Drug delivery and controlled release from biocompatible metal-organic frameworks using mechanical amorphization

We have used a family of Zr-based metal-organic frameworks (MOFs) with different functionalized (bromo, nitro and amino) and extended linkers for drug delivery. We loaded the materials with the fluorescent model molecule calcein and the anticancer drug α-cyano-4-hydroxycinnamic acid (α-CHC), and consequently performed a mechanical amorphization process to attempt to control the delivery of guest molecules. Our analysis revealed that the loading values of both molecules were higher for the MOFs containing unfunctionalized linkers. Confocal microscopy showed that all the materials were able to penetrate into cells, and the therapeutic effect of α-CHC on HeLa cells was enhanced when loaded (20 wt%) into the MOF with the longest linker. On one hand, calcein release required up to 3 days from the crystalline form for all the materials. On the other hand, the amorphous counterparts containing the bromo and nitro functional groups released only a fraction of the total loaded amount, and in the case of the amino-MOF a slow and progressive release was successfully achieved for 15 days. In the case of the materials loaded with α-CHC, no difference was observed between the crystalline and amorphous form of the materials. These results highlight the necessity of a balance between the pore size of the materials and the size of the guest molecules to accomplish a successful and efficient sustained release using this mechanical ball-milling process. Additionally, the endocytic pathway used by cells to internalize these MOFs may lead to diverse final cellular locations and consequently, different therapeutic effects. Understanding these cellular mechanisms will drive the design of more effective MOFs for drug delivery applications.C.A.O. thanks Becas Chile and the Cambridge Trust for funding. D.F.J. thanks the Royal Society (UK) for funding through a University Research Fellowship. RSF thanks the Royal Society for receipt of a University Research Fellowship and the EPSRC (EP/L004461/1) and The University of Glasgow for funding. A.K.C is grateful to the European Research Council for an Advanced Investigator Award

Investor heterogeneity and the cross-section of U.K. investment trust performance

We use the upper and lower bounds derived by Ferson and Lin (2010) to examine the impact of investor heterogeneity on the performance of U.K. investment trusts relative to alternative linear factor models. We find using the upper bounds that investor heterogeneity has an important impact for nearly all investment trusts. The upper bounds are large in economic terms and significantly different from zero. We find no evidence of any trusts where all investors agree on the sign of performance beyond what we expect by chance. Using the lower bound, we find that trusts with a larger disagreement about trust performance have a weaker relation between the trust premium and past Net Asset Value (NAV) performance

Social representations and the politics of participation

Recent work has called for the integration of different perspectives into the field of political psychology (Haste, 2012). This chapter suggests that one possible direction that such efforts can take is studying the role that social representations theory (SRT) can play in understanding political participation and social change. Social representations are systems of common-sense knowledge and social practice; they provide the lens through which to view and create social and political realities, mediate people's relations with these sociopolitical worlds and defend cultural and political identities. Social representations are therefore key for conceptualising participation as the activity that locates individuals and social groups in their sociopolitical world. Political participation is generally seen as conditional to membership of sociopolitical groups and therefore is often linked to citizenship. To be a citizen of a society or a member of any social group one has to participate as such. Often political participation is defined as the ability to communicate one's views to the political elite or to the political establishment (Uhlaner, 2001), or simply explicit involvement in politics and electoral processes (Milbrath, 1965). However, following scholars on ideology (Eagleton, 1991; Thompson, 1990) and social knowledge (Jovchelovitch, 2007), we extend our understanding of political participation to all social relations and also develop a more agentic model where individuals and groups construct, develop and resist their own views, ideas and beliefs. We thus adopt a broader approach to participation in comparison to other political-psychological approaches, such as personality approaches (e.g. Mondak and Halperin, 2008) and cognitive approaches or, more recently, neuropsychological approaches (Hatemi and McDermott, 2012). We move away from a focus on the individual's political behaviour and its antecedents and outline an approach that focuses on the interaction between psychological and political phenomena (Deutsch and Kinnvall, 2002) through examining the politics of social knowledge

Time to positivity in blood cultures of adults with Streptococcus pneumoniae bacteremia

BACKGROUND: previous studies have established that bacterial blood concentration is related with clinical outcome. Time to positivity of blood cultures (TTP) has relationship with bacterial blood concentration and could be related with prognosis. As there is scarce information about the usefulness of TTP, we study the relationship of TTP with clinical parameters in patients with Streptococcus pneumoniae bacteremia. METHODS: TTP of all cases of Streptococcus pneumoniae bacteremia, detected between January 1995 and December 2004 using the BacT/Alert automated blood culture system in a teaching community hospital was analyzed. When multiple cultures were positive only the shortest TTP was selected for the analysis. RESULTS: in the study period 105 patients with Streptococcus pneumoniae bacteremia were detected. Median TTP was 14.1 hours (range 1.2 h to 127 h). Immunosuppressed patients (n = 5), patients with confusion (n = 19), severe sepsis or shock at the time of blood culture extraction (n = 12), those with a diagnosis of meningitis (n = 7) and those admitted to the ICU (n = 14) had lower TTP. Patients with TTP in the first quartile were more frequently hospitalized, admitted to the ICU, had meningitis, a non-pneumonic origin of the bacteremia, and a higher number of positive blood cultures than patients with TTP in the fourth quartile. None of the patients with TTP in the 90(th )decile had any of these factors associated with shorter TTP, and eight out of ten patients with TTP in the 10(th )decile had at least one of these factors. The number of positive blood cultures had an inverse correlation with TTP, suggesting a relationship of TTP with bacterial blood concentration. CONCLUSION: Our data support the relationship of TTP with several clinical parameters in patients with Streptococcus pneumoniae bacteremia, and its potential usefulness as a surrogate marker of outcome

Variance components associated with long-echo-time MR spectroscopic imaging in human brain at 1.5T and 3T

<div><p>Object</p><p>Magnetic resonance spectroscopic imaging (MRSI) is increasingly used in medicine and clinical research. Previous reliability studies have used small samples and focussed on limited aspects of variability; information regarding 1.5T versus 3T performance is lacking. The aim of the present work was to measure the inter-session, intra-session, inter-subject, within-brain and residual variance components using both 1.5T and 3T MR scanners.</p><p>Materials and methods</p><p>Eleven healthy volunteers were invited for MRSI scanning on three occasions at both 1.5T and 3T, with four scans acquired at each visit. We measured variance components, correcting for grey matter and white matter content of voxels, of metabolite peak areas and peak area ratios.</p><p>Results</p><p>Residual variance was in general the largest component at 1.5T (8.6–24.6%), while within-brain variation was the largest component at 3T (12.0–24.7%). Inter-subject variation was around 5%, while inter- and intra-session variance were both generally small.</p><p>Conclusion</p><p>Multiple variance contributions associated with MRSI measurements were quantified and the performance of 1.5T and 3T MRI scanners compared using data from the same group of subjects. Residual error is much lower at 3T, but other variance components remain important.</p></div

The effect of forearm posture on wrist flexion in computer workers with chronic upper extremity musculoskeletal disorders

<p>Abstract</p> <p>Background</p> <p>Occupational computer use has been associated with upper extremity musculoskeletal disorders (UEMSDs), but the etiology and pathophysiology of some of these disorders are poorly understood. Various theories attribute the symptoms to biomechanical and/or psychosocial stressors. The results of several clinical studies suggest that elevated antagonist muscle tension may be a biomechanical stress factor. Affected computer users often exhibit limited wrist range of motion, particularly wrist flexion, which has been attributed to increased extensor muscle tension, rather than to pain symptoms. Recreational or domestic activities requiring extremes of wrist flexion may produce injurious stress on the wrist joint and muscles, the symptoms of which are then exacerbated by computer use. As these activities may involve a variety of forearm postures, we examined whether changes in forearm posture have an effect on pain reports during wrist flexion, or whether pain would have a limiting effect on flexion angle.</p> <p>Methods</p> <p>We measured maximum active wrist flexion using a goniometer with the forearm supported in the prone, neutral, and supine postures. Data was obtained from 5 subjects with UEMSDs attributed to computer use and from 13 control subjects.</p> <p>Results</p> <p>The UEMSD group exhibited significantly restricted wrist flexion compared to the control group in both wrists at all forearm postures with the exception of the non-dominant wrist with the forearm prone. In both groups, maximum active wrist flexion decreased at the supine forearm posture compared to the prone posture. No UEMSD subjects reported an increase in pain symptoms during testing.</p> <p>Conclusion</p> <p>The UEMSD group exhibited reduced wrist flexion compared to controls that did not appear to be pain related. A supine forearm posture reduced wrist flexion in both groups, but the reduction was approximately 100% greater in the UEMSD group. The effect of a supine forearm posture on wrist flexion is consistent with known biomechanical changes in the distal extensor carpi ulnaris tendon that occur with forearm supination. We infer from these results that wrist extensor muscle passive tension may be elevated in UEMSD subjects compared to controls, particularly in the extensor carpi ulnaris muscle. Measuring wrist flexion at the supine forearm posture may highlight flexion restrictions that are not otherwise apparent.</p

Identification of lung cancer with high sensitivity and specificity by blood testing

<p>Abstract</p> <p>Background</p> <p>Lung cancer is a very frequent and lethal tumor with an identifiable risk population. Cytological analysis and chest X-ray failed to reduce mortality, and CT screenings are still controversially discussed. Recent studies provided first evidence for the potential usefulness of autoantigens as markers for lung cancer.</p> <p>Methods</p> <p>We used extended panels of arrayed antigens and determined autoantibody signatures of sera from patients with different kinds of lung cancer, different common non-tumor lung pathologies, and controls without any lung disease by a newly developed computer aided image analysis procedure. The resulting signatures were classified using linear kernel Support Vector Machines and 10-fold cross-validation.</p> <p>Results</p> <p>The novel approach allowed for discriminating lung cancer patients from controls without any lung disease with a specificity of 97.0%, a sensitivity of 97.9%, and an accuracy of 97.6%. The classification of stage IA/IB tumors and controls yielded a specificity of 97.6%, a sensitivity of 75.9%, and an accuracy of 92.9%. The discrimination of lung cancer patients from patients with non-tumor lung pathologies reached an accuracy of 88.5%.</p> <p>Conclusion</p> <p>We were able to separate lung cancer patients from subjects without any lung disease with high accuracy. Furthermore, lung cancer patients could be seprated from patients with other non-tumor lung diseases. These results provide clear evidence that blood-based tests open new avenues for the early diagnosis of lung cancer.</p

Changing Epidemiology of Serious Bacterial Infections in Febrile Infants without Localizing Signs

Objective: Historically, management of infants with fever without localizing signs (FWLS) has generated much controversy, with attempts to risk stratify based on several criteria. Advances in medical practice may have altered the epidemiology of serious bacterial infections (SBIs) in this population. We conducted this study to test the hypothesis that the rate of SBIs in this patient population has changed over time. Patients and Methods: We performed a retrospective review of all infants meeting FWLS criteria at our institution from 1997–2006. We examined all clinical and outcome data and performed statistical analysis of SBI rates and ampicillin resistance rates. Results: 668 infants met criteria for FWLS. The overall rate of SBIs was 10.8%, with a significant increase from 2002–2006 (52/ 361, 14.4%) compared to 1997–2001 (20/307, 6.5%) (p = 0.001). This increase was driven by an increase in E. coli urinary tract infections (UTI), particularly in older infants (31–90 days). Conclusions: We observed a significant increase in E. coli UTI among FWLS infants with high rates of ampicillin resistance. The reasons are likely to be multifactorial, but the results themselves emphasize the need to examine urine in all febrile infants,90days and consider local resistance patterns when choosing empiric antibiotics