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1.
Bone Joint J ; 105-B(11): 1189-1195, 2023 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-37909149

RESUMO

Aims: The aim of this study was to compare the clinical and radiological outcomes of reverse shoulder arthroplasty (RSA) using small and standard baseplates in Asian patients, and to investigate the impact of a mismatch in the sizes of the glenoid and the baseplate on the outcomes. Methods: This was retrospective analysis of 50 and 33 RSAs using a standard (33.8 mm, ST group) and a small (29.5 mm, SM group) baseplate of the Equinoxe reverse shoulder system, which were undertaken between January 2017 and March 2021. Radiological evaluations included the size of the glenoid, the ß-angle, the inclination of the glenoid component, inferior overhang, scapular notching, the location of the central cage in the baseplate within the vault and the mismatch in size between the glenoid and baseplate. Clinical evaluations included the range of motion (ROM) and functional scores. In subgroup analysis, comparisons were performed between those in whom the vault of the glenoid was perforated (VP group) and those in whom it was not perforated (VNP group). Results: Perforation of the vault of the glenoid (p = 0.018) and size mismatch in height (p < 0.001) and width (p = 0.013) were significantly more frequent in the ST group than in the SM group. There was no significant difference in the clinical scores and ROM in the two groups, two years postoperatively (all p > 0.05). In subgroup analysis, the VP group had significantly less inferior overhang (p = 0.009), more scapular notching (p = 0.018), and more size mismatch in height (p < 0.001) and width (p = 0.025) than the VNP group. Conclusion: In Asian patients with a small glenoid, using a 29.5 mm small baseplate at the time of RSA was more effective in reducing size mismatch between the glenoid and the baseplate, decreasing the incidence of perforation of the glenoid vault, and achieving optimal positioning of the baseplate compared with the use of a 33.8 mm standard baseplate. However, longer follow-up is required to assess the impact of these findings on the clinical outcomes.


Assuntos
Artroplastia do Ombro , Articulação do Ombro , Humanos , Artroplastia do Ombro/efeitos adversos , Articulação do Ombro/diagnóstico por imagem , Articulação do Ombro/cirurgia , Estudos Retrospectivos , Radiografia , Escápula/cirurgia , Amplitude de Movimento Articular
3.
Crim Behav Ment Health ; 30(2-3): 132-140, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32537772

RESUMO

Exhibitionism and frotteurism are often considered just nuisance crimes but may cause serious distress to the victims. Previous studies of victim experience have focused on specific groups, such as healthcare professionals or university students. To estimate the prevalence of victimisation by exhibitionism and frotteurism among young general population adults in Korea and to describe the impact of such experiences, trained researchers randomly recruited young adults for face to face interviews at transport hubs and on university campuses. In addition, we posted the questionnaire as a Google survey to a limited number of local websites. Data were analysed descriptively. Of 900 people directly approached, 747 (83%) agreed participation, as did 423 online. These two samples were similar demographically, so combined for analyses. Two hundred and thirty-five (20%) reported experiencing exhibitionism and 130 (11%) frotteurism. Exposure victims were older (means 23.2:21.1 years) and more likely to be women than frotteur victims. All but two exposure and nine frotteur perpetrators were said to be men. Reporting to police was rare (17 exposure, 2 frotteur); most exposure victims (73%) but under half of frotteur victims told family or friends. All but 15% of each group had bad feelings about the experience, varying by experience type. Ten percent of exposure and 20% of frotteur victims described distress lasting months; more reported enduring behaviour changes, like avoiding subways. Although our sample is unlikely to be wholly representative of the general population, our research examines a broader range of people than previous studies. Most victims of these "nuisance crimes" were distressed by them, and, hitherto less well recognised, at least a fifth of such victims may have long-term distress. Further research could establish the extent to which support outside the family or friends' group or treatment would be indicated.


Assuntos
Vítimas de Crime/estatística & dados numéricos , Exibicionismo/epidemiologia , Transtornos Parafílicos/epidemiologia , Adolescente , Adulto , Idoso , Bullying , Vítimas de Crime/psicologia , Estudos Transversais , Exibicionismo/psicologia , Feminino , Humanos , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , Transtornos Parafílicos/psicologia , Polícia , Prevalência , República da Coreia/epidemiologia , Inquéritos e Questionários , Universidades , Adulto Jovem
5.
Neurology ; 93(7): e647-e652, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31337714

RESUMO

OBJECTIVE: To perform a systematic analysis and scoring of brain MRI white matter hyperintensities (WMH) in adult-onset Krabbe disease. METHODS: We retrospectively collected basic clinical data and the first available brain MRI from patients with confirmed Krabbe disease with first clinical manifestations beyond 10 years of age. Data were obtained from our reference center for lysosomal diseases (n = 6) and from contacted authors of published articles describing patients with adult-onset Krabbe disease (n = 15). T2-weighted fluid-attenuated inversion recovery images of each patient were analyzed and scored using a radiologic score of WMH in a single center. RESULTS: The corticospinal tract was always affected by WMH (100% of patients), however, with some distinctions along the tract: the precentral gyrus (100%), corona radiata (95%), and posterior internal capsule (81%) were highly abnormal, whereas the mesencephalon (57%), pons (52%), and medulla oblongata (5%) were less affected. WMH were also frequently present in the posterior lateral periventricular white matter (95%), optic radiations (86%), postcentral gyrus (71%), medial lemniscus (62%), and corpus callosum, especially in the isthmus (71%), whereas the genu was always normal. A few patients did not have the classical MRI pattern but extensive hyperintensities (n = 3), or patchy distribution of hyperintensities mimicking an acquired etiology (n = 2), or very subtle hyperintensities of the corticospinal tract (n = 1). CONCLUSIONS: We specified the main locations of WMH, which were observed in the earliest stages of the disease and were also present in patients with atypical MRI pattern, highlighting the importance of radiologic features to guide the diagnosis.


Assuntos
Encéfalo/diagnóstico por imagem , Leucodistrofia de Células Globoides/patologia , Adolescente , Adulto , Idade de Início , Idoso , Criança , Corpo Caloso/patologia , Doenças Desmielinizantes/patologia , Feminino , Humanos , Cápsula Interna/patologia , Leucodistrofia de Células Globoides/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Tratos Piramidais/patologia , Substância Branca/patologia , Adulto Jovem
6.
Minerva Anestesiol ; 85(3): 279-287, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30207136

RESUMO

BACKGROUND: Tourniquet use during total knee arthroplasty (TKA) produces ischemia-reperfusion injury (IRI), with systemic release of inflammatory cytokines and reactive oxygen species upon tourniquet release. We conducted a randomized, placebo-controlled, double-blind trial to examine whether dexmedetomidine (DEX) as an adjunct during general anesthesia in patients undergoing unilateral TKA could attenuate the rise in inflammatory cytokines and oxidative stress. METHODS: Sixty-eight patients were randomized to either the control or DEX group. DEX was administered at a loading dose of 0.5 µg/kg, followed by an infusion of 0.4 µg/kg/h. We measured serum levels of malondialdehyde (biomarker of oxidative stress) and proinflammatory cytokines (interleukin-6 [IL-6] and tumour necrosis factor-α [TNF-α]) preinduction (baseline), 60 and 90 min post-tourniquet release. We also assessed hemodynamics, intraoperative remifentanil consumption, and postoperative pain scores and analgesic consumption. RESULTS: Malondialdehyde was higher than baseline after tourniquet release in both groups (P≤0.001), but the levels were similar between groups at all times. TNF-α was significantly higher than baseline at 60 min post-tourniquet release only in the control group (P=0.009). Serum IL-6 increased significantly above baseline at 60 and 90 min post-tourniquet release in both groups (P<0.001). At 90 min, IL-6 was significantly lower in the dexmedetomidine group than in the control group (P=0.049). Remifentanil consumption, heart rate, and pain scores were significantly lower in the dexmedetomidine group. CONCLUSIONS: Our results suggest that dexmedetomidine as an adjunct to general anesthesia attenuated the rise in proinflammatory cytokines, providing protective effects in tourniquet-induced IRI.


Assuntos
Anestesia Geral , Dexmedetomidina/farmacologia , Dexmedetomidina/uso terapêutico , Interleucina-6/sangue , Estresse Oxidativo/efeitos dos fármacos , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/prevenção & controle , Torniquetes/efeitos adversos , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
7.
Clin Exp Pharmacol Physiol ; 44(6): 671-679, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28370165

RESUMO

Excessive activation of poly (ADP-ribose) polymerase-1 (PARP-1) is known to develop neuronal apoptosis, necrosis and inflammation after ischaemic brain injury. Therefore, PARP-1 inhibition after ischaemic stroke has been attempted in successful animal studies. The purpose of present work was to develop a novel water soluble PARP-1 inhibitor (JPI-289) and explore its neuroprotective effect on ischaemic injury in an in vitro model. The half-life of JPI-289 after intravenous or oral administration in rats was relatively long (1.4-1.5 hours) with 65.6% bioavailability. The inhibitor strongly inhibited PARP-1 activity (IC50 =18.5 nmol/L) and cellular PAR formation (IC50 =10.7 nmol/L) in the nanomolar range. In rat cortical neuronal cells, JPI-289 did not affect cell viability up to 1 mmol/L as assayed by Trypan blue staining (TBS) and lactate dehydrogenase (LDH) assay. Treatment of JPI-289 for 2 hours after 2 hours of oxygen glucose deprived (OGD) rat cortical neuron attenuated PARP activity and restored ATP and NAD+ levels. Apoptosis-associated molecules such as apoptosis inducing factor (AIF), cytochrome C and cleaved caspase-3 were reduced after JPI-289 treatment in the OGD model. The present findings suggest that the novel PARP-1 inhibitor, JPI-289, is a potential neuroprotective agent which could be useful as a treatment for acute ischaemic stroke.


Assuntos
Encéfalo/citologia , Inibidores Enzimáticos/farmacologia , Naftiridinas/farmacologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Naftiridinas/química , Naftiridinas/farmacocinética , Neurônios/citologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacocinética , Ratos , Transdução de Sinais/efeitos dos fármacos , Solubilidade
8.
Lancet Neurol ; 16(3): 208-216, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28139349

RESUMO

BACKGROUND: Neurite outgrowth inhibitor A (Nogo-A) is thought to have a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). A monoclonal antibody against Nogo-A showed a positive effect in the SOD1G93A mouse model of ALS, and a humanised form of this antibody (ozanezumab) was well tolerated in a first-in-human trial. Therefore, we aimed to assess the safety and efficacy of ozanezumab in patients with ALS. METHODS: This randomised, double-blind, placebo-controlled, phase 2 trial was done in 34 centres in 11 countries. Patients aged 18-80 years with a diagnosis of familial or sporadic ALS were randomly assigned (1:1), centrally according to a computer-generated allocation schedule, to receive ozanezumab (15 mg/kg) or placebo as intravenous infusions over 1 h every 2 weeks for 46 weeks, followed by assessments at week 48 and week 60. Patients and study personnel were masked to treatment assignment. The primary outcome was a joint-rank analysis of function (ALS Functional Rating Scale-Revised) and overall survival, analysed at 48 weeks in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01753076, and with GSK-ClinicalStudyRegister.com, NOG112264, and is completed. FINDINGS: Between Dec 20, 2012, and Nov 1, 2013, we recruited 307 patients, of whom 303 were randomly assigned to receive placebo (n=151) or ozanezumab (n=152). The adjusted mean of the joint-rank score was -14·9 (SE 13·5) for the ozanezumab group and 15·0 (13·6) for the placebo group, with a least squares mean difference of -30·0 (95% CI -67·9 to 7·9; p=0·12). Overall, reported adverse events, serious adverse events, and adverse events leading to permanent discontinuation of study drug or withdrawal from study were similar between the treatment groups, except for dyspepsia (ten [7%] in the ozanezumab group vs four [3%] in the placebo group), depression (11 [7%] vs five [3%]), and diarrhoea (25 [16%] vs 12 [8%]). Respiratory failure was the most common serious adverse event (12 [8%] vs seven [5%]). At week 60, the number of deaths was higher in the ozanezumab group (20 [13%]) than in the placebo group (16 [11%]), mainly as a result of respiratory failure (ten [7%] vs five [3%]). Two deaths were considered related to the study drug (bladder transitional cell carcinoma in the ozanezumab group and cerebrovascular accident in the placebo group). INTERPRETATION: Ozanezumab did not show efficacy compared with placebo in patients with ALS. Therefore, Nogo-A does not seem to be an effective therapeutic target in ALS. FUNDING: GlaxoSmithKline.


Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Fatores Imunológicos/uso terapêutico , Proteínas Nogo/imunologia , Resultado do Tratamento , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/mortalidade , Método Duplo-Cego , Eletrocardiografia , Feminino , Humanos , Cooperação Internacional , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Adulto Jovem
9.
Dement Geriatr Cogn Dis Extra ; 6(2): 214-21, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27350782

RESUMO

AIM: This study aims to provide a brief questionnaire form of the Neuropsychiatric Inventory (NPI-Q) in Korean translated from the original NPI-Q that is intended for the evaluation of behavioral and psychological symptoms of dementia in routine clinical practice. PATIENTS AND METHODS: We developed a Korean version of the NPI-Q (KNPI-Q) and compared subitems with those of the Korean version of the NPI (KNPI) in 63 dementia patients; 47 patients had been diagnosed with Alzheimer's disease with dementia, 8 with vascular dementia, and 8 with dementia with Lewy body disease. The diagnosis was based on the National Institute of Neurological and Communicative Disorders and Stroke - Alzheimer's Disease and Related Disorders Association criteria for possible and probable Alzheimer's disease and the International Statistical Classification of Diseases and Related Health Problems, 10th revision, criteria for vascular dementia and other dementing diseases. All patients received the Korean version of the Mini-Mental State Examination and the Clinical Dementia Rating within 1 month of the KNPI-Q. RESULTS: Test-retest reliability of the KNPI-Q using a Pearson correlation index was r = 0.89 for the total symptom scale and r = 0.90 for the distress scale. The prevalence of analogous symptom ratings differed by less than 6.7%. Convergent validity between the KNPI-Q and the NPI using a Pearson correlation index was r = 0.879 for the total symptom scale and r = 0.92 for the distress scale. CONCLUSIONS: The KNPI-Q is a reliable and brief instrument that can be employed for screening in the evaluation of neuropsychiatric symptoms of dementia and associated caregiver distress. It may be suitable for use in general clinical practice and could be administered as a brief neuropsychiatric interview.

10.
J Alzheimers Dis ; 45(2): 599-608, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25589724

RESUMO

BACKGROUND: Cognitive performance changes with chronological aging. Previous studies investigating clinical heterogeneity in frontotemporal dementia (FTD) according to the age of symptom onset did not consider the effect of chronological aging on cognition. OBJECTIVE: We compared cognitive and behavioral symptoms in patients with early-onset (EO) and late-onset (LO) FTD with consideration of chronological aging effect. METHODS: A total of 166 FTD patients were enrolled consecutively from multi-center memory clinics using a nationwide FTD register. To control for the effects of chronological aging on neuropsychological scores, seven hundred and two subjects with normal cognition were also enrolled and regression models were set up. Neuropsychological scores that were detrended with the regression models and the behavioral symptoms of the EO-FTD and LO-FTD groups were compared. Subgroup analyses were performed for three main subtypes of FTD, behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD), and progressive non-fluent aphasia (PNFA). RESULTS: Among 166 FTD patients, there were 76 bvFTD, 57 SD, and 33 PNFA patients who met new diagnostic criteria for bvFTD or primary progressive aphasia, respectively. LO-FTD (48.2%) was more common than previously thought and the proportions of EO and LO groups differed across FTD subtypes. EO-FTD patients had lower memory and frontal/executive scores and more prominent frontal/behavioral symptoms than LO-FTD patients. CONCLUSION: Our study suggested that FTD could be heterogeneous with respect the age of symptom onset. After controlling for the effects of chronological aging, EO-FTD patients exhibited more profound memory and frontal/executive dysfunction and more behavioral symptoms than LO-FTD patients.


Assuntos
Sintomas Comportamentais/etiologia , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/etiologia , Demência Frontotemporal/complicações , Testes Neuropsicológicos , Idade de Início , Idoso , Feminino , Demência Frontotemporal/classificação , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Estudos Retrospectivos
11.
J Neurochem ; 131(2): 206-18, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24995608

RESUMO

In a previous study, we reported that intrathecal injection of mesenchymal stem cells (MSCs) slowed disease progression in G93A mutant superoxide dismutase1 transgenic mice. In this study, we found that intrathecal MSC administration vastly increased the infiltration of peripheral immune cells into the spinal cord of Amyotrophic lateral sclerosis (ALS) mice (G93A mutant superoxide dismutase1 transgenic). Thus, we investigated the immunomodulatory effect of MSCs on peripheral blood mononuclear cells (PBMCs) in ALS patients, focusing on regulatory T lymphocytes (Treg ; CD4(+) /CD25(high) /FoxP3(+) ) and the mRNA expression of several cytokines (IFN-γ, TNF-α, IL-17, IL-4, IL-10, IL-13, and TGF-ß). Peripheral blood samples were obtained from nine healthy controls (HC) and sixteen patients who were diagnosed with definite or probable ALS. Isolated PBMCs from the blood samples of all subjects were co-cultured with MSCs for 24 or 72 h. Based on a fluorescence-activated cell sorting analysis, we found that co-culture with MSCs increased the Treg /total T-lymphocyte ratio in the PBMCs from both groups according to the co-culture duration. Co-culture of PBMCs with MSCs for 24 h led to elevated mRNA levels of IFN-γ and IL-10 in the PBMCs from both groups. However, after co-culturing for 72 h, although the IFN-γ mRNA level had returned to the basal level in co-cultured HC PBMCs, the IFN-γ mRNA level in co-cultured ALS PBMCs remained elevated. Additionally, the levels of IL-4 and TGF-ß were markedly elevated, along with Gata3 mRNA, a Th2 transcription factor mRNA, in both HC and ALS PBMCs co-cultured for 72 h. The elevated expression of these cytokines in the co-culture supernatant was confirmed via ELISA. Furthermore, we found that the increased mRNA level of indoleamine 2,3-dioxygenase (IDO) in the co-cultured MSCs was correlated with the increase in Treg induction. These findings of Treg induction and increased anti-inflammatory cytokine expression in co-cultured ALS PBMCs provide indirect evidence that MSCs may play a role in the immunomodulation of inflammatory responses when MSC therapy is targeted to ALS patients. We propose the following mechanism for the effect of mesenchymal stem cells (MSCs) administered intrathecally in amyotrophic lateral sclerosis (ALS): MSCs increase infiltration of peripheral immune cells into CNS and skew the infiltrated immune cells toward regulatory T lymphocytes (Treg ) and Th2 lymphocytes. Treg and Th2 secret anti-inflammatory cytokines such as IL-4, IL-10, and TGF-ß. A series of immunomodulatory mechanism provides a new strategy for ALS treatment.


Assuntos
Esclerose Lateral Amiotrófica/imunologia , Esclerose Lateral Amiotrófica/terapia , Imunomodulação/imunologia , Leucócitos Mononucleares/imunologia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/imunologia , Adulto , Animais , Técnicas de Cocultura , Feminino , Humanos , Injeções Espinhais , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Linfócitos T Reguladores/imunologia , Adulto Jovem
12.
J Neurol Sci ; 344(1-2): 215-8, 2014 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-24998513

RESUMO

A 34-year-old man was treated with a TNF-α antagonist for ankylosing spondylitis, and this subsequently developed a CNS infection. Magnetic resonance imaging showed diffuse subcortical white matter lesions. Streptococcus pneumoniae was cultured from the cerebrospinal fluid and blood. The patient died of multifocal widespread brain damage and subarachnoid hemorrhage, despite intensive antibacterial medication. Pneumococcal meningoencephalitis can occur in association with TNF-α antagonists. Clinicians should be aware of both the risk of fatal bacterial meningoencephalitis associated with TNF-α antagonists and the possibility of an unusual presentation of bacterial meningitis.


Assuntos
Meningoencefalite/etiologia , Infecções Pneumocócicas/complicações , Fator de Necrose Tumoral alfa/metabolismo , Aciclovir/uso terapêutico , Adulto , Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , Dexametasona/uso terapêutico , Imagem de Difusão por Ressonância Magnética , Humanos , Masculino , Meningoencefalite/sangue , Meningoencefalite/líquido cefalorraquidiano , Infecções Pneumocócicas/sangue , Infecções Pneumocócicas/líquido cefalorraquidiano , Fator de Necrose Tumoral alfa/antagonistas & inibidores
13.
J Neurochem ; 127(4): 562-74, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23711227

RESUMO

The main purpose of this study was to evaluate whether donepezil, acetylcholinesterase inhibitor, shown to play a protective role through inhibiting glycogen synthesis kinase-3ß (GSK-3ß) activity, could also exert neuroprotective effects by stimulating protein phosphatase 2A (PP2A) activity in the amyloid-beta (Aß)42-induced neuronal toxicity model of Alzheimer's disease. In Aß42-induced toxic conditions, each PP2A and GSK-3ß activity measured at different times showed time-dependent reverse pattern toward the direction of accelerating neuronal deaths with the passage of time. In addition, donepezil pre-treatment showed dose-dependent stepwise increase of neuronal viability and stimulation of PP2A activity. However, such effects on them were significantly reduced through the depletion of PP2A activity with either okadaic acid or PP2Ac siRNA. In spite of blocked PP2A activity in this Aß42 insult, however, donepezil pretreatment showed additional significant recovering effect on neuronal viability when compared to the value without donepezil. Moreover, donepezil partially recovered its dephosphorylating effect on hyperphosphorylated tau induced by Aß42. This observation led us to assume that additional mechanisms of donepezil, including its inhibitory effect on GSK-3ß activity and/or the activation role of nicotinic acetylcholine receptors (nAChRs), might be involved. Taken together, our results suggest that the neuroprotective effects of donepezil against Aß42-induced neurotoxicity are mediated through activation of PP2A, but its additional mechanisms including regulation of GSK-3ß and nAChRs activity would partially contribute to its effects. We investigated neuroprotective mechanisms of donepezil against Aß42 toxicity: Donepezil increased neuronal viability with reduced p-tau by enhancing PP2A activity. Despite of blocked PP2A activity, donepezil showed additional recovering effect on neuronal viability, which findings led us to assume that additional mechanisms of donepezil including its inhibitory effect on GSK-3ß activity and activating role of nicotinic AChRs might be involved.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Indanos/farmacologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/metabolismo , Piperidinas/farmacologia , Proteína Fosfatase 2/metabolismo , Receptores Nicotínicos/metabolismo , Peptídeos beta-Amiloides/toxicidade , Animais , Donepezila , Feminino , Glicogênio Sintase Quinase 3 beta , Masculino , Neurônios/metabolismo , Fragmentos de Peptídeos/toxicidade , Ratos , Ratos Sprague-Dawley
14.
Mol Neurobiol ; 47(2): 757-69, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23254998

RESUMO

Phosphatidylinositol 3-kinase (PI3K) plays several important roles in neuronal survival. Activation of the pathway is essential for the neuroprotective mechanisms of materials that shield neuronal cells from many stressful conditions. However, there have been no reports to date about the effect of the direct activation of the pathway in hypoxic injury of neuronal cells. We investigated whether the direct activation of the PI3K pathway inhibits neuronal cell death induced by hypoxia. Primary cultured cortical neurons (PCCNs) were exposed to hypoxic conditions (less than 1 mol% O2) and/or treated with PI3K activator. Hypoxia reduced the viability of PCCNs in a time-dependent manner, but treatment with PI3K significantly restored viability in a concentration-dependent manner. Among the signaling proteins involved in the PI3K pathway, those associated with survival, including Akt and glycogen synthase kinase-3ß, were decreased shortly after exposure to hypoxia and those associated with cell death, including BAX, apoptosis-induced factor, cytochrome c, caspase-9, caspase-3, and poly(ADP-ribose) polymerase (PARP), were increased. However, treatment with PI3K activator normalized the expression levels of those signaling proteins. PARP activity and levels of ATP and NAD(+) altered by hypoxia were also normalized with direct PI3K activation. All these findings suggest that direct and early activation is important for protecting neuronal cells from hypoxic injury.


Assuntos
Trifosfato de Adenosina/metabolismo , Córtex Cerebral/metabolismo , NAD/metabolismo , Neurônios/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Regulação para Cima/fisiologia , Animais , Hipóxia Celular/fisiologia , Células Cultivadas , Córtex Cerebral/patologia , Regulação para Baixo/fisiologia , Ativação Enzimática/fisiologia , Neurônios/patologia , Fosfatidilinositol 3-Quinase/fisiologia , Poli(ADP-Ribose) Polimerases/fisiologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia
16.
Neurologist ; 18(2): 92-5, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22367839

RESUMO

Amyotrophic lateral sclerosis (ALS) can present with heterogeneous symptoms resulting from the involvement of multiple brain systems including extramotor cortical areas. Involvement of other brain areas can cause diverse clinical symptoms including cognitive impairment and extrapyramidal symptoms. We report the case of a 50-year-old woman with bulbar onset ALS and frontotemporal lobar degeneration (FTLD), confirmed as cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The patient and her first-degree relatives harbored a mutation (R75P) in the NOTCH3 gene, indicative of vascular deficits. The details of this case add plausibility to the idea that ALS, FTLD, and CADASIL are different aspects of a spectrum of disorders with overlapping pathologic mechanisms.


Assuntos
Esclerose Lateral Amiotrófica/genética , CADASIL/genética , Degeneração Lobar Frontotemporal/genética , Predisposição Genética para Doença/genética , Adulto , Esclerose Lateral Amiotrófica/complicações , Esclerose Lateral Amiotrófica/patologia , CADASIL/complicações , CADASIL/patologia , Feminino , Degeneração Lobar Frontotemporal/complicações , Degeneração Lobar Frontotemporal/patologia , Humanos , Pessoa de Meia-Idade , Mutação/genética
17.
Neurol Res Int ; 2011: 205761, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21603026

RESUMO

Glycogen synthase kinase-3ß (GSK-3ß) is known to affect a diverse range of biological functions controlling gene expression, cellular architecture, and apoptosis. GSK-3ß has recently been identified as one of the important pathogenic mechanisms in motor neuronal death related to amyotrophic lateral sclerosis (ALS). Therefore, the development of methods to control GSK-3ß could be helpful in postponing the symptom progression of ALS. Here we discuss the known roles of GSK-3ß in motor neuronal cell death in ALS and the possibility of employing GSK-3ß modulators as a new therapeutic strategy.

18.
J Burn Care Res ; 32(3): e37-44, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21422942

RESUMO

Severe thermal injury is associated with pronounced changes in intestinal physiology, which may cause ischemia, infarction, and pneumatosis intestinalis (PI). PI is a pathologic condition defined as infiltration of gas into the gastrointestinal tract wall. Historically, PI prompted urgent surgery, yet some surgeons "watch and wait" to avoid the risks of a negative laparotomy. The authors reviewed experience with PI at a single burn center. They retrospectively identified burn center intensive care unit patients with radiographic or pathologic evidence of PI. Data included demographics, injury severity score, TBSA burned, operative findings, length of stay, and mortality. From January 2003 through August 2009, 1129 patients were admitted to the authors' burn center intensive care unit. Fifteen had PI. Twelve had radiographic evidence of PI, and 10 had PI associated with intestinal infarction. Nonsurvivors had lower base deficits (P = .02), higher lactate levels (P = .05), and required vasopressor support (P = .02) within 24 hours of developing PI. Massive intestinal infarction (P = .004) and open abdomens (P = .004) were more common among nonsurvivors. PI can be identified by radiologic or pathologic findings. The authors' experience with PI among patients with burn injury revealed a high mortality rate. Because of the association of bowel ischemia with PI, exploratory laparotomy should be strongly considered in patients with burn injury with radiographic evidence of PI.


Assuntos
Queimaduras/complicações , Causas de Morte , Pneumatose Cistoide Intestinal/etiologia , Pneumatose Cistoide Intestinal/mortalidade , Adulto , Unidades de Queimados , Queimaduras/diagnóstico , Queimaduras/mortalidade , Estudos de Coortes , Cuidados Críticos/métodos , Diagnóstico Precoce , Tratamento de Emergência/métodos , Feminino , Seguimentos , Humanos , Escala de Gravidade do Ferimento , Laparotomia/métodos , Masculino , Pessoa de Meia-Idade , Pneumatose Cistoide Intestinal/diagnóstico por imagem , Pneumatose Cistoide Intestinal/cirurgia , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Análise de Sobrevida , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento , Adulto Jovem
19.
J Atheroscler Thromb ; 17(10): 1009-18, 2010 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-20720374

RESUMO

AIM: The abnormal proliferation of vascular smooth muscle cells (VSMCs) in arterial walls is an important pathogenic factor of vascular disorders such as atherosclerosis and restenosis after angioplasty. During atherogenesis or in response to vessel injury, VSMC proliferation is induced by a number of peptide growth factors released from platelets and VSMCs. Cilostazol is a phosphodiesterase (PDE) 3 inhibitor that increases intracellular cAMP levels and decreases intracellular Ca(2+) levels, inhibiting platelet aggregation and inducing vasodilatation. Cilostazol is also known to have an inhibitory effect on the proliferation of VSMCs, but the anti-proliferative mechanism of cilostazol in VSMCs has not yet been established. In the present study, we investigated whether the anti-proliferative mechanism of cilostazol is associated with the suppression of extracellular signal-regulated kinases (ERK) and phosphatidylinositol 3 kinase (PI3K) signaling pathways. METHODS: To confirm the anti-proliferative effects of cilostazol on VSMCs, VSMCs were induced to proliferate by serum-induced mitogenesis and then were treated with cilostazol for 24 h. And, to investigate whether the anti-proliferative mechanism of cilostazol in VSMCs involves the suppression of the ERK and PI3K pathways, expression of the phosphorylated forms of ERK1/2, Raf, Akt, and glycogen synthase kinase (GSK)-3 were evaluated by western blot. RESULTS: Cilostazol inhibited VSMC proliferation in a dose-dependent manner. Phosphorylated ERK1/2 and Raf were significantly reduced in a dose-dependent manner, whereas phosphorylated Akt and GSK-3 were not changed. CONCLUSION: These results suggest that suppression of the ERK pathway but not the PI3K pathway is an important mechanism in the anti-proliferative effect of cilostazol on VSMCs.


Assuntos
Broncodilatadores/farmacologia , Proliferação de Células/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Músculo Liso Vascular/citologia , Tetrazóis/farmacologia , Aorta/citologia , Aorta/efeitos dos fármacos , Aorta/metabolismo , Western Blotting , Bromodesoxiuridina , Células Cultivadas , Cilostazol , Relação Dose-Resposta a Droga , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Músculo Liso Vascular/enzimologia , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
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