Hyperthermia and Thermosensitive Liposomes for Improved Delivery of Chemotherapeutic Drugs to Solid Tumors

Lipid-based nanocarriers or liposomes have been proven successful in the delivery of chemotherapeutic agents and are currently applied clinically in the treatment of various types of cancer. Liposomes offer the advantage of a high drug payload, decreased drug toxicity and enhanced drug accumulation at tumor sites. Increased accumulation is due to the relatively leaky tumor vasculature that allows liposome extravasation. Between different types of tumors and even within one tumor, vascular permeability and thus liposome extravasation may differ greatly. Furthermore, upon accumulation of liposomes in the tumor area, drug bioavailability is not guaranteed. At present, these are the major issues for clinically used liposomal drugs

Monoaminergic neuropathology in Alzheimer's disease

None of the proposed mechanisms of Alzheimer’s disease (AD) fully explains the distribution patterns of the neuropathological changes at the cellular and regional levels, and their clinical correlates. One aspect of this problem lies in the complex genetic, epigenetic, and environmental landscape of AD: early-onset AD is often familial with autosomal dominant inheritance, while the vast majority of AD cases are late-onset, with the ε4 variant of the gene encoding apolipoprotein E (APOE) known to confer a 5–20 fold increased risk with partial penetrance. Mechanisms by which genetic variants and environmental factors influence the development of AD pathological changes, especially neurofibrillary degeneration, are not yet known. Here we review current knowledge of the involvement of the monoaminergic systems in AD. The changes in the serotonergic, noradrenergic, dopaminergic, histaminergic, and melatonergic systems in AD are briefly described. We also summarize the possibilities for monoamine-based treatment in AD. Besides neuropathologic AD criteria that include the noradrenergic locus coeruleus (LC), special emphasis is given to the serotonergic dorsal raphe nucleus (DRN). Both of these brainstem nuclei are among the first to be affected by tau protein abnormalities in the course of sporadic AD, causing behavioral and cognitive symptoms of variable severity. The possibility that most of the tangle-bearing neurons of the LC and DRN may release amyloid β as well as soluble monomeric or oligomeric tau protein trans-synaptically by their diffuse projections to the cerebral cortex emphasizes their selective vulnerability and warrants further investigations of the monoaminergic systems in AD

Comparative analysis between shape memory alloy-based correction and traditional correction technique in pedicle screws constructs for treating severe scoliosis

The three-dimensional correction of severe rigid scoliosis has been improved by segmental pedicle screw instrumentation. However, there can be significant difficulty related to the use of a rigid rod, especially in the apex region of severe scoliosis. This study is a retrospective matched cohort study to evaluate the advantages of Nitinol shape memory alloy (SMA) rod-based correction by comparing the clinical and radiographic results obtained from using a temporary SMA rod and those from a standard rod in the correction of severe scoliosis. From May 2004 to September 2006, patients with matched curve type, ages at surgery, operative methods and fusion levels in our institute and instrumented with either SMA rods (n = 14) or traditional correction techniques (n = 16) were reviewed. In SMA group, the SMA rods served as a temporary intraoperative tool for deformity correction and were replaced by standard rods. The blood loss at surgery averaged 778 ± 285 ml in the traditional group and 585 ± 188 ml in the SMA group (P < 0.05). Operative time averaged 284 ± 53 min in the SMA group and 324 ± 41 min in the traditional group (P < 0.05). In the SMA group, the preoperative major curve was 92.6° ± 13.7° with a flexibility of 25.5 ± 7.3% was corrected to 29.4° ± 5.7° demonstrating a 68.4% immediate postoperative correction. In the traditional group, the preoperative major curve was 88.6° ± 14.6° with a flexibility of 29.3 ± 6.6% was corrected to 37.2° ± 7.3° demonstrating a 57.8% immediate postoperative correction. There was a statistic difference between the SMA group and traditional group in correction rate of the major thoracic curve. In the SMA group, one case suffered from deep infection 2 months postoperatively. In the traditional group, 6 of 16 cases suffered pedicle screw pull out or loosening during placement of the standard rod at the apex vertebrae on the concave side. In three cases, the mono-axial pedicle screws near the apex were abandoned and in five cases replaced with poly-axial pedicle screws. This study shows that the temporary use of SMA rod may reduce the operative time, blood loss, while improve the correction of the coronal plane when compared with standard techniques

αA-Crystallin Peptide 66SDRDKFVIFLDVKHF80 Accumulating in Aging Lens Impairs the Function of α-Crystallin and Induces Lens Protein Aggregation

The eye lens is composed of fiber cells that are filled with α-, β- and γ-crystallins. The primary function of crystallins is to maintain the clarity of the lens through ordered interactions as well as through the chaperone-like function of α-crystallin. With aging, the chaperone function of α-crystallin decreases, with the concomitant accumulation of water-insoluble, light-scattering oligomers and crystallin-derived peptides. The role of crystallin-derived peptides in age-related lens protein aggregation and insolubilization is not understood.We found that αA-crystallin-derived peptide, (66)SDRDKFVIFLDVKHF(80), which accumulates in the aging lens, can inhibit the chaperone activity of α-crystallin and cause aggregation and precipitation of lens crystallins. Age-related change in the concentration of αA-(66-80) peptide was estimated by mass spectrometry. The interaction of the peptide with native crystallin was studied by multi-angle light scattering and fluorescence methods. High molar ratios of peptide-to-crystallin were favourable for aggregation and precipitation. Time-lapse recordings showed that, in the presence of αA-(66-80) peptide, α-crystallin aggregates and functions as a nucleus for protein aggregation, attracting aggregation of additional α-, β- and γ-crystallins. Additionally, the αA-(66-80) peptide shares the principal properties of amyloid peptides, such as β-sheet structure and fibril formation.These results suggest that crystallin-derived peptides such as αA-(66-80), generated in vivo, can induce age-related lens changes by disrupting the structure and organization of crystallins, leading to their insolubilization. The accumulation of such peptides in aging lenses may explain a novel mechanism for age-related crystallin aggregation and cataractogenesis

PKCδ regulates force signaling during VEGF/CXCL4 induced dissociation of endothelial tubes

Wound healing requires the vasculature to re-establish itself from the severed ends; endothelial cells within capillaries must detach from neighboring cells before they can migrate into the nascent wound bed to initiate angiogenesis. The dissociation of these endothelial capillaries is driven partially by platelets' release of growth factors and cytokines, particularly the chemokine CXCL4/platelet factor-4 (PF4) that increases cell-cell de-adherence. As this retraction is partly mediated by increased transcellular contractility, the protein kinase c-δ/myosin light chain-2 (PKCδ/MLC-2) signaling axis becomes a candidate mechanism to drive endothelial dissociation. We hypothesize that PKCδ activation induces contractility through MLC-2 to promote dissociation of endothelial cords after exposure to platelet-released CXCL4 and VEGF. To investigate this mechanism of contractility, endothelial cells were allowed to form cords following CXCL4 addition to perpetuate cord dissociation. In this study, CXCL4-induced dissociation was reduced by a VEGFR inhibitor (sunitinib malate) and/or PKCδ inhibition. During combined CXCL4+VEGF treatment, increased contractility mediated by MLC-2 that is dependent on PKCδ regulation. As cellular force is transmitted to focal adhesions, zyxin, a focal adhesion protein that is mechano-responsive, was upregulated after PKCδ inhibition. This study suggests that growth factor regulation of PKCδ may be involved in CXCL4-mediated dissociation of endothelial cords. © 2014 Jamison et al

Research workshop to research work: initial steps in establishing health research systems on Malaita, Solomon Islands

<p>Abstract</p> <p>Introduction</p> <p>Atoifi Adventist Hospital is a 90 bed general hospital in East Kwaio, Malaita, Solomon Islands providing services to the population of subsistence villagers of the region. Health professionals at the hospital and attached College of Nursing have considerable human capacity and willingness to undertake health research. However they are constrained by limited research experience, training opportunities, research systems, physical infrastructure and access to resources. This brief commentary describes an 'Introduction to Health Research' workshop delivered at Atoifi Adventist Hospital in September 2009 and efforts to move from 'research workshop' to 'research work'.</p> <p>The Approach</p> <p>Using a participatory-action research approach underpinned by decolonising methodologies, staff from Atoifi Adventist Hospital and James Cook University (Queensland, Australia) collaboratively designed, implemented and evaluated a health research workshop. Basic health research principles and methods were presented using active learning methodologies. Following the workshop, Atoifi Adventist Hospital and Atoifi College of Nursing staff, other professionals and community members reported an increased awareness and understanding of health research. The formation of a local Research Committee, improved ethics review procedures and the identification of local research mentors followed the week long workshop. The workshop has acted as a catalyst for research activity, increasing structural and human resource capacity for local health professionals and community leaders to engage in research.</p> <p>Discussion and Conclusions</p> <p>Participants from a variety of educational backgrounds participated in, and received benefit from, a responsive, culturally and linguistically accessible health research workshop. Improving health research systems at a remote hospital and aligning these with local and national research agendas is establishing a base to strengthen public health research and practice on Malaita, Solomon Islands.</p

A population-based study of anxiety as a precursor for depression in childhood and adolescence

BACKGROUND: Anxiety and depression co-occur in children and adolescents with anxiety commonly preceding depression. Although there is some evidence to suggest that the association between early anxiety and later depression is explained by a shared genetic aetiology, the contribution of environmental factors is less well examined and it is unknown whether anxiety itself is a phenotypic risk factor for later depression. These explanations of the association between early anxiety and later depression were evaluated. METHODS: Anxiety and depressive symptoms were assessed longitudinally in a U.K. population-based sample of 676 twins aged 5–17 at baseline. At baseline, anxiety and depression were assessed by parental questionnaire. Depression was assessed three years later by parental and adolescent questionnaire. RESULTS: Shared genetic effects between early anxiety and later depression were found. A model of a phenotypic risk effect from early anxiety on later depression provided a poor fit to the data. However, there were significant genetic effects specific to later depression, showing that early anxiety and later depression do not index entirely the same genetic risk. CONCLUSIONS: Anxiety and depression are associated over time because they share a partly common genetic aetiology rather than because the anxiety phenotype leads to later depression

"You have to get wet to learn how to swim" applied to bridging the gap between research into personnel scheduling and its implementation in practice

Personnel scheduling problems have attracted research interests for several decades. They have been considerably changed over time, accommodating a variety of constraints related to legal and organisation requirements, part-time staff, flexible hours of staff, staff preferences, etc. This led to a myriad of approaches developed for solving personnel scheduling problems including optimisation, meta-heuristics, artificial intelligence, decision-support, and also hybrids of these approaches. However, this still does not imply that this research has a large impact on practice and that state-of-the art models and algorithms are widely in use in organisations. One can find a reasonably large number of software packages that aim to assist in personnel scheduling. A classification of this software based on its purpose will be proposed, accompanied with a discussion about the level of support that this software offers to schedulers. A general conclusion is that the available software, with some exceptions, does not benefit from the wealth of developed models and methods. The remaining of the paper will provide insights into some characteristics of real-world scheduling problems that, in the author’s opinion, have not been given a due attention in the personnel scheduling research community yet and which could contribute to the enhancement of the implementation of research results in practice. Concluding remarks are that in order to bridge the gap that still exists between research into personnel scheduling and practice, we need to engage more with schedulers in practice and also with software developers; one may say we need to get wet if we want to learn how to swim