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One Pathway (one + pathway)
Selected AbstractsMixed lineage kinase,c-jun N-terminal kinase signaling pathway: A new therapeutic target in Parkinson's diseaseMOVEMENT DISORDERS, Issue 6 2005Robert M. Silva PhD Abstract There is growing evidence that the molecular pathways of programmed cell death play a role in neurodegenerative disease, including Parkinson's disease, so there has been increased interest in them as therapeutic targets for the development of neuroprotective strategies. One pathway of cell death that has attracted particular attention is the mixed lineage kinase (MLK) ,c-jun N-terminal kinase (JNK) signaling cascade, which leads to the phosphorylation and activation of the transcription factor c-jun. There is much evidence, from in vitro and in vivo studies, that this cascade can mediate cell death. In addition, there is evidence that it is operative upstream in the death process. It is possible that abrogation of this pathway may forestall death before irreversible cellular injury. One class of compounds that has shown promise for their ability to block cell death by inhibiting this cascade are the inhibitors of the MLKs, which are upstream in the activation of c-jun. One of these compounds, CEP1347, is now in a Phase II/III clinical trial for neuroprotection in PD. Whether this trial is successful or not, this signaling cascade is likely to be a focus of future therapeutic development. This review, therefore, outlines the principles of signaling within this kinase pathway, and the evidence for its role in cell death. We review the evidence that inhibition of the MLKs can prevent dopamine neuron cell death and the degeneration of their axons. These studies suggest important future directions for the development of therapies that will target this important cell death pathway. © 2005 Movement Disorder Society [source] Depression in family caregivers of elders: A theoretical model of caregiver burden, sociotropy, and autonomy,RESEARCH IN NURSING & HEALTH, Issue 1 2010Michele C. Clark Abstract To test the diathesis-stress model for family caregivers, two structural equation models were developed to explain depression measured by the Center for Epidemiologic Studies Depression Scale. A cross-sectional convenience sample of 112 caregivers completed questionnaires to measure burden, personality traits, dysfunctional attitudes, and depression. The final model included direct paths from caregiver burden to autonomy and sociotropy, and indirect paths from burden to depression through sociotropy and autonomy. The final model fit adequately (,2 [224, N,=,112],=,308.60, p,<,.00; CFI,=,.951; RMSEA,=,.058). Levels of burden influenced caregiver depression scores. One pathway to depression was though the personality traits of sociotropy and autonomy; both had a larger influence on depression scores than burden alone. © 2009 Wiley Periodicals, Inc. Res Nurs Health 33:20,34, 2010 [source] Pathways to care for patients with bipolar disorderBIPOLAR DISORDERS, Issue 3 2005Dinesh Bhugra Bipolar disorder is a chronic, debilitating psychiatric illness with serious ramifications for patients, their families, and society. Despite the availability of effective treatments, this disease often goes untreated due to medical, financial, legal/governmental, and cultural barriers. In this review we explore possible reasons for this problem. Misdiagnosis of bipolar disorders is a common medical barrier. One pathway to care for individuals with bipolar disorder is through referral from primary care, but primary care physicians generally have not received special training in the recognition and management of bipolar disorder. This often leads to diagnostic delays or errors, which prevents timely ,filtering' of patients into specialized care. Using data bases we explored these pathways. Legislation in the USA, such as the Emergency Medical Treatment and Active Labor Act (EMTALA), designed to ensure access to inpatient mental health care, has instead given hospitals financial incentives to limit inpatient mental health care capacities. Reimbursement of mental health care expenses is a significant issue impacting a patient's ability to gain access to care, as bipolar disorder is a costly disease to treat. Improving access to care among the bipolar community will require multilateral strategies to influence the actions and attitudes of patients, communities, providers, health care systems, and state/national governments. In other cultures, barriers to care differ according to a number of factors such as type of services, explanatory models of illness, misdiagnosis and perceptions of care givers. It is essential that clinicians are aware of pathways and barriers so that appropriate and accessible care can be provided. [source] In vivo expression of signal transducer and activator of transcription factor 6 (STAT6) in nasal mucosa from atopic allergic rhinitis: effect of topical corticosteroidsCLINICAL & EXPERIMENTAL ALLERGY, Issue 1 2000Ghaffar Background The allergen-induced late nasal response is associated with a high local expression of interleukin (IL) -4, a TH2-type cytokine implicated in immunoglobulin (Ig) E production, tissue eosinophilia and other events considered to be relevant to allergic inflammation. Interaction of IL-4 with its receptor activates at least two distinct signalling pathways that culminate in the transcription of specific target genes. One pathway involves the activation of a transcription factor termed signal transducer and activator of transcription factor 6 (STAT6). Objective To investigate the expression of STAT6 in the allergen-induced late nasal response and to examine the effect of local steroid treatment on STAT6 expression. Methods Inferior turbinate biopsies were obtained from subjects with allergic rhinitis out of the allergen season. Subjects were then randomized into topical steroid- (n = 6) and placebo-treated (n = 6) groups in a double-blind fashion. After a 6-week treatment period, a second nasal biopsy was performed 24 h after local challenge with allergen. STAT6 immunoreactivity was examined in biopsy specimens by immunocytochemistry using a specific monoclonal antibody. Numbers of inflammatory cells (CD3+ T cells and MBP+ eosinophils) and IL-4 mRNA+ cells were investigated by immunocytochemistry and in situ hybridization, respectively. Results STAT6 immunoreactivity was detected in all biopsies studied and localized predominantly to inflammatory tissue of the nasal mucosa. After allergen challenge, expression of STAT6 was markedly increased in placebo-treated patients (P < 0.01). By confocal microscopy, STAT6 was localized to the cytoplasm and the nucleus of positively-staining cells. The allergen-induced increase in STAT6 immunoreactive cells was not observed in the steroid-treated patients. The change in STAT6 immunoreactivity after allergen challenge correlated significantly with the change in numbers IL-4 mRNA+ cells (r = 0.74, P = 0.006) and CD3+ T cells (r = 0.76, P = 0.004), but not MBP+ eosinophils. Conclusion This study provides the first evidence of increased STAT6 expression in vivo in human allergic inflammation. The results support a role for STAT6 and IL-4 in the pathogenesis of late nasal response and show that decreases in STAT6 expression parallel the reduction in IL-4 expression that occurs with topical steroid treatment. [source] New N6 -substituted 8-alkyl-2-phenylmethylsulfanyl-adenines.JOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 4 2004Title compounds bearing substituents on C(2), C(6) and C(8) were prepared from a newly synthesized pyrimidine derivative 11. The new pyrimidine 11 was generated from compound 2 through two different synthetic schemes. In one pathway, compound 2 was nitrosated, reduced and alkylated to produce com pounds 9, 10 and 11 respectively (Scheme). In an alternate route using compound 2 as the starting material, a coupling reaction using the diazonium salt derived from p -methylaniline afforded the azo derivative 7, which was subsequently alkylated and reductively cleaved to form compounds 8 and 11 respectively (See Scheme). Compound 11 was annulated to the corresponding hypoxanthine derivatives 12,14; compounds 12 and 13 were chlorinated with phosphorus oxychloride, then reacted with amines to yield compound 17 and 20 respectively. Compounds 21, 22 and 23 were obtained by oxidation of the corresponding sulfide as depicted in Scheme. Alkylation of the thiol function of 1 gave a mixture of 3 and 4. Compound 3 was chlo rinated to 5. Nitration of 5 resulted in electrophilic aromatic substitution of the aryl ring and concomitant oxidation of the sulfide to the sulfoxide, producing 6. [source] | ||||||||||