Cell type-specific anti-cancer properties of valproic acid: independent effects on HDAC activity and Erk1/2 phosphorylation

<p>Abstract</p> <p>Background</p> <p>The anti-epileptic drug valproic acid (VPA) has attracted attention as an anti-cancer agent.</p> <p>Methods</p> <p>The present study investigated effects of VPA exposure on histone deacetylase (HDAC) inhibition, cell growth, cell speed, and the degree of Erk1/2 phosphorylation in 10 cell lines (BT4C, BT4Cn, U87MG, N2a, PC12-E2, CSML0, CSML100, HeLa, L929, Swiss 3T3).</p> <p>Results</p> <p>VPA induced significant histone deacetylase (HDAC) inhibition in most of the cell lines, but the degree of inhibition was highly cell type-specific. Moreover, cell growth, motility and the degree of Erk1/2 phosphorylation were inhibited, activated, or unaffected by VPA in a cell type-specific manner. Importantly, no relationship was found between the effects of VPA on HDAC inhibition and changes in the degree of Erk1/2 phosphorylation, cell growth, or motility. In contrast, VPA-induced modulation of the MAPK pathway downstream of Ras but upstream of MEK (i.e., at the level of Raf) was important for changes in cell speed.</p> <p>Conclusions</p> <p>These results suggest that VPA can modulate the degree of Erk1/2 phosphorylation in a manner unrelated to HDAC inhibition and emphasize that changes in the degree of Erk1/2 phosphorylation are also important for the anti-cancer properties of VPA.</p

Water channel pore size determines exclusion properties but not solute selectivity

Aquaporins (AQPs) are a ubiquitous family of transmembrane water channel proteins. A subgroup of AQP water channels also facilitates transmembrane diffusion of small, polar solutes. A constriction within the pore, the aromatic/arginine (ar/R) selectivity filter, is thought to control solute permeability: previous studies on single representative water channel proteins suggest narrow channels conduct water, whilst wider channels permit passage of solutes. To assess this model of selectivity, we used mutagenesis, permeability measurements and in silico comparisons of water-specific as well as glycerol-permeable human AQPs. Our studies show that single amino acid substitutions in the selectivity filters of AQP1, AQP4 and AQP3 differentially affect glycerol and urea permeability in an AQP-specific manner. Comparison between in silico-calculated channel cross-sectional areas and in vitro permeability measurements suggests that selectivity filter cross-sectional area predicts urea but not glycerol permeability. Our data show that substrate discrimination in water channels depends on a complex interplay between the solute, pore size, and polarity, and that using single water channel proteins as representative models has led to an underestimation of this complexity

Impact of Scoliosis Severity on Functional Capacity in Patients With Adolescent Idiopathic Scoliosis

Purpose: The aim of this study is to evaluate the walked distance and physiological responses during incremental shuttle walk test in patients with different degrees of adolescent idiopathic scoliosis (AIS). Methods: We evaluated 20 healthy teenagers and 46 patients with AISthey were divided into 2 groups: AIS > 45 degrees and AIS 45 degrees presented significant reduced incremental shuttle walked distance compared with the AIS < 45 degrees and control group [447 (85), 487 (95), and 603 (85), respectively]. Patients with AIS also showed reduced forced vital capacity (P = .001) and expiratory volume in the first second (P = .005) compared with control group. Moderate correlations between forced vital capacity (r = -.506) and tidal volume (r = -.476) with scoliosis angles were found. Conclusions: The incremental shuttle walk test was capable of identifying reduced functional capacity in patients with different degrees of AIS. Moreover, the severity of spinal curvature may exert influence on ventilatory and metabolic variables.Fed Univ Sao Paulo UNIFESP, Dept Human Movement Sci, Lab Epidemiol & Human Movement, Santos, SP, BrazilAlbert Einstein Hosp, Dept Orthoped, Sao Paulo, SP, BrazilFed Univ Sao Paulo UNIFESP, Dept Human Movement Sci, Lab Epidemiol & Human Movement, Santos, SP, BrazilWeb of Scienc

Radiographic and functional evaluation of the iliac bone graft in the treatment of adolescent idiopathic scoliosis

This study aimed to assess the impact of the use of an additional iliac bone graft on functional and radiographic results after thoracic spine arthrodesis with pedicle screws in patients with adolescent idiopathic scoliosis. Participants were divided into two groups: a control group that received only local bone (n = 19) and a second group that, in addition to this procedure, received an iliac graft (n = 22). the evaluations were performed on preoperative, immediate postoperative, and last follow-up (mean 29.7 months; minimum 12 months). Radiographic evaluations included the loss of correction and the presence of nonunion. the functional outcome was evaluated using the Scoliosis Research Society-30 questionnaire. Surgical complications and the presence of iliac donor site pain were also described. There were no significant differences between groups in the pseudoarthrosis rate, loss of correction over time, and quality of life. We concluded that the addition of bone graft from the iliac yielded no benefit in terms of the fusion rate and functional outcomes. the appropriate facetectomy, bed preparation, and filling with a local bone graft must be adequate to achieve an adequate fusion on surgical treatment of adolescent idiopathic scoliosis. (C) 2014 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.Santa Casa Misericordia Santos, Dept Orthopaed & Traumatol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Phys Therapy, São Paulo, BrazilFac Med ABC, Dept Orthopaed Surg, BR-09060650 Santo Andre, SP, BrazilUniversidade Federal de São Paulo, Dept Phys Therapy, São Paulo, BrazilWeb of Scienc

Multicenter Studies Of Oral Ziprazidone For The Treatment Of Patients With Schizophrenia And Schizoaffective Disorder [estudos Multicêntricos Da Ziprasidona Oral No Tratamento De Pacientes Com Esquizofrenia Ou Transtorno Esquizoafetivo]

Background: The oral ziprasidone efficacy, safety, and tolerability on Brazilian patients with schizophrenic and schizoaffective disorder were evaluated through two sequential clinical trials. Methods: Prospective open studies. At the first 6-week trial patients received 80 to 160 mg/day of ziprasidone, and were evaluated using the Positive and Negative Symptom Scale (PANSS), Clinical Global Impression-Severity Scale (CGI-S), Intensity Care Questionnaire (ICQ) e Patient Preference Scale (PPS). Safety and tolerability were evaluated by clinical, EKG, and laboratorial analysis, Extrapyramidal Symptom Rating Scale (ESRS), and Barnes Akathisia Scale (BAS). Responsive patients were included on one up to 12-month second trial. Results: 162 patients were analyzed regarding drug efficacy, and 164 regarding tolerability at first clinical trial. From baseline to endpoint treatment decreased PANSS scores from 94.3 to 76.2 (P<.0001). Either scores on CGI-S and ICQ showed significantly reduction. Ziprasidone had the patient's preference (64.8%) compared to the last medication used through the PPS application. Neither, extrapyramidal symptoms or EKG alterations were found. From 106 included patients at the second trial, 86 were analyzed regarding efficacy. The median of treatment duration was 5.6 months, and the mean of PANSS was kept during the evaluation. The adverse events profiles from both studies were similar. Conclusion: Oral ziprasidone is an effective and safe drug for chronic treatment of patients with schizophrenic and schizoaffective disorder. © Copyright Moreira Jr. Editora.644170176Kane, J., Honigfeld, G., Singer, J., Meltzer, H., Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine (1988) Arch Gen Psychiatry, 45, pp. 789-796Freedman, R., Schizophrenia (2003) N Engl J Med, 349, pp. 1738-1749Meltzer, H.Y., Clinical studies on the mechanism of action of clozapine: The dopamine-serotonin hypothesis of schizophrenia (1989) Psychopharmacology (Berl), 99, pp. S18-S27Kane, J.M., Oral ziprasidone in the treatment of schizophrenia: A review of short-term trials (2003) J Clin Psychiatry, 64 (SUPPL. 19), pp. 19-25Gunasekara, N.S., Spencer, C.M., Keating, G.M., Ziprasidone: A review of its use in schizophrenia and schizoaffective disorder (2002) Drugs, 62 (8), pp. 1217-1251Glassman, A.H., Bigger Jr., J.T., Antipsychotic drugs: Prolonged QTc interval, torsade de pointes, and sudden death (2001) Am J Psychiatry, 158, pp. 1774-1782Diagnostic and Statistical Manual of Mental Disorders, 4th ed.: DSM-IV. Washington, D.C.: American Psychiatric Association, 1994Chaves, A.C., Shirakawa, I., Escala das síndromes negativa e positiva - PANSS e seu uso no Brasil (1998) Rev Psiq Clín, 25 (6), pp. 337-343Clinical Global Impression Severity Scale (1976) ECDEU Assessment Manual of Psychopharmacology, , National Institute of Mental Health, Guy W Ed, Washington, DC: U. S. Government Printing OfficeChouinard, G., Margolese, H.C., Manual for the Extrapyramidal Symptom Rating Scale (ESRS) (2005) Schizophr Res, 76 (2-3), pp. 247-265Barnes, T.R., A rating scale for drug-induced akathisia (1989) B J Psychiatry, 154, pp. 672-676Awad, A.G., Hogan, T.P., Subjective response to neuroleptic drugs and the quality of life: Implication for treatment outcome (1994) Acta psychiatr Scand, p. 89. , spplm 380 27-32Arato, M., O'Connor, R., Meltzer, H.Y., A 1-year, double-blind, placebo-controlled trial of ziprasidone 40, 80 and 160 mg/day in chronic schizophrenia: The Ziprasidone Extended Use in Schizophrenia (ZEUS) study (2002) Int Clin Psychopharmacol, 17, pp. 207-215Hirsch, S.R., Kissling, W., Bauml, J., Power, A., O'Connor, R., A 28-week comparison of ziprasidone and haloperidol in outpatients with stable schizophrenia (2002) J Clin Psychiatry, 63, pp. 516-523Weiden, P.J., Simpson, G.M., Potkin, S.G., O'Sullivan, R.L., Effectiveness of switching to ziprasidone for stable but symptomatic outpatients with schizophrenia (2003) J Clin Psychiatry, 64, pp. 580-588Harvey, P.D., Meltzer, H., Simpson, G.M., Potkin, S.G., Loebel, A., Siu, C., Romano, S.J., Improvement in cognitive function following a switch to ziprasidone from conventional antipsychotics, olanzapine, or risperidone in outpatients with schizophrenia (2004) Schizophr Res, 66, pp. 101-113Weiden, P.J., Daniel, D.G., Simpson, G.M., Romano, S.J., Improvement in indices of health status in outpatients with schizophrenia switched to ziprasidone (2003) J Clin Psychopharmacol, 23, pp. 595-600Lieberman, J.A., Stroup, T.S., McEvoy, J.P., Swartz, M.S., Rosenheck, R.A., Perkins, D.O., Effectiveness of antipsychotic drugs in patients with chronic schizophrenia (2005) N Engl J Med, 353, pp. 1209-1223Kingsbury, S.J., Fayek, M., Trufasiu, D., Zada, J., Simpson, G.M., The apparent effects of ziprasidone on plasma lipids and glucose (2001) J Clin Psychiatry, 62, pp. 347-349Cohen, S., Fitzgerald, B., Okos, A., Khan, S., Khan, A., Weight, lipids, glucose, and behavioral measures with ziprasidone treatment in a population with mental retardation (2003) J Clin Psychiatry, 64, pp. 60-6

Influência da extensão da artrodese lombossacra nos resultados clínicos e funcionais Influencia de la extensión de la artrodesis lumbosacra en los resultados clínicos y funcionales Influence of the extent of lumbosacral arthrodesis in clinical and functional outcomes

OBJETIVO: Verificar a influência da extensão da fusão póstero-lateral lombossacra e seu impacto nos resultados clínicos e funcionais. MÉTODOS: Foram avaliados 22 pacientes portadores de estenose central, foraminal ou hérnia de disco lombar, associadas a instabilidade segmentar, submetidos ao tratamento cirúrgico para a descompressão neural e artrodese póstero-lateral. Os pacientes foram divididos em dois grupos, de acordo com quantidade de níveis artrodesados: Grupo 1: fusão em um nível e Grupo 2: fusão em dois ou mais níveis. Os pacientes preencheram questionários referentes ao acompanhamento pós-operatório (uso de medicamentos analgésicos e satisfação com o tratamento) e escala analógica visual de dor lombar e ciática. Além disto, foram aplicados os questionários Oswestry e SF-36 para avaliação da qualidade de vida. RESULTADOS: Os resultados do SF-36 mostraram bons níveis de qualidade de vida em ambos os grupos, com exceção do domínio "Aspectos Físicos". Não houve correlação significativa entre a extensão da artrodese e os desfechos clínicos. CONCLUSÕES: Os pacientes submetidos à artrodese póstero-lateral apresentaram qualidade de vida satisfatória, exceto pela diminuição da aptidão física. Entretanto, o maior número de níveis artrodesados não teve impacto negativo sobre os aspectos clínicos e funcionais.<br>OBJETIVO: Investigar la influencia del grado de la fusión posterolateral lumbosacral y su impacto en los resultados clínicos y funcionales. MÉTODOS: Se evaluaron 22 pacientes con estenosis central, foraminal o hernia de disco lumbar, asociadas a inestabilidad segmentaria; se sometieron a cirugía para la descompresión neural y la artrodesis posterolateral. Los pacientes fueron divididos en dos grupos según el número de niveles fusionados: Grupo 1: la fusión en un nivel, y Grupo 2: la fusión en dos o más niveles. Los pacientes completaron cuestionarios sobre seguimiento posoperatorio (uso de medicamentos analgésicos y satisfacción con el tratamiento) y la escala analógica visual para el dolor lumbar y la ciática. Por otra parte, se aplicaran los cuestionarios Oswestry y SF-36 para evaluar la calidad de vida. RESULTADOS: El SF-36 mostró resultados de buenos niveles de calidad de vida en ambos grupos, excepto en el campo "Aspectos Físicos". No hubo correlación significativa entre la magnitud de la artrodesis y los resultados clínicos. CONCLUSIONES: Los pacientes que fueron sometidos a artrodesis posterolateral mostraron calidad de vida satisfactoria, con excepción de disminución de la aptitud física. Sin embargo, el mayor número de niveles fusionados no tuvo un impacto negativo en los aspectos clínicos y funcionales.<br>OBJECTIVE: Investigate the influence of the extent of posterolateral lumbosacral fusion and its impact on clinical and functional results. METHODS: We evaluated 22 patients with central or foraminal stenosis or lumbar disc herniation associated with segmental instability that underwent to surgery for nerve decompression and posterolateral arthrodesis. Patients were divided into two groups according to the number of levels fused: Group 1: fusion at one level and Group 2: fusion of two or more levels. Patients completed questionnaires regarding postoperative follow-up (use of analgesic medications and treatment satisfaction) and visual analog scale for lumbar pain and sciatica. Moreover, the questionnaires Oswestry and SF-36 were administered to assess quality of life. RESULTS: SF-36 showed good levels of quality of life in both groups, except the field "Physical Aspects". There was no significant correlation between the extent of the arthrodesis and clinical outcomes. CONCLUSIONS: Patients who underwent posterolateral arthrodesis showed satisfactory quality of life, except for a decrease of physical fitness. However, the higher number of levels fused did not have negative impact on clinical and functional aspects