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1.
Polymers (Basel) ; 15(14)2023 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-37514401

RESUMO

This work investigates the effect of dilution on the phase separation process of binary charged polysaccharide-surfactant mixtures formed by two cationic polysaccharides and up to four surfactants of different nature (anionic, zwitterionic, and neutral), as well as the potential impact of dilution-induced phase separation on the formation of conditioning deposits on charged surfaces, mimicking the negative charge and wettability of damaged hair fibers. The results obtained showed that the dilution behavior of model washing formulations (concentrated polysaccharide-surfactant mixtures) cannot be described in terms of a classical complex precipitation framework, as phase separation phenomena occur even when the aggregates are far from the equilibrium phase separation composition. Therefore, dilution-enhanced deposition cannot be predicted in terms of the worsening of colloidal stability due to the charge neutralization phenomena, as common phase separation and, hence, enhanced deposition occurs even for highly charged complexes.

2.
OTA Int ; 5(3 Suppl): e198, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35949498

RESUMO

Fragility fractures represent a growing global problem, including in the United Kingdom and European countries. Reports demonstrate the benefits of national guidance and organized fragility fracture programs through fracture liaison services to deliver care to patients who sustain these injuries. The challenge of assembling multidisciplinary teams, providing routine screening of appropriate patients, and monitoring therapies where there is a known compliance problem, remains an obstacle to the success of fragility fracture treatment programs to all. Efforts should continue to introduce and maintain fracture liaison services through coordinated national approaches and advanced systems.

3.
Polymers (Basel) ; 14(7)2022 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-35406209

RESUMO

Mixtures of polyelectrolytes and surfactants are commonly used in many technological applications where the challenge is to provide well-defined modifications of the surface properties, as is the case of washing formulations in cosmetics. However, if contemporary experimental and theoretical methods can provide insights on their behavior in concentrated formulations, less is known on their behavior under practical use conditions, e.g., under dilution and vectorization of deposits. This makes it difficult to make predictions for specific performance, as, for example, good hair manageability after a shampoo or a comfortable sensorial appreciation after a skin cleanser. This is especially important when considering the formulation of new, more eco-friendly formulations. In this work, a detailed study of the phase separation process induced by dilution is described, as well as the impact on the deposition of conditioning material on negatively charged surfaces. In order to gain a more detailed physical insight, several polyelectrolyte-surfactant pairs, formed by two different polymers and five surfactants that, although non-natural or eco-friendly, can be considered as models of classical formulations, have been studied. The results evidenced that upon dilution the behavior, and hence its deposition onto the surface, cannot be predicted in terms of the behavior of simpler pseudo-binary (mixtures of a polymer and a surfactant) or pseudo-ternary mixtures (two polymers and a surfactant). In many cases, phase separation was observed for concentrations similar to those corresponding to the components in some technological formulations, whereas the latter appeared as monophasic systems. Therefore, it may be assumed that the behavior in multicomponent formulations is the result of a complex interplay of synergistic interactions between the different components that will require revisiting when new, more eco-sustainable ingredients are considered.

4.
World J Orthop ; 13(2): 150-159, 2022 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-35317403

RESUMO

BACKGROUND: Hemiarthroplasty is the most common treatment in elderly patients with displaced intra-capsular femoral neck fracture (FNF). Prosthetic joint infection (PJI) is one of the most feared and frequent complications post-surgery because of the frail health status of these patients and the need for fast track surgery. Therefore, priorities should lie in effective preventive strategies to mitigate this burden. AIM: To determine how much the implementation of the routine use of antibiotic-loaded bone cement (ALBC) as a relatively easy-to-apply amendment to the surgical practice reduces the infection rate in our hemiarthroplasty cohort. METHODS: We retrospectively assessed all demographic, health status and treatment-related data of our FNF patients undergoing cemented hemiarthroplasty in the period from 2011 to 2017; 241 patients were further analyzed after exclusion of patients with cancer-related sequelae and those who died before the end of the 1-year observation period. The PJI rate as diagnosed on basis of the Musculoskeletal Infection Society (MSIS) criteria 2011 was determined for each included patient and compared in function of the bone cement used for hip stem fixation. Patients were split into a group receiving a plain bone cement in the period from January 2011 to June 2013 (non-ALBC group) and into a group receiving an ALBC in the period July 2013 to December 2017 (ALBC group). Data analysis was performed with statistical software. We further calculated the cost-efficacy of the implementation of routine use of ALBC in the second group balancing the in-hospital infection related treatment costs with the extra costs of use of ALBC. RESULTS: In total 241 FNF patients who received cemented hemiarthroplasty in the period from January 2011 to January 2017 were eligible for inclusion in this retrospective study. There were 8 PJI cases identified in the ALBC group among n = 94 patients, whereas 28 PJI cases were observed in the non-ALBC group among n = 147 patients. The statistical analysis showed an infection risk reduction of 55.3% (in particular due to the avoidance of chronic delayed infections) in the ALBC group (95%CI: 6.2%-78.7%; P = 0.0025). The cost-evaluation analysis demonstrated a considerable cost saving of 3.500 € per patient, related to the implementation of routine use of ALBC in this group. CONCLUSION: Use of ALBC is a potent infection preventive factor in FNF patients receiving cemented hemiarthroplasties. It was further found to be highly cost-effective.

5.
JTO Clin Res Rep ; 3(1): 100266, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35024640

RESUMO

INTRODUCTION: SCLC is one of the most lethal malignancies. Classically, staging has been performed using a dual classification distinguishing limited from the extensive stage. This study aimed to evaluate the prognostic value of TNM staging in a real-world population of patients with SCLC. METHODS: Patients were selected from the Surveillance Epidemiology and End Results database. Chi-square bivariate analysis was used for the association of binary qualitative variables. A multivariate Cox regression analysis was performed to determine the impact of these prognostic factors on median overall survival (mOS) and long-term survival. RESULTS: A total of 26,221 patients were included (50.7% men, 55.7% ≥65 y, 82% White). At diagnosis, 18,574 (70.83%) presented metastases, which were more frequent in the liver (n = 11,896, 64%). In the overall population, mOS was 8 (7.86-8.14) months, which decreased according to each increasing category of TNM staging (p < 0.0001). The worse mOS was found among patients with stage IV SCLC (6 mo, 95% confidence interval: 5.83-6.17). Long-term survival decreased according to TNM staging, with patients having stage IV SCLC exhibiting the lowest survival rates at all follow-up time points. Within stage IV, the lowest mOS values were found in patients greater than or equal to 65 years and in those with liver metastases. Among the TNM stages corresponding to the limited stage, stage IB revealed the lowest hazard ratios value for risk of death compared with stage IA (hazard ratio = 1.161, 95% confidence interval: 0.97-1.40, p = 0.114), which increased gradually within the limited-stage SCLC. In the multivariate analysis, TNM staging, male sex, and older age resulted in poor prognostic factors for survival. CONCLUSIONS: TNM staging seems to define prognosis in patients with SCLC in the real-world setting, particularly for those patients with earlier disease.

6.
BMC Musculoskelet Disord ; 22(1): 360, 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33863319

RESUMO

BACKGROUND: 3D printing technology in hospitals facilitates production models such as point-of-care manufacturing. Orthopedic Surgery and Traumatology is the specialty that can most benefit from the advantages of these tools. The purpose of this study is to present the results of the integration of 3D printing technology in a Department of Orthopedic Surgery and Traumatology and to identify the productive model of the point-of-care manufacturing as a paradigm of personalized medicine. METHODS: Observational, descriptive, retrospective and monocentric study of a total of 623 additive manufacturing processes carried out in a Department of Orthopedic Surgery and Traumatology from November 2015 to March 2020. Variables such as product type, utility, time or materials for manufacture were analyzed. RESULTS: The areas of expertise that have performed more processes are Traumatology, Reconstructive and Orthopedic Oncology. Pre-operative planning is their primary use. Working and 3D printing hours, as well as the amount of 3D printing material used, vary according to the type of product or material delivered to perform the process. The most commonly used 3D printing material for manufacturing is polylactic acid, although biocompatible resin has been used to produce surgical guides. In addition, the hospital has worked on the co-design of customized implants with manufacturing companies. CONCLUSIONS: The integration of 3D printing in a Department of Orthopedic Surgery and Traumatology allows identifying the conceptual evolution from "Do-It-Yourself" to "POC manufacturing".


Assuntos
Procedimentos Ortopédicos , Traumatologia , Humanos , Modelos Anatômicos , Sistemas Automatizados de Assistência Junto ao Leito , Impressão Tridimensional , Estudos Retrospectivos
7.
Cell ; 184(10): 2715-2732.e23, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33852912

RESUMO

Traumatic brain injury (TBI) is the largest non-genetic, non-aging related risk factor for Alzheimer's disease (AD). We report here that TBI induces tau acetylation (ac-tau) at sites acetylated also in human AD brain. This is mediated by S-nitrosylated-GAPDH, which simultaneously inactivates Sirtuin1 deacetylase and activates p300/CBP acetyltransferase, increasing neuronal ac-tau. Subsequent tau mislocalization causes neurodegeneration and neurobehavioral impairment, and ac-tau accumulates in the blood. Blocking GAPDH S-nitrosylation, inhibiting p300/CBP, or stimulating Sirtuin1 all protect mice from neurodegeneration, neurobehavioral impairment, and blood and brain accumulation of ac-tau after TBI. Ac-tau is thus a therapeutic target and potential blood biomarker of TBI that may represent pathologic convergence between TBI and AD. Increased ac-tau in human AD brain is further augmented in AD patients with history of TBI, and patients receiving the p300/CBP inhibitors salsalate or diflunisal exhibit decreased incidence of AD and clinically diagnosed TBI.


Assuntos
Doença de Alzheimer/etiologia , Doença de Alzheimer/prevenção & controle , Lesões Encefálicas Traumáticas/complicações , Neuroproteção , Proteínas tau/metabolismo , Acetilação , Doença de Alzheimer/metabolismo , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Biomarcadores/sangue , Biomarcadores/metabolismo , Lesões Encefálicas Traumáticas/metabolismo , Linhagem Celular , Diflunisal/uso terapêutico , Feminino , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora) , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Salicilatos/uso terapêutico , Sirtuína 1/metabolismo , Fatores de Transcrição de p300-CBP/antagonistas & inibidores , Fatores de Transcrição de p300-CBP/metabolismo , Proteínas tau/sangue
8.
Neurotrauma Rep ; 2(1): 1-13, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33748810

RESUMO

The jet-flow overpressure chamber (OPC) has been previously reported as a model of blast-mediated traumatic brain injury (bTBI). However, rigorous characterization of the features of this injury apparatus shows that it fails to recapitulate exposure to an isolated blast wave. Through combined experimental and computational modeling analysis of gas-dynamic flow conditions, we show here that the jet-flow OPC produces a collimated high-speed jet flow with extreme dynamic pressure that delivers a severe compressive impulse. Variable rupture dynamics of the diaphragm through which the jet flow originates also generate a weak and infrequent shock front. In addition, there is a component of acceleration-deceleration injury to the head as it is agitated in the headrest. Although not a faithful model of free-field blast exposure, the jet-flow OPC produces a complex multi-modal model of TBI that can be useful in laboratory investigation of putative TBI therapies and fundamental neurophysiological processes after brain injury.

9.
Antioxid Redox Signal ; 35(7): 511-530, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-33501899

RESUMO

Aims: Impaired embryonic cortical interneuron development from prenatal stress is linked to adult neuropsychiatric impairment, stemming in part from excessive generation of reactive oxygen species in the developing embryo. Unfortunately, there are no preventive medicines that mitigate the risk of prenatal stress to the embryo, as the underlying pathophysiologic mechanisms are poorly understood. Our goal was to interrogate the molecular basis of prenatal stress-mediated damage to the embryonic brain to identify a neuroprotective strategy. Results: Chronic prenatal stress in mice dysregulated nicotinamide adenine dinucleotide (NAD+) synthesis enzymes and cortical interneuron development in the embryonic brain, leading to axonal degeneration in the hippocampus, cognitive deficits, and depression-like behavior in adulthood. Offspring were protected from these deleterious effects by concurrent maternal administration of the NAD+-modulating agent P7C3-A20, which crossed the placenta to access the embryonic brain. Prenatal stress also produced axonal degeneration in the adult corpus callosum, which was not prevented by maternal P7C3-A20. Innovation: Prenatal stress dysregulates gene expression of NAD+-synthesis machinery and GABAergic interneuron development in the embryonic brain, which is associated with adult cognitive impairment and depression-like behavior. We establish a maternally directed treatment that protects offspring from these effects of prenatal stress. Conclusion: NAD+-synthesis machinery and GABAergic interneuron development are critical to proper embryonic brain development underlying postnatal neuropsychiatric functioning, and these systems are highly susceptible to prenatal stress. Pharmacologic stabilization of NAD+ in the stressed embryonic brain may provide a neuroprotective strategy that preserves normal embryonic development and protects offspring from neuropsychiatric impairment. Antioxid. Redox Signal. 35, 511-530.


Assuntos
Disfunção Cognitiva , Fármacos Neuroprotetores , Efeitos Tardios da Exposição Pré-Natal , Animais , Carbazóis/farmacologia , Carbazóis/uso terapêutico , Feminino , Hipocampo , Camundongos , Neurogênese , Fármacos Neuroprotetores/farmacologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Estresse Psicológico/complicações
10.
Mol Psychiatry ; 26(6): 2286-2298, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-32332995

RESUMO

Post-traumatic stress disorder (PTSD) is characterized by persistent fear memory of remote traumatic events, mental re-experiencing of the trauma, long-term cognitive deficits, and PTSD-associated hippocampal dysfunction. Extinction-based therapeutic approaches acutely reduce fear. However, many patients eventually relapse to the original conditioned fear response. Thus, understanding the underlying molecular mechanisms of this condition is critical to developing new treatments for patients. Mutations in the neuropsychiatric risk gene CACNA1C, which encodes the Cav1.2 isoform of the L-type calcium channel, have been implicated in both PTSD and highly comorbid neuropsychiatric conditions, such as anxiety and depression. Here, we report that male mice with global heterozygous loss of cacna1c exhibit exacerbated contextual fear that persists at remote time points (up to 180 days after shock), despite successful acute extinction training, reminiscent of PTSD patients. Because dopamine has been implicated in contextual fear memory, and Cav1.2 is a downstream target of dopamine D1-receptor (D1R) signaling, we next generated mice with specific deletion of cacna1c from D1R-expressing neurons (D1-cacna1cKO mice). Notably, D1-cacna1cKO mice also show the same exaggerated remote contextual fear, as well as persistently elevated anxiety-like behavior and impaired spatial memory at remote time points, reminiscent of chronic anxiety in treatment-resistant PTSD. We also show that D1-cacna1cKO mice exhibit elevated death of young hippocampal neurons, and that treatment with the neuroprotective agent P7C3-A20 eradicates persistent remote fear. Augmenting survival of young hippocampal neurons may thus provide an effective therapeutic approach for promoting durable remission of PTSD, particularly in patients with CACNA1C mutations or other genetic aberrations that impair calcium signaling or disrupt the survival of young hippocampal neurons.


Assuntos
Transtornos de Estresse Pós-Traumáticos , Animais , Canais de Cálcio Tipo L/genética , Condicionamento Clássico , Dopamina , Extinção Psicológica , Medo , Humanos , Masculino , Camundongos , Neurônios , Transtornos de Estresse Pós-Traumáticos/genética
11.
Pain ; 162(4): 1163-1175, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33027220

RESUMO

ABSTRACT: Chronic complications of traumatic brain injury represent one of the greatest financial burdens and sources of suffering in the society today. A substantial number of these patients suffer from posttraumatic headache (PTH), which is typically associated with tactile allodynia. Unfortunately, this phenomenon has been understudied, in large part because of the lack of well-characterized laboratory animal models. We have addressed this gap in the field by characterizing the tactile sensory profile of 2 nonpenetrating models of PTH. We show that multimodal traumatic brain injury, administered by a jet-flow overpressure chamber that delivers a severe compressive impulse accompanied by a variable shock front and acceleration-deceleration insult, produces long-term tactile hypersensitivity and widespread sensitization. These are phenotypes reminiscent of PTH in patients, in both cephalic and extracephalic regions. By contrast, closed head injury induces only transient cephalic tactile hypersensitivity, with no extracephalic consequences. Both models show a more severe phenotype with repetitive daily injury for 3 days, compared with either 1 or 3 successive injuries in a single day, providing new insight into patterns of injury that may place patients at a greater risk of developing PTH. After recovery from transient cephalic tactile hypersensitivity, mice subjected to closed head injury demonstrate persistent hypersensitivity to established migraine triggers, including calcitonin gene-related peptide and sodium nitroprusside, a nitric oxide donor. Our results offer the field new tools for studying PTH and preclinical support for a pathophysiologic role of calcitonin gene-related peptide in this condition.


Assuntos
Lesões Encefálicas Traumáticas , Transtornos de Enxaqueca , Cefaleia Pós-Traumática , Animais , Lesões Encefálicas Traumáticas/complicações , Peptídeo Relacionado com Gene de Calcitonina , Humanos , Hiperalgesia/etiologia , Camundongos , Transtornos de Enxaqueca/etiologia
12.
OTA Int ; 4(1 Suppl): e112, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38630066

RESUMO

The world was not prepared for the global of pandemic in early 2020 with the arrival of COVID 19. Europe has some of the most developed health care systems in the world and this article explains the initial response to the pandemic from an orthopaedic and trauma viewpoint from 8 nations. Italy reported the first cluster in February, which then rapidly spread around the continent, requiring a rapid reorganization of services. The reports highlight how elective surgery was universally stopped, surgical services were reconfigured, and new practices, such as the widespread use of telemedicine, may well become permanent. It also emphasizes how the pandemic has re-educated us on the importance of a consistent and central approach to deal with a global health crisis, and how medical services need to remain flexible and responsive to new ways of working.

13.
Proc Natl Acad Sci U S A ; 117(44): 27667-27675, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33087571

RESUMO

Chronic neurodegeneration in survivors of traumatic brain injury (TBI) is a major cause of morbidity, with no effective therapies to mitigate this progressive and debilitating form of nerve cell death. Here, we report that pharmacologic restoration of the blood-brain barrier (BBB), 12 mo after murine TBI, is associated with arrested axonal neurodegeneration and cognitive recovery, benefits that persisted for months after treatment cessation. Recovery was achieved by 30 d of once-daily administration of P7C3-A20, a compound that stabilizes cellular energy levels. Four months after P7C3-A20, electron microscopy revealed full repair of TBI-induced breaks in cortical and hippocampal BBB endothelium. Immunohistochemical staining identified additional benefits of P7C3-A20, including restoration of normal BBB endothelium length, increased brain capillary pericyte density, increased expression of BBB tight junction proteins, reduced brain infiltration of immunoglobulin, and attenuated neuroinflammation. These changes were accompanied by cessation of TBI-induced chronic axonal degeneration. Specificity for P7C3-A20 action on the endothelium was confirmed by protection of cultured human brain microvascular endothelial cells from hydrogen peroxide-induced cell death, as well as preservation of BBB integrity in mice after exposure to toxic levels of lipopolysaccharide. P7C3-A20 also protected mice from BBB degradation after acute TBI. Collectively, our results provide insights into the pathophysiologic mechanisms behind chronic neurodegeneration after TBI, along with a putative treatment strategy. Because TBI increases the risks of other forms of neurodegeneration involving BBB deterioration (e.g., Alzheimer's disease, Parkinson's disease, vascular dementia, chronic traumatic encephalopathy), P7C3-A20 may have widespread clinical utility in the setting of neurodegenerative conditions.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Lesões Encefálicas Traumáticas/tratamento farmacológico , Carbazóis/farmacologia , Cognição/efeitos dos fármacos , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Barreira Hematoencefálica/citologia , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/ultraestrutura , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/patologia , Carbazóis/uso terapêutico , Células Cultivadas , Doença Crônica/tratamento farmacológico , Cognição/fisiologia , Modelos Animais de Doenças , Células Endoteliais , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Humanos , Masculino , Camundongos , Microscopia Eletrônica , Microvasos/citologia , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/fisiopatologia , Fármacos Neuroprotetores/uso terapêutico , Cultura Primária de Células , Sobreviventes
14.
Injury ; 50 Suppl 1: S24-S29, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31036366

RESUMO

BACKGROUND: Between the different options in pelvic external fixation, the supra-acetabular pin placement is considered the best option by many authors. The aim of this study is to describe the surgical technique of the ultrasound-guided supra-acetabular pelvic external fixator (US-SA FIX). SURGICAL TECHNIQUE: Description of the steps to perform the US-SA FIX technique. DISCUSSION: The supra-acetabular pin placement is considered the best option and it is the most wildly used because it combines three crucial qualities: safety, simplicity, and effectiveness. Notwithstanding, when a severely multiple injured patient arrives at the emergency room we need to perform an emergency external fixation, however trained x-ray technicians or pelvic surgeons are not always present, making it difficult to perform the surgery with the proper intra-operative imaging, increasing the surgical time with potentially serious repercussions, a case scenario where the ultrasound can be a very helpful tool. Ultrasound-guided supra-acetabular pelvic external fixator pin placement is feasible without compromising the reliability of its placement, and the application of this new technique in clinical practice in our centre brings encouraging results.


Assuntos
Acetábulo/diagnóstico por imagem , Fixadores Externos , Fixação de Fratura , Fraturas Ósseas/diagnóstico por imagem , Ultrassonografia de Intervenção , Acetábulo/lesões , Acetábulo/cirurgia , Fenômenos Biomecânicos , Pinos Ortopédicos , Fixação de Fratura/métodos , Fraturas Ósseas/patologia , Fraturas Ósseas/cirurgia , Humanos , Estudos Retrospectivos
15.
ACS Chem Neurosci ; 10(3): 1595-1602, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30421909

RESUMO

Compounds targeting the sigma 2 receptor, which we recently cloned and showed to be identical with transmembrane protein 97 (σ2R/TMEM97), are broadly applicable therapeutic agents currently in clinical trials for imaging in breast cancer and for treatment of Alzheimer's disease and schizophrenia. These promising applications coupled with our previous observation that the σ2R/TMEM97 modulator SAS-0132 has neuroprotective attributes and improves cognition in wild-type mice suggests that modulating σ2R/TMEM97 may also have therapeutic benefits in other neurodegenerative conditions such as traumatic brain injury (TBI). Herein, we report that DKR-1677, a novel derivative of SAS-0132 with increased affinity and selectivity for σ2R/Tmem97 ( Ki = 5.1 nM), is neuroprotective after blast-induced and controlled cortical impact (CCI) TBI in mice. Specifically, we discovered that treatment with DKR-1677 decreases axonal degeneration after blast-induced TBI and enhances survival of cortical neurons and oligodendrocytes after CCI injury. Furthermore, treatment with DKR-1677 preserves cognition in the Morris water maze after blast TBI. Our results support an increasingly broad role for σ2R/Tmem97 modulation in neuroprotection and suggest a new approach for treating patients suffering from TBI.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Proteínas de Membrana/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Receptores sigma/efeitos dos fármacos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Neurônios/efeitos dos fármacos
16.
Transl Psychiatry ; 8(1): 202, 2018 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-30258178

RESUMO

There is a critical need for translating basic science discoveries into new therapeutics for patients suffering from difficult to treat neuropsychiatric and neurodegenerative conditions. Previously, a target-agnostic in vivo screen in mice identified P7C3 aminopropyl carbazole as capable of enhancing the net magnitude of postnatal neurogenesis by protecting young neurons from death. Subsequently, neuroprotective efficacy of P7C3 compounds in a broad spectrum of preclinical rodent models has also been observed. An important next step in translating this work to patients is to determine whether P7C3 compounds exhibit similar efficacy in primates. Adult male rhesus monkeys received daily oral P7C3-A20 or vehicle for 38 weeks. During weeks 2-11, monkeys received weekly injection of 5'-bromo-2-deoxyuridine (BrdU) to label newborn cells, the majority of which would normally die over the following 27 weeks. BrdU+ cells were quantified using unbiased stereology. Separately in mice, the proneurogenic efficacy of P7C3-A20 was compared to that of NSI-189, a proneurogenic drug currently in clinical trials for patients with major depression. Orally-administered P7C3-A20 provided sustained plasma exposure, was well-tolerated, and elevated the survival of hippocampal BrdU+ cells in nonhuman primates without adverse central or peripheral tissue effects. In mice, NSI-189 was shown to be pro-proliferative, and P7C3-A20 elevated the net magnitude of hippocampal neurogenesis to a greater degree than NSI-189 through its distinct mechanism of promoting neuronal survival. This pilot study provides evidence that P7C3-A20 safely protects neurons in nonhuman primates, suggesting that the neuroprotective efficacy of P7C3 compounds is likely to translate to humans as well.


Assuntos
Carbazóis/administração & dosagem , Hipocampo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Administração Oral , Animais , Carbazóis/farmacocinética , Hipocampo/fisiologia , Macaca mulatta , Masculino , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/fisiologia , Neurônios/fisiologia , Projetos Piloto
17.
Injury ; 49 Suppl 2: S36-S43, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30219146

RESUMO

We describe the methodical and possibilities of 3D surgical printing in preoperative planning for a total hip arthroplasty in acetabular deformity after acetabular fractures, showing a case of a 43-year-old with posttraumatic arthritis after both column fracture of the left acetabulum that was treated non operatively, supporting the do it yourself mode.


Assuntos
Acetábulo/diagnóstico por imagem , Artroplastia de Quadril , Tratamento Conservador/efeitos adversos , Fraturas Ósseas/cirurgia , Luxação do Quadril/cirurgia , Osteoartrite do Quadril/diagnóstico por imagem , Impressão Tridimensional , Acetábulo/anatomia & histologia , Acetábulo/lesões , Adulto , Osso Esponjoso/patologia , Fraturas Ósseas/diagnóstico por imagem , Luxação do Quadril/diagnóstico por imagem , Humanos , Masculino , Osteoartrite do Quadril/etiologia , Osteoartrite do Quadril/cirurgia , Resultado do Tratamento
18.
Neuroscience ; 380: 90-102, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29660444

RESUMO

Ca2+-binding protein 1 (CaBP1) is a Ca2+-sensing protein similar to calmodulin that potently regulates voltage-gated Ca2+ channels. Unlike calmodulin, however, CaBP1 is mainly expressed in neuronal cell-types and enriched in the hippocampus, where its function is unknown. Here, we investigated the role of CaBP1 in hippocampal-dependent behaviors using mice lacking expression of CaBP1 (C-KO). By western blot, the largest CaBP1 splice variant, caldendrin, was detected in hippocampal lysates from wild-type (WT) but not C-KO mice. Compared to WT mice, C-KO mice exhibited mild deficits in spatial learning and memory in both the Barnes maze and in Morris water maze reversal learning. In contextual but not cued fear-conditioning assays, C-KO mice showed greater freezing responses than WT mice. In addition, the number of adult-born neurons in the hippocampus of C-KO mice was ∼40% of that in WT mice, as measured by bromodeoxyuridine labeling. Moreover, hippocampal long-term potentiation was significantly reduced in C-KO mice. We conclude that CaBP1 is required for cellular mechanisms underlying optimal encoding of hippocampal-dependent spatial and fear-related memories.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Hipocampo/fisiologia , Potenciação de Longa Duração/fisiologia , Memória/fisiologia , Aprendizagem Espacial/fisiologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
19.
J Stroke Cerebrovasc Dis ; 27(5): 1412-1416, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29398531

RESUMO

BACKGROUND: Exogenous administration of uric acid, a naturally occurring antioxidant that scavenges reactive oxygen species in vasculature, has shown protective efficacy in both rodent models of stroke and human stroke patients in Spain as an adjuvant treatment to mechanical thrombectomy. Before clinical trials can be initiated in the United States, however, confirmation of efficacy in alternative preclinical models is required in accordance with stroke therapy academic industry roundtable-RIGOR criteria. To date, preclinical efficacy has only been established in the acute setting in male rodents. METHODS: To address this need, we subjected 7- to 9-week old ovariectomized female mice to filament-induced right middle cerebral artery ischemia and reperfusion, an established preclinical model of mechanical thrombectomy. Fidelity of the procedure was monitored by laser Doppler flowmetry. A separate lab randomly assigned animals to vehicle versus uric acid infusion, which was initiated immediately after 45 minutes of reperfusion. Poststroke analysis of infarction size and neurologic function were conducted by investigators blind to treatment group, with a 7-day primary endpoint and a 3-day intermediary analysis at 1and. RESULTS: Infarct size and neurologic function at 7 days poststroke were significantly improved in uric acid-treated animals, relative to vehicle. CONCLUSION: Efficacy of uric acid in preclinical models of stroke is now expanded to include female mice analyzed at a later time point than has been investigated previously. These results support stroke therapy academic industry roundtable-RIGOR driven determination of the suitability of acute administration of uric acid as an adjuvant to mechanical thrombectomy in clinical trials for patients with stroke.


Assuntos
Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Ácido Úrico/farmacologia , Animais , Encéfalo/patologia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Feminino , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Camundongos Endogâmicos C57BL , Ovariectomia , Recuperação de Função Fisiológica , Fatores de Tempo
20.
Int Orthop ; 42(8): 1811-1818, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29484473

RESUMO

INTRODUCTION: Acetabular revision surgery poses a challenge due to the increased frequency of severe defects and poor quality of the remaining bone. We compare the clinical and radiological outcomes, complications, and survival of two systems commonly used in complex acetabular revisions (AAOS types II, III, and IV): trabecular metal system (TM) and Burch-Schneider antiprotrusion cages (BS). METHODS: Eighty-four patients underwent acetabular revision surgery with TM or BS in our centre between 2008 and 2014. Comparison was made of demographic and clinical characteristics, satisfaction, radiographic parameters, complications, and survival of the implants. A BS was implanted in 30.9% of the patients, while 69.1% received a TM implant. The mean follow-up was 4.77 years. RESULTS: The BS group required a significantly greater number of constrained implants (p = 0.001) and more walking aids (p = 0.04). The mean satisfaction (p = 0.02) and HHS scores at the end of the follow-up were higher in the TM group (p = 0.003). No differences were observed in the incidence of complications, though the only two cases of implant rupture corresponded to the BS group. The overall survival rate was 88.1% after 7.5 years. CONCLUSION: TM implants afforded better clinical outcomes and greater patient satisfaction than antiprotrusion cages in the treatment of severe acetabular defects.


Assuntos
Acetábulo/cirurgia , Artroplastia de Quadril/instrumentação , Prótese de Quadril/efeitos adversos , Reoperação/instrumentação , Idoso , Idoso de 80 Anos ou mais , Artroplastia de Quadril/efeitos adversos , Feminino , Humanos , Masculino , Metais/efeitos adversos , Pessoa de Meia-Idade , Satisfação do Paciente/estatística & dados numéricos , Complicações Pós-Operatórias/epidemiologia , Desenho de Prótese/efeitos adversos , Reoperação/efeitos adversos , Reoperação/métodos , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento
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