454 research outputs found
Design, synthesis, in vitro inhibition and toxicological evaluation of human carbonic anhydrases I, II and IX inhibitors in 5-nitroimidazole series
With the aim to obtain novel compounds possessing both strong affinity against human carbonic anhydrases and low toxicity, we synthesised novel thiourea and sulphonamide derivatives 3, 4 and 10, and studied their in vitro inhibitory properties against human CA I, CA II and CA IX. We also evaluated the toxicity of these compounds using zebrafish larvae. Among the three compounds, derivative 4 showed efficient inhibition against hCA II (KI = 58.6 nM). Compound 10 showed moderate inhibition against hCA II (KI = 199.2 nM) and hCA IX (KI = 147.3 nM), whereas it inhibited hCA I less weakly at micromolar concentrations (KI = 6428.4 nM). All other inhibition constants for these compounds were in the submicromolar range. The toxicity evaluation studies showed no adverse effects on the zebrafish larvae. Our study suggests that these compounds are suitable for further preclinical characterisation as potential inhibitors of hCA I, II and IX
‘Trying to pin down jelly’ - exploring intuitive processes in quality assessment for meta-ethnography
Background:
Studies that systematically search for and synthesise qualitative research are becoming more evident in health care, and they can make an important contribution to patient care. However, there is still no agreement as to whether, or how we should appraise studies for inclusion. We aimed to explore the intuitive processes that determined the ‘quality’ of qualitative research for inclusion in qualitative research syntheses. We were particularly interested to explore the way that knowledge was constructed.
Methods:
We used qualitative methods to explore the process of quality appraisal within a team of seven qualitative researchers funded to undertake a meta-ethnography of chronic non-malignant musculoskeletal pain. Team discussions took place monthly between October 2010 and June 2012 and were recorded and transcribed. Data was coded and organised using constant comparative method. The development of our conceptual analysis was both iterative and collaborative. The strength of this team approach to quality came from open and honest discussion, where team members felt free to agree, disagree, or change their position within the safety of the group.
Results:
We suggest two core facets of quality for inclusion in meta-ethnography - (1) Conceptual clarity; how clearly has the author articulated a concept that facilitates theoretical insight. (2) Interpretive rigour; fundamentally, can the interpretation ‘be trusted?’ Our findings showed that three important categories help the reader to judge interpretive rigour: (ii) What is the context of the interpretation? (ii) How inductive is the interpretation? (iii) Has the researcher challenged their interpretation?
Conclusions:
We highlight that methods alone do not determine the quality of research for inclusion into a meta-ethnography. The strength of a concept and its capacity to facilitate theoretical insight is integral to meta-ethnography, and arguably to the quality of research. However, we suggest that to be judged ‘good enough’ there also needs to be some assurance that qualitative findings are more than simply anecdotal. Although our conceptual model was developed specifically for meta-ethnography, it may be transferable to other research methodologies
Cortical thickness, surface area and volume measures in Parkinson's disease, multiple system atrophy and progressive supranuclear palsy
OBJECTIVE
Parkinson's disease (PD), Multiple System Atrophy (MSA) and Progressive Supranuclear Palsy (PSP) are neurodegenerative diseases that can be difficult to distinguish clinically. The objective of the current study was to use surface-based analysis techniques to assess cortical thickness, surface area and grey matter volume to identify unique morphological patterns of cortical atrophy in PD, MSA and PSP and to relate these patterns of change to disease duration and clinical features.
METHODS
High resolution 3D T1-weighted MRI volumes were acquired from 14 PD patients, 18 MSA, 14 PSP and 19 healthy control participants. Cortical thickness, surface area and volume analyses were carried out using the automated surface-based analysis package FreeSurfer (version 5.1.0). Measures of disease severity and duration were assessed for correlation with cortical morphometric changes in each clinical group.
RESULTS
Results show that in PSP, widespread cortical thinning and volume loss occurs within the frontal lobe, particularly the superior frontal gyrus. In addition, PSP patients also displayed increased surface area in the pericalcarine. In comparison, PD and MSA did not display significant changes in cortical morphology.
CONCLUSION
These results demonstrate that patients with clinically established PSP exhibit distinct patterns of cortical atrophy, particularly affecting the frontal lobe. These results could be used in the future to develop a useful clinical application of MRI to distinguish PSP patients from PD and MSA patients
Thieno[2,3-b]pyridine derivatives are potent anti-platelet drugs, inhibiting platelet activation, aggregation and showing synergy with aspirin
Drugs which inhibit platelet function are commonly used to prevent blood clot formation in patients with Acute Coronary Syndromes (ACS) or those at risk of stroke. The thieno[3,2-c]pyridine class of therapeutic agents, of which clopidogrel is the most commonly used, target the P2Y12 receptor, and are often used in combination with acetylsalicylic acid (ASA). Six thieno[2,3-b]pyridine were assessed for in vitro anti-platelet activity; all derivatives showed effects on both platelet activation and aggregation, and showed synergy with ASA. Some compounds demonstrated greater activity when compared to clopidogrel. These compounds, therefore, represent potential novel P2Y12 inhibitors for improved treatment for patients
New Strategies for Research in Clinical Practice: A focus on self–harm.
This article suggests new ways of approaching clinical-based research in an era of evidence-based practice. Using the example of self-harm, we identify three distinct problems with current dominant approaches to research in this area. These include insufficient clarity about target issues, an overreliance on predetermined outcomes which prioritise behavioural measures (such as self-harm cessation) and an undue focus on treatment techniques. We argue that clinical research requires flexible, user-centred and practice-based methods, informed by a focus on principles instead of techniques. Therefore, we outline key practice-based principles that we argue need to be embedded within clinical research strategies. We then demonstrate how traditional behavioural approaches to research can be enriched with more qualitative cognitive and emotionally based data. We conclude that such strategies provide thickened, meaningful and context-specific research which is more relevant for service commissioners, clinicians and service users
Birth weight and cognitive performance in older women: the Rancho Bernardo study
Low birth weight is associated with poorer cognitive function from infancy through early adulthood, but little is known about low birth weight and cognitive performance in the elderly. This study examines the association of birth weight with cognitive function in community-dwelling older women. Participants were 292 community-dwelling women aged 55–89 (median = 71 years) who attended a 1988–91 clinic visit when cognitive function was assessed, and responded to a 1991 mailed questionnaire assessing birth weight. All analyses were adjusted for age and education. Birth weight ranged from 2 to 12 pounds (lbs; mean = 7.4 ± 1.9). When birth weight was categorized into tertiles (2–6.9 lbs, 7–8 lbs, and 8.1–12.4 lbs), women in the lowest tertile had significantly lower (“poorer”) scores on Serial 7’s, a test of concentration and calculation (p < 0.05). Other birth weight categorizations (lowest quartile or quintile, or birth weight <5.5 lbs vs. 5.6–8.9 lbs and ≥9 lbs) did not improve the prediction of poor performance on Serial 7’s. Birth weight as a continuous variable was significantly and positively associated with Serial 7’s test scores (p = 0.04). Results suggest that small decrements in cognitive function tasks involving calculation may persist throughout life in women who were of relatively low birth weight. Although this association could be spurious, it deserves further evaluation
Astrocytic αVβ3 Integrin Inhibits Neurite Outgrowth and Promotes Retraction of Neuronal Processes by Clustering Thy-1
Thy-1 is a membrane glycoprotein suggested to stabilize or inhibit growth of neuronal processes. However, its precise function has remained obscure, because its endogenous ligand is unknown. We previously showed that Thy-1 binds directly to αVβ3 integrin in trans eliciting responses in astrocytes. Nonetheless, whether αVβ3 integrin might also serve as a Thy-1-ligand triggering a neuronal response has not been explored. Thus, utilizing primary neurons and a neuron-derived cell line CAD, Thy-1-mediated effects of αVβ3 integrin on growth and retraction of neuronal processes were tested. In astrocyte-neuron co-cultures, endogenous αVβ3 integrin restricted neurite outgrowth. Likewise, αVβ3-Fc was sufficient to suppress neurite extension in Thy-1(+), but not in Thy-1(−) CAD cells. In differentiating primary neurons exposed to αVβ3-Fc, fewer and shorter dendrites were detected. This effect was abolished by cleavage of Thy-1 from the neuronal surface using phosphoinositide-specific phospholipase C (PI-PLC). Moreover, αVβ3-Fc also induced retraction of already extended Thy-1(+)-axon-like neurites in differentiated CAD cells as well as of axonal terminals in differentiated primary neurons. Axonal retraction occurred when redistribution and clustering of Thy-1 molecules in the plasma membrane was induced by αVβ3 integrin. Binding of αVβ3-Fc was detected in Thy-1 clusters during axon retraction of primary neurons. Moreover, αVβ3-Fc-induced Thy-1 clustering correlated in time and space with redistribution and inactivation of Src kinase. Thus, our data indicates that αVβ3 integrin is a ligand for Thy-1 that upon binding not only restricts the growth of neurites, but also induces retraction of already existing processes by inducing Thy-1 clustering. We propose that these events participate in bi-directional astrocyte-neuron communication relevant to axonal repair after neuronal damage
Epithelial-to-mesenchymal transition supports ovarian carcinosarcoma tumorigenesis and confers sensitivity to microtubule-targeting with eribulin
Ovarian carcinosarcoma (OCS) is an aggressive and rare tumour type with limited treatment options. OCS is hypothesised to develop via the combination theory, with a single progenitor resulting in carcinomatous and sarcomatous components, or alternatively via the conversion theory, with the sarcomatous component developing from the carcinomatous component through epithelial-to-mesenchymal transition (EMT). In this study, we analysed DNA variants from isolated carcinoma and sarcoma components to show that OCS from 18 women is monoclonal. RNA sequencing indicated the carcinoma components were more mesenchymal when compared with pure epithelial ovarian carcinomas, supporting the conversion theory and suggesting that EMT is important in the formation of these tumours. Preclinical OCS models were used to test the efficacy of microtubule-targeting drugs, including eribulin, which has previously been shown to reverse EMT characteristics in breast cancers and induce differentiation in sarcomas. Vinorelbine and eribulin more effectively inhibited OCS growth than standard-of-care platinum-based chemotherapy, and treatment with eribulin reduced mesenchymal characteristics and N-MYC expression in OCS patient-derived xenografts (PDX). Eribulin treatment resulted in an accumulation of intracellular cholesterol in OCS cells, which triggered a down-regulation of the mevalonate pathway and prevented further cholesterol biosynthesis. Finally, eribulin increased expression of genes related to immune activation and increased the intratumoral accumulation of CD8+ T cells, supporting exploration of immunotherapy combinations in the clinic. Together, these data indicate EMT plays a key role in OCS tumourigenesis and support the conversion theory for OCS histogenesis. Targeting EMT using eribulin could help improve OCS patient outcomes
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