Wound healing and hyper-hydration - a counter intuitive model

Winters seminal work in the 1960s relating to providing an optimal level of moisture to aid wound healing (granulation and re-epithelialisation) has been the single most effective advance in wound care over many decades. As such the development of advanced wound dressings that manage the fluidic wound environment have provided significant benefits in terms of healing to both patient and clinician. Although moist wound healing provides the guiding management principle confusion may arise between what is deemed to be an adequate level of tissue hydration and the risk of developing maceration. In addition, the counter-intuitive model ‘hyper-hydration’ of tissue appears to frustrate the moist wound healing approach and advocate a course of intervention whereby tissue is hydrated beyond what is a normally acceptable therapeutic level. This paper discusses tissue hydration, the cause and effect of maceration and distinguishes these from hyper-hydration of tissue. The rationale is to provide the clinician with a knowledge base that allows optimisation of treatment and outcomes and explains the reasoning behind wound healing using hyper-hydration

Photo-antagonism of the GABAA receptor

Neurotransmitter receptor trafficking is fundamentally important for synaptic transmission and neural network activity. GABAA receptors and inhibitory synapses are vital components of brain function, yet much of our knowledge regarding receptor mobility and function at inhibitory synapses is derived indirectly from using recombinant receptors, antibody-tagged native receptors and pharmacological treatments. Here we describe the use of a set of research tools that can irreversibly bind to and affect the function of recombinant and neuronal GABAA receptors following ultraviolet photoactivation. These compounds are based on the competitive antagonist gabazine and incorporate a variety of photoactive groups. By using site-directed mutagenesis and ligand-docking studies, they reveal new areas of the GABA binding site at the interface between receptor β and α subunits. These compounds enable the selected inactivation of native GABAA receptor populations providing new insight into the function of inhibitory synapses and extrasynaptic receptors in controlling neuronal excitation

Determining the neurotransmitter concentration profile at active synapses

Establishing the temporal and concentration profiles of neurotransmitters during synaptic release is an essential step towards understanding the basic properties of inter-neuronal communication in the central nervous system. A variety of ingenious attempts has been made to gain insights into this process, but the general inaccessibility of central synapses, intrinsic limitations of the techniques used, and natural variety of different synaptic environments have hindered a comprehensive description of this fundamental phenomenon. Here, we describe a number of experimental and theoretical findings that has been instrumental for advancing our knowledge of various features of neurotransmitter release, as well as newly developed tools that could overcome some limits of traditional pharmacological approaches and bring new impetus to the description of the complex mechanisms of synaptic transmission

Super-Resolution Dynamic Imaging of Dendritic Spines Using a Low-Affinity Photoconvertible Actin Probe

The actin cytoskeleton of dendritic spines plays a key role in morphological aspects of synaptic plasticity. The detailed analysis of the spine structure and dynamics in live neurons, however, has been hampered by the diffraction-limited resolution of conventional fluorescence microscopy. The advent of nanoscopic imaging techniques thus holds great promise for the study of these processes. We implemented a strategy for the visualization of morphological changes of dendritic spines over tens of minutes at a lateral resolution of 25 to 65 nm. We have generated a low-affinity photoconvertible probe, capable of reversibly binding to actin and thus allowing long-term photoactivated localization microscopy of the spine cytoskeleton. Using this approach, we resolve structural parameters of spines and record their long-term dynamics at a temporal resolution below one minute. Furthermore, we have determined changes in the spine morphology in response to pharmacologically induced synaptic activity and quantified the actin redistribution underlying these changes. By combining PALM imaging with quantum dot tracking, we could also simultaneously visualize the cytoskeleton and the spine membrane, allowing us to record complementary information on the morphological changes of the spines at super-resolution

Synapse Geometry and Receptor Dynamics Modulate Synaptic Strength

Synaptic transmission relies on several processes, such as the location of a released vesicle, the number and type of receptors, trafficking between the postsynaptic density (PSD) and extrasynaptic compartment, as well as the synapse organization. To study the impact of these parameters on excitatory synaptic transmission, we present a computational model for the fast AMPA-receptor mediated synaptic current. We show that in addition to the vesicular release probability, due to variations in their release locations and the AMPAR distribution, the postsynaptic current amplitude has a large variance, making a synapse an intrinsic unreliable device. We use our model to examine our experimental data recorded from CA1 mice hippocampal slices to study the differences between mEPSC and evoked EPSC variance. The synaptic current but not the coefficient of variation is maximal when the active zone where vesicles are released is apposed to the PSD. Moreover, we find that for certain type of synapses, receptor trafficking can affect the magnitude of synaptic depression. Finally, we demonstrate that perisynaptic microdomains located outside the PSD impacts synaptic transmission by regulating the number of desensitized receptors and their trafficking to the PSD. We conclude that geometrical modifications, reorganization of the PSD or perisynaptic microdomains modulate synaptic strength, as the mechanisms underlying long-term plasticity

The importance of organizational characteristics for improving outcomes in patients with chronic disease: a systematic review of congestive heart failure

Luci K. Leykum, Jacqueline Pugh, Valerie Lawrence, and Polly H. Noel are with the South Texas Veterans Health Care System and Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio TX, 78229, USA -- Michael Parchman is with the South Texas Veterans Health Care System and Department of Family and Community Medicine, University of Texas Health Science Center at San Antonio, San Antonio TX, 78229, USA -- Reuben R. McDaniel Jr. is with the McComb's School of Business, University of Texas at Austin, Austin TX, USABackground: Despite applications of models of care and organizational or system-level interventions to improve patient outcomes for chronic disease, consistent improvements have not been achieved. This may reflect a mismatch between the interventions and the nature of the settings in which they are attempted. The application of complex adaptive systems (CAS) framework to understand clinical systems and inform efforts to improve them may lead to more successful interventions. We performed a systematic review of interventions to improve outcomes of patients with congestive heart failure (CHF) to examine whether interventions consistent with CAS are more likely to be effective. We then examine differences between interventions that are most effective for improving outcomes for patients with CHF versus previously published data for type 2 diabetes to explore the potential impact of the nature of the disease on the types of interventions that are more likely to be effective. Methods: We conducted a systematic review of the literature between 1998 and 2008 of organizational interventions to improve care of patients with CHF. Two independent reviewers independently assessed studies that met inclusion criteria to determine whether each reported intervention reflected one or more CAS characteristics. The effectiveness of interventions was rated as either 0 (no effect), 0.5 (mixed effect), or 1.0 (effective) based on the type, number, and significance of reported outcomes. Fisher's exact test was used to examine the association between CAS characteristics and intervention effectiveness. Specific CAS characteristics associated with intervention effectiveness for CHF were contrasted with previously published data for type 2 diabetes. Results and discussion: Forty-four studies describing 46 interventions met eligibility criteria. All interventions utilized at least one CAS characteristic, and 85% were either 'mixed effect' or 'effective' in terms of outcomes. The number of CAS characteristics present in each intervention was associated with effectiveness (p < 0.001), supporting the idea that interventions consistent with CAS are more likely to be effective. The individual CAS characteristics associated with CHF intervention effectiveness were learning, self-organization, and co-evolution, a finding different from our previously published analysis of interventions for diabetes. We suggest this difference may be related to the degree of uncertainty involved in caring for patients with diabetes versus CHF. Conclusion: These results suggest that for interventions to be effective, they must be consistent with the CAS nature of clinical systems. The difference in specific CAS characteristics associated with intervention effectiveness for CHF and diabetes suggests that interventions must also take into account attributes of the disease.McCombs School of [email protected]

Full characterization of GPCR monomer–dimer dynamic equilibrium by single molecule imaging

A single-molecule tracking technique coupled with mathematical modeling was developed for fully determining the dynamic monomer–dimer equilibrium of molecules in or on the plasma membrane, which will provide a framework for understanding signal transduction pathways initiated and regulated by dynamic dimers of membrane-localized receptors

European Space Agency experiments on thermodiffusion of fluid mixtures in space

Abstract.: This paper describes the European Space Agency (ESA) experiments devoted to study thermodiffusion of fluid mixtures in microgravity environment, where sedimentation and convection do not affect the mass flow induced by the Soret effect. First, the experiments performed on binary mixtures in the IVIDIL and GRADFLEX experiments are described. Then, further experiments on ternary mixtures and complex fluids performed in DCMIX and planned to be performed in the context of the NEUF-DIX project are presented. Finally, multi-component mixtures studied in the SCCO project are detailed

Prenatal Activation of Microglia Induces Delayed Impairment of Glutamatergic Synaptic Function

BACKGROUND: Epidemiological studies have linked maternal infection during pregnancy to later development of neuropsychiatric disorders in the offspring. In mice, experimental inflammation during embryonic development impairs behavioral and cognitive performances in adulthood. Synaptic dysfunctions may be at the origin of cognitive impairments, however the link between prenatal inflammation and synaptic defects remains to be established. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we show that prenatal alteration of microglial function, including inflammation, induces delayed synaptic dysfunction in the adult. DAP12 is a microglial signaling protein expressed around birth, mutations of which in the human induces the Nasu-Hakola disease, characterized by early dementia. We presently report that synaptic excitatory currents in mice bearing a loss-of-function mutation in the DAP12 gene (DAP12(KI) mice) display enhanced relative contribution of AMPA. Furthermore, neurons from DAP12(KI) P0 pups cultured without microglia develop similar synaptic alterations, suggesting that a prenatal dysfunction of microglia may impact synaptic function in the adult. As we observed that DAP12(KI) microglia overexpress genes for IL1beta, IL6 and NOS2, which are inflammatory proteins, we analyzed the impact of a pharmacologically-induced prenatal inflammation on synaptic function. Maternal injection of lipopolysaccharides induced activation of microglia at birth and alteration of glutamatergic synapses in the adult offspring. Finally, neurons cultured from neonates born to inflamed mothers and cultured without microglia also displayed altered neuronal activity. CONCLUSION/SIGNIFICANCE: Our results demonstrate that prenatal inflammation is sufficient to induce synaptic alterations with delay. We propose that these alterations triggered by prenatal activation of microglia provide a cellular basis for the neuropsychiatric defects induced by prenatal inflammation

The histone deacetylase inhibitor trichostatin A downregulates human MDR1 (ABCB1) gene expression by a transcription-dependent mechanism in a drug-resistant small cell lung carcinoma cell line model

Tumour drug-resistant ABCB1 gene expression is regulated at the chromatin level through epigenetic mechanisms. We examined the effects of the histone deacetylase inhibitor trichostatin A (TSA) on ABCB1 gene expression in small cell lung carcinoma (SCLC) drug-sensitive (H69WT) or etoposide-resistant (H69VP) cells. We found that TSA induced an increase in ABCB1 expression in drug-sensitive cells, but strongly decreased it in drug-resistant cells. These up- and downregulations occurred at the transcriptional level. Protein synthesis inhibition reduced these modulations, but did not completely suppress them. Differential temporal patterns of histone acetylation were observed at the ABCB1 promoter: increase in H4 acetylation in both cell lines, but different H3 acetylation with a progressive increase in H69WT cells but a transient one in H69VP cells. ABCB1 regulations were not related with the methylation status of the promoter −50GC, −110GC, and Inr sites, and did not result in further changes to these methylation profiles. Trichostatin A treatment did not modify MBD1 binding to the ABCB1 promoter and similarly increased PCAF binding in both H69 cell lines. Our results suggest that in H69 drug-resistant SCLC cell line TSA induces downregulation of ABCB1 expression through a transcriptional mechanism, independently of promoter methylation, and MBD1 or PCAF recruitment