fracture union rate was high, according to the literature, as was control of infection.
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http://dx.doi.org/10.1590/1413-785220192705220540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901156PMC
December 2019

Influence of postoperative immobilization on pain control of patients with distal radius fracture treated with volar locked plating: A prospective, randomized clinical trial.

Injury 2019 Feb 4;50(2):386-391. Epub 2018 Dec 4.

Universidade de Sao Paulo, Faculdade de Medicina, Hospital das Clinicas, Instituto de Ortopedia e Traumatologia (IOT-HCFMUSP), Sao Paulo, SP, Brasil.

Objectives: The purpose of this study was to compare the pain scores and the rates and doses of opioid use in patients undergoing volar locked plate fixation of intra-articular distal radius fractures using or not postoperative immobilization.

Methods: This was a prospective randomized controlled trial. Thirty-nine patients with distal radius fractures scheduled to receive volar plate fixation were randomly assigned to receive a short forearm splint for two weeks postoperatively or conventional bandage with early wrist mobilization. Thirty-six patients completed the follow-up. The outcome measurements included pain scores (0-10 points); rates and doses of tramadol use; DASH score; wrist range of motion; patient satisfaction; and complication rates. The last follow-up assessment was performed at 6 months.

Results: The pain scores were similar between the groups during hospital stay, as well as after hospital discharge within the first week and in subsequent assessments up to six months. The rates of tramadol use were greater in the No splint group during hospital stay, but this difference was not statistically significant (No splint = 65%; Splint = 47%; p = 0.296). Likewise, the doses of tramadol intake were higher in the No splint group during hospital stay (No splint = 218 mg; Splint = 167 mg; p = 0.273) and after discharge (2 day: No splint = 112 mg; Splint = 75 mg; p = 0.286), with no statistically significant differences. The functional results and complication rates were similar between the groups.

Conclusions: In this study, there was a trend to a greater use of tramadol in patients who did not use immobilization and started early wrist mobilization after volar locked plating of distal radius fracture, compared with patients who were immobilized for two weeks. The pain scores were similar but may have been influenced by the unbalanced use of opioids between the groups. The functional results and complication rates were not influenced by the use of immobilization.

Level Of Evidence: Therapeutic Level I.
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http://dx.doi.org/10.1016/j.injury.2018.12.001DOI Listing
February 2019

Functional results and isokinetic muscle strength in patients with Fraser type I floating knee treated with internal fixation.

Injury 2017 Oct;48 Suppl 4:S2-S5

Department of Orthopedics and Traumatology, University of Sao Paulo, Brazil.

Introduction: According to Fraser's description, ipsilateral femoral and tibial diaphyseal fractures are characterised as type I floating knee and have a better prognosis than fractures with joint involvement (type II). There are few reports of functional and muscle strength in these patients. The objective of this study was to evaluate the functional and isokinetic muscle strength of patients with type I floating knee undergoing femoral and tibial internal fixation.

Methods: Patients with type I floating knee undergoing concomitant femoral and tibial internal fixation were invited for clinical evaluation. The parameters evaluated included the following: Karlstrom and Olerud score; Lysholm score; isokinetic thigh and hip muscle evaluation; knee range of motion; pain level; investigation of associated knee injuries by clinical evaluation and MRI; and types of complications.

Results: Twenty-one patients were included in the study; 11 of these were clinically evaluated, with a mean follow-up of 23.9 months. Six patients had an acceptable result according to the Karlstrom criteria, whereas eight patients had a poor result based on the Lysholm scale. The peak torque deficit was 61% for knee extensors, 37% for flexors and -9% for hip abductors. The mean pain level was 5.9. Three patients had a partial anterior cruciate ligament (ACL) injury; one patient had a posterior cruciate ligament (PCL) injury; and three patients had a meniscal injury. There were four cases of tibial or femoral nonunion at one year and two cases of chronic osteomyelitis.

Conclusion: Patients with type I floating knee had unsatisfactory functional results, significant knee extensor and flexor muscle strength deficits and a significant rate of complications at the two-year follow-up.
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http://dx.doi.org/10.1016/S0020-1383(17)30767-2DOI Listing
October 2017

FEMORAL NECK FRACTURES GARDEN I AND II: EVALUATION OF THE DEVIATION IN LATERAL VIEW.

Acta Ortop Bras 2017 Mar-Apr;25(2):107-109

1 Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, Instituto de Ortopedia e Traumatologia, São Paulo, SP, Brazil.

Objective: To evaluate the rate of deviation in the lateral radiographic incidence in patients with femoral neck fracture classified as non-diverted in the anteroposterior view (Garden I and II).

Methods: Nineteen selected patients with femoral neck fractures classified as Garden I and II were retrospectively evaluated, estimating the degree of deviation in the lateral view.

Results: Fifteen cases (79%) presented deviations in lateral view, with a mean of 18.6 degrees (±15.5).

Conclusion: Most fractures of the femoral neck classified as Garden I and II present some degree of posterior deviation in the X-ray lateral view.
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http://dx.doi.org/10.1590/1413-785220172502169349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474424PMC
June 2017

The incidence and microbiological profile of surgical site infections following internal fixation of closed and open fractures.

Rev Bras Ortop 2016 Jul-Aug;51(4):396-9. Epub 2016 Feb 2.

Universidade de São Paulo, Hospital das Clínicas, Instituto de Ortopedia e Traumatologia, São Paulo, SP, Brazil.

Objective: To evaluate the incidence and microbiological profile of surgical site infections (SSIs) associated with internal fixation of fractures and to compare differences in the SSIs observed among patients with closed and open fractures.

Methods: Retrospective study. Analyzed data included information from all patients who underwent surgery for fixation of closed or open fractures from January 2005 to December 2012 and remained outpatients for at least one year following surgery. Incidence of surgical site infection (SSI) was compared between patients with closed and open infection, as well as polymicrobial infection and infection related to Gram-negative bacilli (GNB). Cumulative antibiograms were performed to describe microbiological profiles.

Results: Overall incidence of SSI was 6%. This incidence was significantly higher among patients with open fractures (14.7%) than among patients with closed fractures (4.2%). The proportions of patients with polymicrobial infections and infections due to GNB were also significantly higher among patients with open fractures. Staphylococcus aureus and coagulase-negative Staphylococcus (CoNS) species were the primary infectious agents isolated from both groups. The overall incidence of MRSA (methicillin-resistant S. aureus) was 72%. A. baumannii was the predominant GNB isolate recovered from patients with open fractures and P. aeruginosa was the most frequent isolate recovered from patients with closed fractures, both exhibited low rates of susceptibility to carbapenems.

Conclusions: Incidence of SSIs related to the internal fixation of fractures was significantly higher among patients with open fractures, indicating that an open fracture can be a risk factor for infection. Among the bacterial isolates, S. aureus (with a high prevalence of MRSA) and CoNS species were most prevalent. A. baumannii and P. aeruginosa isolates underscored the low rate of susceptibility to carbapenems that was observed in the present study.
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http://dx.doi.org/10.1016/j.rboe.2015.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4974164PMC
August 2016

Alcohol and drug involvement in motorcycle driver injuries in the city of Sao Paulo, Brazil: Analysis of crash culpability and other associated factors.

Drug Alcohol Depend 2016 May 16;162:199-205. Epub 2016 Mar 16.

Department of Traumatology and Orthopaedics, University of Sao Paulo Medical School, Sao Paulo 05403-010, Brazil. Electronic address:

Background: Earlier studies have already identified that a greater proportion of injured drivers are under the effects of illicit drugs than alcohol in Brazil, but the crash risk attributable to each substance is still unknown.

Methods: Injured motorcycle drivers who were involved in traffic accidents in the West Zone of the city of Sao Paulo were recruited for a cross-sectional study based on crash culpability analysis. Alcohol and drug positivity among drivers was evaluated according to their responsibility for the crash. Culpability ratios were generated based on the proportion of drivers who were deemed culpable in relation to those considered not culpable according to the use of drugs and alcohol.

Results: Of the 273 drivers recruited, 10.6% tested positive for alcohol. Among those who were also tested for drugs (n=232), 20.3% had consumed either alcohol and/or other drugs, 15.5% of whom were positive only for drugs other than alcohol, specifically cannabis and cocaine. Drivers who tested positive for alcohol were significantly less likely to possess a valid driver's license and to report driving professionally, whereas those who had consumed only drugs were more likely to drive professionally. The culpability ratio estimated for alcohol-positive drivers was three times higher than that for alcohol-free drivers, showing a superior ratio than drivers who had consumed only drugs other than alcohol, who presented a 1.7 times higher culpability ratio than drug-free drivers.

Conclusion: Substance use was overrepresented among culpable motorcycle drivers, with alcohol showing a greater contribution to crash culpability than other drugs.
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http://dx.doi.org/10.1016/j.drugalcdep.2016.03.007DOI Listing
May 2016

Advances in treating exposed fractures.

Rev Bras Ortop 2015 Mar-Apr;50(2):125-30. Epub 2015 Feb 26.

Department of Orthopedics and Traumatology, Hospital das Clínicas, School of Medicine, Universidade de São Paulo, São Paulo, SP, Brazil.

The management of exposed fractures has been discussed since ancient times and remains of great interest to present-day orthopedics and traumatology. These injuries are still a challenge. Infection and nonunion are feared complications. Aspects of the diagnosis, classification and initial management are discussed here. Early administration of antibiotics, surgical cleaning and meticulous debridement are essential. The systemic conditions of patients with multiple trauma and the local conditions of the limb affected need to be taken into consideration. Early skeletal stabilization is necessary. Definitive fixation should be considered when possible and provisional fixation methods should be used when necessary. Early closure should be the aim, and flaps can be used for this purpose.
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http://dx.doi.org/10.1016/j.rboe.2015.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4519576PMC
August 2015

Single, superiorly placed reconstruction plate compared with flexible intramedullary nailing for midshaft clavicular fractures: a prospective, randomized controlled trial.

J Bone Joint Surg Am 2015 Apr;97(8):620-6

Institute of Orthopedics and Traumatology, University of São Paulo, Brazil, Rua Ovidio Pires de Campos 333, 05403-010 São Paulo, Brazil. E-mail address for F.B. Andrade-Silva:

Background: Previous studies have shown good clinical results in patients with midshaft clavicular fractures treated with reconstruction plate fixation or elastic stable intramedullary nailing. The objective of this study was to compare these methods in terms of clinical and radiographic results.

Methods: In this prospective, randomized controlled trial, fifty-nine patients with displaced midshaft clavicular fractures were randomly assigned to receive fixation with either a reconstruction plate (thirty-three patients), known as the plate group, or elastic stable intramedullary nailing (twenty-six patients), known as the nail group. The primary outcome was the six-month Disabilities of the Arm, Shoulder and Hand (DASH) score. The secondary outcomes included the Constant-Murley score, time to fracture union, residual shortening, level of postoperative pain, percentage of satisfied patients, and complication rates.

Results: The mean six-month DASH score was 9.9 points in the plate group and 8.5 points in the nail group (p = 0.329). Similarly, there were no differences in the twelve-month DASH and Constant-Murley scores. Time to union was equivalent (p = 0.352) between the groups at 16.8 weeks for the plate group and 15.9 weeks for the nail group, whereas the residual shortening was 0.4 cm greater in the plate group (p = 0.032). The visual analog scale pain score and the satisfaction rate were similar between the groups. Implant-related pain was more frequent in the nail group (p = 0.035). There were no differences in terms of major complications.

Conclusions: Reconstruction plates and elastic stable intramedullary nailing yielded similar functional results, time to union, level of postoperative pain, and patient satisfaction rates. Both methods were safe in terms of major complications.
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http://dx.doi.org/10.2106/JBJS.N.00497DOI Listing
April 2015

Outcomes evaluation of locking plate osteosynthesis in displaced fractures of the proximal humerus.

Rev Bras Ortop 2013 Nov-Dec;48(6):491-499. Epub 2013 Dec 25.

Instituto de Ortopedia e Traumatologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.

Objective: To evaluate functional outcomes, radiographic findings and complications of proximal humeral fractures treated with locking plates and to determine prognostic factors for successful clinical outcomes.

Methods: Forty patients undergoing internal fixation of fractures of the proximal humerus with the Philos plate were included in the study. The surgeries were performed between 2004 and 2011 and the patients underwent radiographic and clinical evaluation, by Constant-Murley and Dash score. Outcomes were analyzed by use of multivariate regression with several different variables.

Results: Patients were on average of 61.8 ± 16.28 years, and most were female (70%). The Constant-Murley score was 72.03 ± 14.01 and Dash score was 24.96 ± 19.99. The postoperative radiographs showed a head-shaft angle of 135.43° ± 11.82. Regression analysis showed that the patient's age and the Hertel classification influenced the Constant-Murley scale ( = 0.0049 and 0.012, respectively). Other prognostic criteria such as Neer and AO classification, head-shaft angle, the presence of metaphyseal comminution and extension of the humeral metaphyseal fragment showed no effect on prognosis. Complications occurred in four patients (10%).

Conclusion: The fixation with the Philos plate provided good clinical and radiographic results in fractures of the proximal humerus, with a low complication rate. Patient's age and Hertel classification were defined as prognostic factors that led to worse functional outcomes.
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http://dx.doi.org/10.1016/j.rboe.2013.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565971PMC
December 2013

GABA expression and regulation by sensory experience in the developing visual system.

PLoS One 2012 5;7(1):e29086. Epub 2012 Jan 5.

Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.

The developing retinotectal system of the Xenopus laevis tadpole is a model of choice for studying visual experience-dependent circuit maturation in the intact animal. The neurotransmitter gamma-aminobutyric acid (GABA) has been shown to play a critical role in the formation of sensory circuits in this preparation, however a comprehensive neuroanatomical study of GABAergic cell distribution in the developing tadpole has not been conducted. We report a detailed description of the spatial expression of GABA immunoreactivity in the Xenopus laevis tadpole brain at two key developmental stages: stage 40/42 around the onset of retinotectal innervation and stage 47 when the retinotectal circuit supports visually-guided behavior. During this period, GABAergic neurons within specific brain structures appeared to redistribute from clusters of neuronal somata to a sparser, more uniform distribution. Furthermore, we found that GABA levels were regulated by recent sensory experience. Both ELISA measurements of GABA concentration and quantitative analysis of GABA immunoreactivity in tissue sections from the optic tectum show that GABA increased in response to a 4 hr period of enhanced visual stimulation in stage 47 tadpoles. These observations reveal a remarkable degree of adaptability of GABAergic neurons in the developing brain, consistent with their key contributions to circuit development and function.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0029086PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3252287PMC
May 2012

Developing ANDI: a novel approach to health product R&D in Africa.

PLoS Med 2010 Jun 29;7(6):e1000293. Epub 2010 Jun 29.

UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), World Health Organization, Geneva, Switzerland.

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http://dx.doi.org/10.1371/journal.pmed.1000293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2893959PMC
June 2010

Type A GABA-receptor-dependent synaptic transmission sculpts dendritic arbor structure in Xenopus tadpoles in vivo.

J Neurosci 2009 Apr;29(15):5032-43

Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.

The emergence of dendritic arbor structure in vivo depends on synaptic inputs. We tested whether inhibitory GABAergic synaptic transmission regulates Xenopus optic tectal cell dendritic arbor development in vivo by expressing a peptide corresponding to an intracellular loop (ICL) of the gamma2 subunit of type A GABA receptors (GABA(A)R), which is required to anchor GABA(A) receptors to the postsynaptic scaffold. Enhanced green fluorescent protein (EGFP)-tagged ICL (EGFP-ICL) was distributed in a punctate pattern at putative inhibitory synapses, identified by vesicular GABA transporter immunoreactive puncta. ICL expression completely blocked GABA(A)R-mediated transmission in 36% of transfected neurons and significantly reduced GABA(A)R-mediated synaptic currents relative to AMPA receptor-mediated synaptic currents in the remaining transfected neurons without altering release probability or neuronal excitability. Further analysis of ICL-expressing neurons with residual GABA(A)R-mediated inputs showed that the capacity of benzodiazepine to enhance GABAergic synaptic responses was reduced in ICL-expressing neurons, indicating that they were likely depleted of gamma2 subunit-containing GABA(A)R. Neurons expressing a mutant form of ICL were comparable to controls. In vivo time-lapse images showed that ICL-expressing neurons have more sparsely branched dendritic arbors, which expand over larger neuropil areas than EGFP-expressing control neurons. Analysis of branch dynamics indicated that ICL expression affected arbor growth by reducing rates of branch addition. Furthermore, we found that decreasing GABAergic synaptic transmission with ICL expression blocked visual experience dependent dendritic arbor structural plasticity. Our findings establish an essential role for inhibitory GABAergic synaptic transmission in the regulation of dendritic structural plasticity in Xenopus in vivo.
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http://dx.doi.org/10.1523/JNEUROSCI.5331-08.2009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2706946PMC
April 2009

Localized recruitment and activation of RhoA underlies dendritic spine morphology in a glutamate receptor-dependent manner.

J Cell Biol 2006 Jan;172(3):453-67

Cavalieri Ottolenghi Scientific Institute, Universita Degli Studi di Torino, Azienda Ospedaliera San Luigi Gonzaga, Regione Gonzole 10, 10043 Orbassano (Torino), Italy.

Actin is the major cytoskeletal source of dendritic spines, which are highly specialized protuberances on the neuronal surface where excitatory synaptic transmission occurs (Harris, K.M., and S.B. Kater. 1994. Annu. Rev. Neurosci. 17:341-371; Yuste, R., and D.W. Tank. 1996. Neuron. 16:701-716). Stimulation of excitatory synapses induces changes in spine shape via localized rearrangements of the actin cytoskeleton (Matus, A. 2000. Science. 290:754-758; Nagerl, U.V., N. Eberhorn, S.B. Cambridge, and T. Bonhoeffer. 2004. Neuron. 44:759-767). However, what remains elusive are the precise molecular mechanisms by which different neurotransmitter receptors forward information to the underlying actin cytoskeleton. We show that in cultured hippocampal neurons as well as in whole brain synaptosomal fractions, RhoA associates with glutamate receptors (GluRs) at the spine plasma membrane. Activation of ionotropic GluRs leads to the detachment of RhoA from these receptors and its recruitment to metabotropic GluRs. Concomitantly, this triggers a local reduction of RhoA activity, which, in turn, inactivates downstream kinase RhoA-specific kinase, resulting in restricted actin instability and dendritic spine collapse. These data provide a direct mechanistic link between neurotransmitter receptor activity and the changes in spine shape that are thought to play a crucial role in synaptic strength.
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http://dx.doi.org/10.1083/jcb.200506136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2063654PMC
January 2006

Centrosome localization determines neuronal polarity.

Nature 2005 Aug;436(7051):704-8

Cavalieri Ottolenghi Scientific Institute, Universita degli Studi di Torino, 10043 Orbassano, Torino, Italy.

Neuronal polarization occurs shortly after mitosis. In neurons differentiating in vitro, axon formation follows the segregation of growth-promoting activities to only one of the multiple neurites that form after mitosis. It is unresolved whether such spatial restriction makes use of an intrinsic program, like during C. elegans embryo polarization, or is extrinsic and cue-mediated, as in migratory cells. Here we show that in hippocampal neurons in vitro, the axon consistently arises from the neurite that develops first after mitosis. Centrosomes, the Golgi apparatus and endosomes cluster together close to the area where the first neurite will form, which is in turn opposite from the plane of the last mitotic division. We show that the polarized activities of these organelles are necessary and sufficient for neuronal polarization: (1) polarized microtubule polymerization and membrane transport precedes first neurite formation, (2) neurons with more than one centrosome sprout more than one axon and (3) suppression of centrosome-mediated functions precludes polarization. We conclude that asymmetric centrosome-mediated dynamics in the early post-mitotic stage instruct neuronal polarity, implying that pre-mitotic mechanisms with a role in division orientation may in turn participate in this event.
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http://dx.doi.org/10.1038/nature03811DOI Listing
August 2005

Asymmetric membrane ganglioside sialidase activity specifies axonal fate.

Nat Neurosci 2005 May 17;8(5):606-15. Epub 2005 Apr 17.

Cavalieri Ottolenghi Scientific Institute, University of Turin, 10043 Orbassano, Turin, Italy.

Axon specification triggers the polarization of neurons and requires the localized destabilization of filamentous actin. Here we show that plasma membrane ganglioside sialidase (PMGS) asymmetrically accumulates at the tip of one neurite of the unpolarized rat neuron, inducing actin instability. Suppressing PMGS activity blocks axonal generation, whereas stimulating it accelerates the formation of a single (not several) axon. PMGS induces axon specification by enhancing TrkA activity locally, which triggers phosphatidylinositol-3-kinase (PI3K)- and Rac1-dependent inhibition of RhoA signaling and the consequent actin depolymerization in one neurite only. Thus, spatial restriction of an actin-regulating molecular machinery, in this case a membrane enzymatic activity, before polarization is enough to determine axonal fate.
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http://dx.doi.org/10.1038/nn1442DOI Listing
May 2005

Citron-N is a neuronal Rho-associated protein involved in Golgi organization through actin cytoskeleton regulation.

Nat Cell Biol 2003 Dec 2;5(12):1071-8. Epub 2003 Nov 2.

Dipartimento di Genetica, Biologia e Biochimica, Università Degli Studi di Torino Via Santena, 5 bis, Torino, Italy.

The actin cytoskeleton is best known for its role during cellular morphogenesis. However, other evidence suggests that actin is also crucial for the organization and dynamics of membrane organelles such as endosomes and the Golgi complex. As in morphogenesis, the Rho family of small GTPases are key mediators of organelle actin-driven events, although it is unclear how these ubiquitously distributed proteins are activated to regulate actin dynamics in an organelle-specific manner. Here we show that the brain-specific Rho-binding protein Citron-N is enriched at, and associates with, the Golgi apparatus of hippocampal neurons in culture. Suppression of the whole protein or expression of a mutant form lacking the Rho-binding activity results in dispersion of the Golgi apparatus. In contrast, high intracellular levels induce localized accumulation of RhoA and filamentous actin, protecting the Golgi from the rupture normally produced by actin depolymerization. Biochemical and functional analyses indicate that Citron-N controls actin locally by assembling together the Rho effector ROCK-II and the actin-binding, neuron-specific, protein Profilin-IIa (PIIa). Together with recent data on endosomal dynamics, our results highlight the importance of organelle-specific Rho modulators for actin-dependent organelle organization and dynamics.
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http://dx.doi.org/10.1038/ncb1064DOI Listing
December 2003

Obstruction to the pulmonary venous flow in an infant.

Rev Port Cardiol 2003 Jun;22(6):841-3

Serviços de Cardiologia Pediátrica e Neonatologia, Hospital de S. João, Porto.

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June 2003

RhoA/ROCK regulation of neuritogenesis via profilin IIa-mediated control of actin stability.

J Cell Biol 2003 Sep;162(7):1267-79

Cavalieri Ottolenghi Scientific Institute, University of Turin, 10043 Orbassano, Torino, Italy.

Neuritogenesis, the first step of neuronal differentiation, takes place as nascent neurites bud from the immediate postmitotic neuronal soma. Little is known about the mechanisms underlying the dramatic morphological changes that characterize this event. Here, we show that RhoA activity plays a decisive role during neuritogenesis of cultured hippocampal neurons by recruiting and activating its specific kinase ROCK, which, in turn, complexes with profilin IIa. We establish that this previously uncharacterized brain-specific actin-binding protein controls neurite sprouting by modifying actin stability, a function regulated by ROCK-mediated phosphorylation. Furthermore, we determine that this novel cascade is switched on or off by physiological stimuli. We propose that RhoA/ROCK/PIIa-mediated regulation of actin stability, shown to be essential for neuritogenesis, may constitute a central mechanism throughout neuronal differentiation.
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http://dx.doi.org/10.1083/jcb.200304021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2173969PMC
September 2003

Proteomic characterisation of neuronal sphingolipid-cholesterol microdomains: role in plasminogen activation.

Brain Res 2003 Oct;987(1):107-16

Cavalieri Ottolenghi Scientific Institute, Universita degli Studi di Torino, Ospedale San Luigi, Regione Gonzole 10, 10043 Turin, Orbassano, Italy.

Sorting of certain membrane proteins requires a mechanism involving rafts, protein-lipid complexes enriched in glycosphingolipids and cholesterol. These microdomains remain at the plasma membrane of different cell types and play a role in signal transduction. Although recent reports have begun to describe molecules associated with rafts, their protein composition remains largely unknown, especially in neuronal cells. To address this question, we have purified detergent-insoluble raft fractions (DRMs) from primary cultures of hippocampal neurons. Bidimensional gel analysis and pharmacological raft lipid manipulation allowed the identification of neuronal raft proteins and their characterisation by MALDI-TOF analysis. Enolases were found among the proteins identified and functional studies demonstrate their participation in plasminogen binding. We also show the specific enrichment in rafts of several other plasminogen binding molecules and the exclusive activation of plasminogen to the protease plasmin in these microdomains. These observations suggest that neuronal rafts may play, in addition to intracellular signaling, a role in extracellular/membrane protein proteolysis.
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http://dx.doi.org/10.1016/s0006-8993(03)03296-7DOI Listing
October 2003

Breaking the neuronal sphere: regulation of the actin cytoskeleton in neuritogenesis.

Nat Rev Neurosci 2002 Sep;3(9):694-704

Cavalieri Ottolenghi Scientific Institute, Universita Degli Studi di Torino, A.O. San Luigi Gonzaga, Regione Gonzole 10, 10024 Orbassano, Torino, Italy.

The sprouting of neurites, which will later become axons and dendrites, is an important event in early neuronal differentiation. Studies in living neurons indicate that neuritogenesis begins immediately after neuronal commitment, with the activation of membrane receptors by extracellular cues. These receptors activate intracellular cascades that trigger changes in the actin cytoskeleton, which promote the initial breakdown of symmetry. Then, through the regulation of gene transcription, and of microtubule and membrane dynamics, the newly formed neurite becomes stabilized. A key challenge is to define the molecular machinery that regulates the actin cytoskeleton during initial neurite sprouting. We propose that analysing the molecules involved in actin-dependent mechanisms in non-neuronal systems, such as budding yeast and migrating fibroblasts, could help to uncover the secrets of neuritogenesis.
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http://dx.doi.org/10.1038/nrn918DOI Listing
September 2002
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