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New Treatment Strategies (new + treatment_strategy)
Selected AbstractsNogo-A antibodies and training reduce muscle spasms in spinal cord-injured ratsANNALS OF NEUROLOGY, Issue 1 2010Roman R. Gonzenbach MD Objective Spinal cord injury (SCI) leads to permanent motor and sensory deficits due to the damage of ascending and descending fiber tracts. In addition, malfunctions such as neuropathic pain or muscle spasms develop in many patients, possibly caused by injury-induced plastic changes of neuronal circuits above and below the lesion. New treatment strategies for spinal cord injury aim at enhancing plasticity and neurite growth, for example, by blocking the key neurite growth inhibitor Nogo-A or its downstream effectors. It is therefore crucial to investigate potential effects of such treatments on malfunctions such as muscle spasms. In addition, locomotor training, now a standard therapeutic tool to improve walking ability in incomplete SCI subjects, can be expected to influence the rearrangement of spinal cord circuits and the development of muscle spasms and other malfunctions. Methods and Results Here we present and validate a new rat model for muscle spasms after incomplete SCI and show that both intrathecal anti,Nogo-A antibody treatment and locomotor training, started early after injury, permanently reduce the development of muscle spasms. Interpretation The results show that an antibody-mediated suppression of the growth inhibitory protein Nogo-A leads to functional recovery and a lower level of malfunctions, suggesting the formation of functionally meaningful connections in the damaged spinal cord. Treadmill training early after SCI also has a beneficial effect. ANN NEUROL 2010;68:48,57 [source] Transesophageal Echocardiography Risk Factors for Stroke in Nonvalvular Atrial FibrillationECHOCARDIOGRAPHY, Issue 4 2000F.R.C.P.C., SUSAN M. FAGAN M.D. Atrial fibrillation is a common arrhythmia, particularly in the older age groups. It confers an increased risk of thromboembolism to these patients, and multiple clinical risk factors have been identified to be useful in predicting the risks of thromboembolic events. Recent studies have evaluated the role of transesophageal echocardiography (TEE) in the evaluation of patients with atrial fibrillation. The purpose of this review is to evaluate the significance of transesophageal echocardiography findings in the prediction of thromboembolic events, particularly stroke, in patients with nonvalvular atrial fibrillation, with an emphasis on recently reported prospective studies. Aortic plaque and left atrial appendage abnormalities are identified as independent predictors of thromboembolic events. Although they are associated with clinical events, they also have independent incremental prognostic values. Other transesophageal echocardiographic findings, such as patent foramen ovale and atrial septal aneurysm, have not been found to be predictors of thromboembolic events in this patient group. Thus, TEE is a useful tool in stratifying patients with nonvalvular atrial fibrillation into different risk groups in terms of thromboembolic events, and it will likely play an important role in future studies to assess new treatment strategies in high-risk patients with atrial fibrillation. [source] Proliferative activity of plasma cells is the most relevant prognostic factor in elderly multiple myeloma patientsINTERNATIONAL JOURNAL OF CANCER, Issue 5 2004R. García-Sanz Abstract Although multiple myeloma (MM) is predominantly a disease of the elderly, few studies have focused on the identification of prognostic factors in this group of patients. Four hundred twenty five MM patients >65 years were uniformly treated with chemotherapy (MP or VCMP/VBAD). Multivariate analysis identified 4 factors with independent unfavorable prognostic influence: high percentage of S-phase bone marrow plasma cells (>2.5%); elevated ,2 microglobulin (B2M) (>4 mg/L); age >80 years old; and LDH serum levels (above normal limit). The S-phase value was the most powerful independent prognostic factor to discriminate subgroups of patients with different prognosis. Thus, 3 main risk categories could be identified according to S-phase values: ,1%, 1,3% and >3%, with median survivals of 34, 22 and 12 months, respectively (p < 0.0001). Our study also proved the value for elderly patients of the recently developed International Score System (ISS) based on B2M and albumin. Furthermore, the number of S-phase cells helped to subdivide the ISS III Group identifying a subset of patients with very poor prognosis defined by an additional high S-phase, who displayed a median survival of only 8 months. These results demonstrate that elderly patients can be accurately classified according to prognosis, which may be particularly valuable when comparing the efficacy of new treatment strategies. Moreover, our results underline the high prognostic value of proliferative activity of PC, a parameter that should be considered in routine laboratory investigations of MM. © 2004 Wiley-Liss, Inc. [source] Anticancer effects of zoledronic acid against human osteosarcoma cellsJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 6 2006B. Kubista Abstract Based on neoadjuvant chemotherapy, the prognosis of osteosarcoma patients has improved dramatically. However, due to therapy resistance in patient subgroups, the development of new treatment strategies is still of utmost importance. The aim of our study was to test the effects of the nitrogen-containing bisphosphonate zoledronic acid (ZOL) on osteosarcoma cell lines (N,=,9). Exposure to ZOL at low micromolar concentrations induced a dose- and time-dependent block of DNA synthesis and cell cycle progression followed by microfilament breakdown and apoptosis induction. The ZOL-induced cell cycle accumulation in S phase was accompanied by significant changes in the expression of cyclins and cyclin-dependent kinase inhibitors with a prominent loss of cyclin E and D1. ZOL not only inhibited growth but also migration of osteosarcoma cells. The mevalonate pathway intermediary geranyl-geraniol (GGOH) but not farnesol (FOH) significantly inhibited the anticancer effects of ZOL against osteosarcoma cells. Correspondingly, ZOL sensitivity correlated with the blockade of protein geranylgeranylation indicated by unprenylated Rap1. Overexpression of even high levels of P-glycoprotein, as frequently present in therapy-resistant osteosarcomas, did not impair the anticancer activity of ZOL. Summarizing, our data suggest that ZOL, which selectively accumulates in the bone, represents a promising agent to improve osteosarcoma therapy. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res [source] Actions of Acute and Chronic Ethanol on Presynaptic TerminalsALCOHOLISM, Issue 2 2006Marisa Roberto This article presents the proceedings of a symposium entitled "The Tipsy Terminal: Presynaptic Effects of Ethanol" (held at the annual meeting of the Research Society on Alcoholism, in Santa Barbara, CA, June 27, 2005). The objective of this symposium was to focus on a cellular site of ethanol action underrepresented in the alcohol literature, but quickly becoming a "hot" topic. The chairs of the session were Marisa Roberto and George Robert Siggins. Our speakers were chosen on the basis of the diverse electrophysiological and other methods used to discern the effects of acute and chronic ethanol on presynaptic terminals and on the basis of significant insights that their data provide for understanding ethanol actions on neurons in general, as mechanisms underlying problematic behavioral effects of alcohol. The 5 presenters drew from their recent studies examining the effects of acute and chronic ethanol using a range of sophisticated methods from electrophysiological analysis of paired-pulse facilitation and spontaneous and miniature synaptic currents (Drs. Weiner, Valenzuela, Zhu, and Morrisett), to direct recording of ion channel activity and peptide release from acutely isolated synaptic terminals (Dr. Treistman), to direct microscopic observation of vesicular release (Dr. Morrisett). They showed that ethanol administration could both increase and decrease the probability of release of different transmitters from synaptic terminals. The effects of ethanol on synaptic terminals could often be correlated with important behavioral or developmental actions of alcohol. These and other novel findings suggest that future analyses of synaptic effects of ethanol should attempt to ascertain, in multiple brain regions, the role of presynaptic terminals, relevant presynaptic receptors and signal transduction linkages, exocytotic mechanisms, and their involvement in alcohol's behavioral actions. Such studies could lead to new treatment strategies for alcohol intoxication, alcohol abuse, and alcoholism. [source] Aerosol therapy in cystic fibrosis: Weighing the evidencePEDIATRIC PULMONOLOGY, Issue S9 2008Felix Ratjen MD Abstract Aggressive treatment of CF lung disease has markedly increased survival of CF patients and intense research efforts over the last decades have led to new treatment strategies, many of which target the lower airways directly via aerosol. The addition of any new therapy not only needs to be assessed in view of its individual efficacy, but also in context with other established therapies. This review will summarize the current evidence on aerosol therapy in CF focussing on therapies that hydrate airways, mucolytic therapy with dornase alfa and inhaled antibiotics. The different therapeutic regimens will be critically assessed in context to address the question of whether these different drugs can be used interchangeably or should be used in combination in CF lung disease. Pediatr Pulmonol. 2008; 43:S3,S4. © 2008 Wiley-Liss, Inc. [source] Clinical aspects and immune reactions in sarcoidosis,THE CLINICAL RESPIRATORY JOURNAL, Issue 2 2007Johan Grunewald Abstract Introduction:, Sarcoidosis is a granulomatous disorder of unknown aetiology, affecting young adults and frequently involving the lungs. Objective:, The aim of the present review was to give an overview of the clinical aspects in sarcoidosis. Results:, The majority of patients recover, but some develop a chronic disease that may result in fibrosis and respiratory failure. Besides the lungs, peripheral lymph nodes, the skin, the liver and the eyes are commonly affected as well. The genetic background, as well as environmental factors, is of importance for developing sarcoidosis. The incidence varies in different populations, in the Nordic countries approximately with 20/100 000 new patients yearly. Sarcoidosis is diagnosed when clinical and radiological findings are supported by histological evidence in the form of non-caseating epithelioid cell granulomas, and when other causes of these features are excluded. Patients in need of treatment are usually treated with corticosteroids, topically or as oral steroids. A clinical effect of immunomodulatory drugs blocking tumour necrosis factor (TNF), has been suggested from several case reports, while two controlled studies showed only minor effects; however, with a tendency to a more pronounced effect on patients with a more severe disease. The immune response in sarcoidosis, with a typical accumulation of CD4+ T-cells to the lungs, indicate the existence of specific antigens in this disease. Recently, antigens derived from infectious agents such as Mycobacteria and Proprionibacterium acnes have come into focus. Lymphocyte populations with immunoregulatory functions have recently been investigated and seem to be dysfunctional in sarcoidosis, opening the possibility of developing new treatment strategies in this disease. Conclusion:, Recent technical developments have provided better tools, enabling detailed and more thorough analyses of the inflammatory process in sarcoidosis. Please cite this paper as: Grunewald J. Clinical aspects and immune reactions in sarcoidosis. The Clinical Respiratory Journal 2007; 1:64,73. [source] Magnetic Resonance Imaging and the Female Sexual Response: Overview of Techniques, Results, and Future DirectionsTHE JOURNAL OF SEXUAL MEDICINE, Issue 7 2008Kenneth R. Maravilla ABSTRACT Introduction., Magnetic resonance imaging (MRI) is becoming a frequently used tool in the study of sexual physiology and neurophysiology. Aim., This report reviews various MRI methods used to study the female sexual arousal response. Methods., Retrospective review of pertinent literature. Results., Dynamic genital MRI studies enable the visualization of the physiologic arousal response that provides the direct observation of the time course and magnitude of this response, along with the variability that appears to occur in women with sexual arousal disorder. Functional brain MR studies are described and summarized along with an overview of what we have learned. Finally, the speculation on how we may be able to use MRI technology to better understand the female sexual response and to help in validating new drug treatments or in devising new treatment strategies for sexual dysfunction is also presented. Conclusions., Neuroimaging has already been proven as an invaluable research tool to study the sexual response in women both in the pelvis as well as within the brain. Using these techniques, major inroads are being made to improve the understanding of the sexual arousal process in women. Maravilla KR, and Yang CC. Magnetic resonance imaging and the female sexual response: Overview of techniques, results, and future directions. J Sex Med 2008;5:1559,1571. [source] The International Prognostic Index determines the outcome of patients with nodal mature T-cell lymphomasBRITISH JOURNAL OF HAEMATOLOGY, Issue 3 2005Ruth Sonnen Summary The World Health Organization (WHO) lymphoma classification recognises anaplastic large cell lymphoma (ALCL), angioimmunoblastic lymphoma (AIL) and peripheral T-cell lymphoma, unspecified (PTCU) as nodal mature T-cell lymphomas. Little is known about long-term outcome and prognostic factors of these diseases. A retrospective analysis on 125 patients with ALCL, AIL or PTCU was performed to evaluate outcome parameters, taking into account histological subtype and the International Prognostic Index (IPI). Median age was 54 years (range 17,90 years). Complete remission (CR) was achieved in 51% of patients. Five-year overall survival (OS) was 43%, and 5-year relapse-free survival was 69%. Five-year OS was 61% for ALCL, 45% for PTCU and 28% for AIL. With regard to the IPI, 5-year OS was 74%, 49%, 21% and 6% for the low, low-intermediate, high-intermediate and high risk groups, respectively. In the multivariate analysis, the IPI but not the histological subtype significantly predicted survival. To a large extent, the IPI score explains the differences in survival between histological subtypes of nodal mature T-cell lymphomas. The IPI may therefore be used for risk stratification in clinical trials to identify patients who would benefit most from new treatment strategies, such as high-dose chemotherapy followed by stem cell or bone marrow transplantation. [source] Overexpression of the Wilms' tumor gene WT1 in pancreatic ductal adenocarcinomaCANCER SCIENCE, Issue 7 2004Yusuke Oji The expression of the Wilms' tumor gene WT1 was examined by immunohistochemistry in 40 cases of pancreatic ductal adenocarcinoma. WT1 protein was expressed in 30 (75%) of the 40 pancreatic ductal adenocarcinomas, but not in the remaining 10 (25%). In normal pancreatic ductal cells, WT1 protein was undetectable. No correlations between WT1 expression and clinicopathological parameters such as age, sex, T or N stage, tumor location, and tumor differentiation were observed. Treatment with WT1 anti-sense oligomers significantly inhibited the growth of five human pancreatic cancer cell lines, PSN1, MiaPaCa2, ASPC1, BxPC3, and PCI6, expressing the WT1 gene. These results indicate an important role of the WT1 gene in the tumorigenesis of pancreatic ductal adenocarcinoma expressing WT1 and provide a rationale for new treatment strategies to treat pancreatic ductal adenocarcinoma by targeting the WT1 gene and its product. [source] Mechanisms of osteoporosis in spinal cord injuryCLINICAL ENDOCRINOLOGY, Issue 5 2006Sheng-Dan Jiang Summary Osteoporosis is a known complication of spinal cord injury (SCI), but its mechanism remains unknown. The pathogenesis of osteoporosis after SCI is generally considered disuse. However, although unloading is an important factor in the pathogenesis of osteoporosis after SCI, neural lesion and hormonal changes also seem to be involved in this process. Innervation and neuropeptides play an important role in normal bone remodelling. SCI results in denervation of the sublesional bones and the neural lesion itself may play a pivotal role in the development of osteoporosis after SCI. Although upper limbs are normally loaded and innervated, bone loss also occurs in the upper extremities in patients with paraplegia, indicating that hormonal changes may be associated with osteoporosis after SCI. SCI-mediated hormonal changes may contribute to osteoporosis after SCI by different mechanisms: (1) increased renal elimination and reduced intestinal absorption of calcium leading to a negative calcium balance; (2) vitamin D deficiency plays a role in the pathogenesis of SCI-induced osteoporosis; (3) SCI antagonizes gonadal function and inhibits the osteoanabolic action of sex steroids; (4) hyperleptinaemia after SCI may contribute to the development of osteoporosis; (5) pituitary suppression of TSH may be another contributory factor to bone loss after SCI; and (6) bone loss after SCI may be caused directly, at least in part, by insulin resistance and IGFs. Thus, oversupply of osteoclasts relative to the requirement for bone resorption and/or undersupply of osteoblasts relative to the requirement for cavity repair results in bone loss after SCI. Mechanisms for the osteoporosis following SCI include a range of systems, and osteoporosis after SCI should not be simply considered as disuse osteoporosis. Unloading, neural lesion and hormonal changes after SCI result in severe bone loss. The aim of this review is to improve understanding with regard to the mechanisms of osteoporosis after SCI. The understanding of the pathogenesis of osteoporosis after SCI can help in the consideration of new treatment strategies. Because bone resorption after SCI is very high, intravenous bisphosphonates and denosumab should be considered for the treatment of osteoporosis after SCI. [source] The efficacy of nicotinamide gel 4% as an adjuvant therapy in the treatment of cutaneous erosions of pemphigus vulgarisDERMATOLOGIC THERAPY, Issue 3 2010Fariba Iraji ABSTRACT The high rate of morbidity and mortality resulting from long-term use of corticosteroids in pemphigus vulgaris (PV) warrants discovery of a new treatment strategy. Based on the pathophysiology of PV, nicotinamide can block the process of blister formation through its anti-inflammatory properties. This study was conducted to evaluate the clinical effectiveness of nicotinamide gel in the treatment of skin lesions of PV. In a double-blind, placebo-controlled study, eight PV patients with a total of 60 skin lesions were treated by either nicotinamide or placebo gel. After 30 days of treatment, epithelialization index of the two groups was compared. The mean of the epithelialization index in skin lesions that received nicotinamide was significantly higher than that of the placebo group (26 vs. ,5.8, p < 0.001). Our results were suggestive that nicotinamide gel can effectively be used as an adjunctive treatment for PV lesions. [source] Superior virological response to boosted protease inhibitor-based highly active antiretroviral therapy in an observational treatment programmeHIV MEDICINE, Issue 2 2007E Wood Background The use of boosted protease inhibitor (PI)-based antiretroviral therapy has become increasingly recommended in international HIV treatment consensus guidelines based on the results of randomized clinical trials. However, the impact of this new treatment strategy has not yet been evaluated in community-treated cohorts. Methods We evaluated baseline characteristics and plasma HIV RNA responses to unboosted and boosted PI-based highly active antiretroviral therapy (HAART) among antiretroviral-naïve HIV-infected patients in British Columbia, Canada who initiated HAART between August 1997 and September 2003 and who were followed until September 2004. We evaluated time to HIV-1 RNA suppression (<500 HIV-1 RNA copies/mL) and HIV-1 RNA rebound (,500 copies/mL), while stratifying patients into those that received boosted and unboosted PI-based HAART as the initial regimen, using Kaplan,Meier methods and Cox proportional hazards regression. Results During the study period, 682 patients initiated therapy with unboosted PI and 320 individuals initiated HAART with a boosted PI. Those who initiated therapy with a boosted PI were more likely to have a CD4 cell count <200 cells/,L and to have a plasma HIV RNA>100 000 copies/mL, and to have AIDS at baseline (all P<0.001). However, when we examined virological response rates, those who initiated HAART with a boosted PI achieved more rapid virological suppression [relative hazard 1.26, 95% confidence interval (CI) 1.06,1.51, P=0.010]. Conclusions Patients prescribed boosted PIs achieved superior virological response rates despite baseline factors that have been associated with inferior virological responses to HAART. Despite the inherent limitations of observational studies which require this study be interpreted with caution, these findings support the use of boosted PIs for initial HAART therapy. [source] Multiexon skipping leading to an artificial DMD protein lacking amino acids from exons 45 through 55 could rescue up to 63% of patients with Duchenne muscular dystrophy,HUMAN MUTATION, Issue 2 2007Christophe Béroud Abstract Approximately two-thirds of Duchenne muscular dystrophy (DMD) patients show intragenic deletions ranging from one to several exons of the DMD gene and leading to a premature stop codon. Other deletions that maintain the translational reading frame of the gene result in the milder Becker muscular dystrophy (BMD) form of the disease. Thus the opportunity to transform a DMD phenotype into a BMD phenotype appeared as a new treatment strategy with the development of antisense oligonucleotides technology, which is able to induce an exon skipping at the pre-mRNA level in order to restore an open reading frame. Because the DMD gene contains 79 exons, thousands of potential transcripts could be produced by exon skipping and should be investigated. The conventional approach considers skipping of a single exon. Here we report the comparison of single- and multiple-exon skipping strategies based on bioinformatic analysis. By using the Universal Mutation Database (UMD)-DMD, we predict that an optimal multiexon skipping leading to the del45-55 artificial dystrophin (c.6439_8217del) could transform the DMD phenotype into the asymptomatic or mild BMD phenotype. This multiple-exon skipping could theoretically rescue up to 63% of DMD patients with a deletion, while the optimal monoskipping of exon 51 would rescue only 16% of patients. Hum Mutat 28(2), 196,202, 2007. © 2006 Wiley-Liss, Inc. [source] | ||||||||||||||||||||||