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Chang J.-Y.,University of Houston | Chang J.-Y.,Institute of Molecular Medicine

The pathway of oxidative folding of disulfide proteins exhibits a high degree of diversity, which is manifested mainly by distinct structural heterogeneity and diverse rearrangement pathways of folding intermediates. During the past two decades, the scope of this diversity has widened through studies of more than 30 disulfide-rich proteins by various laboratories. A more comprehensive landscape of the mechanism of protein oxidative folding has emerged. This review will cover three themes. (1) Elaboration of the scope of diversity of disulfide folding pathways, including the two opposite extreme models, represented by bovine pancreatic trypsin inhibitor (BPTI) and hirudin. (2) Demonstration of experimental evidence accounting for the underlying mechanism of the folding diversity. (3) Discussion of the convergence between the extreme models of oxidative folding and models of conventional conformational folding (framework model, hydrophobic collapse model). © 2011 American Chemical Society. Source

Caeiro L.,Institute of Molecular Medicine | Caeiro L.,Stroke Unit | Ferro J.M.,Stroke Unit | Costa J.,Center for Evidence Based Medicine and Cochrane Coordinating Center Portugal
Cerebrovascular Diseases

Background: Apathy is a disturbance of motivation, frequent in survivors of stroke. Several studies have evaluated the rate of apathy secondary to stroke and risk factors. Different conclusions and contradictory findings have been published. We aimed to perform a systematic review and meta-analysis of all studies evaluating apathy secondary to stroke to better estimate its rate and risk factors, and explore associations with poorer outcomes. Methods: We searched PubMed, Cochrane Library, PsychINFO and PsycBITE databases and screened references of included studies and review articles for additional citations. Search results and data extraction was performed independently. We systematically reviewed available publications reporting investigations on ischemic and intracerebral hemorrhagic stroke and apathy. Quality assessment of the studies was performed independently. Subgroup analyses were performed according to stroke phase (acute and post-acute), stroke past history (first-ever and any-stroke) and patient age (younger and older patients). Pooled odds ratios (OR) and standardized mean difference, and 95% confidence intervals (CI), were derived by random-effects meta-analysis. Heterogeneity was assessed with I2 test. Results: From the initial 1,399 publications, we included 19 studies (2,221 patients). The pooled rate of apathy was 36.3% (95% CI 30.3-42.8; I2 = 46.8), which was similar for acute [39.5% (95% CI 28.9-51.1)] and post-acute phase [34.3% (95% CI 27.8-41.4)], and about three times higher than the rate of depression [12.1% (95% CI 8.2-17.3)]. Apathetic patients were on average 2.74 years older (95% CI 1.25-4.23; I2 = 0%). No gender differences were found. Depression (OR 2.29; 95% CI 1.41-3.72; I2 = 44%) and cognitive impairment (OR 2.90; 95% CI 1.09-7.72; I 2 = 14%) were more frequent and severe in apathetic patients. Apathy rate was similar for ischemic and hemorrhagic stroke type and for left- and right-sided hemispheric lesions. Clinical global outcome was similar between apathetic and nonapathetic patients. Conclusion: Apathy secondary to stroke is a more frequent neuropsychiatric disturbance than depression. Apathetic patients are more frequently and severely depressed and cognitively impaired. A negative impact of apathy secondary to stroke on clinical global outcome cannot be ascribed. Future research should properly address its predictor factors and evaluate the impact of apathy treatment options in stroke patients. Copyright © 2013 S. Karger AG, Basel. Source

Louis E.D.,Columbia University | Ferreira J.J.,Institute of Molecular Medicine
Movement Disorders

Essential tremor (ET) is among the more prevalent neurological disorders, yet prevalence estimates have varied enormously, making it difficult to establish prevalence with precision. We: (1) reviewed the worldwide prevalence of ET in population-based epidemiological studies, (2) derived as precisely as possible an estimate of disease prevalence, and (3) examined trends and important differences across studies. We identified 28 population-based prevalence studies (19 countries). In a meta-analysis, pooled prevalence (all ages) = 0.9%, with statistically significant heterogeneity across studies (I2 = 99%, P < 0.001). In additional descriptive analyses, crude prevalence (all ages) = 0.4%. Prevalence increased markedly with age, and especially with advanced age. In the meta-analysis, prevalence (age ≥ 65 years) = 4.6%, and in additional descriptive analyses, median crude prevalence (age ≥ 60-65) = 6.3%. In one study of those age ≥ 95 years, crude prevalence = 21.7%. Several studies reported ethnic differences in prevalence, although more studies are needed. Greater than one-third of studies show a gender difference, with most demonstrating a higher prevalence among men. This possible gender preference is interesting given clinical, epidemiological, and pathological associations between ET and Parkinson's disease. Precise prevalence estimates such as those we provide are important because they form the numerical basis for planned public health initiatives, provide data on the background occurrence of disease for family studies, and offer clues about the existence of environmental or underlying biological factors of possible mechanistic importance. © 2010 Movement Disorder Society. Source

Senge M.O.,Trinity College Dublin | Senge M.O.,Institute of Molecular Medicine
Chemical Communications

Advances in the synthesis of unsymmetrically meso substituted porphyrins are based on the development of new total syntheses and porphyrin functionalization methods. These methods have replaced earlier mixed condensation reactions and give synthetic access to almost any desired meso-substituted porphyrin. They include the complete series of porphyrin homologues and regioisomers of the Ax-series with either alkyl or aryl residues, and numerous examples of ABCD-type chromophores. The syntheses are based on a combination of classic functionalization reactions, the use of organolithium reagents in SNAr reactions, and organometallic reactions with Pd, Ni, Cr, Ru, B, and Sn catalysis. This feature article gives an account of our work in the past decade to develop synthetic methods for the Ax- and ABCD-type porphyrins and their use as optical materials and photosensitizers. © 2011 The Royal Society of Chemistry. Source

Holst J.J.,Copenhagen University | Burcelin R.,Institute of Molecular Medicine | Nathanson E.,Watermeadow Medical United States
Current Medical Research and Opinion

In the past few years, the development of pharmaceutical agents that enhance the physiological effects of glucagon-like peptide-1 (GLP-1), either through GLP-1 receptor agonism (GLP-1 agonists) or by inhibiting GLP-1 degradation (dipeptidylpeptidase-4 inhibitors) has broadened the range of treatment options for individuals with type 2 diabetes. It has been recognized for some time that GLP-1 also has extra-pancreatic effects, notably targeting the brain, where it regulates appetite and satiety, as well as peripheral functions highly controlled by the autonomic nervous system, such as gastric emptying. Furthermore, data are beginning to emerge that indicate a potential role for GLP-1 in neuroprotection. The increased risk of Alzheimer'™s disease, Parkinson'™s disease and stroke in people with type 2 diabetes suggests that shared mechanisms/pathways of cell death, possibly related to insulin dysregulation, may underlie all of these disorders. Although the disease anatomy varies with each disorder, a wide range of genetic and environmental triggers result in activation of similar biochemical pathways in all of them, suggesting a complex network of biochemical events that feed in to a final common path towards cellular dysfunction and death. This article summarizes the evidence for neuronal activity of GLP-1 and examines the limited data that currently exist on the therapeutic potential of GLP-1 in specific neurological and neurodegenerative conditions, namely Alzheimer'™s disease, Parkinson'™s disease, Huntingdon'™s disease, stroke and peripheral sensory neuropathy. © 2011 Informa UK Ltd. Source

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