A pre-clinical functional assessment of an acellular scaffold intended for the treatment of hard-to-heal wounds

Dermal wound healing is a biochemical and cellular process critical to life. While the majority of the population will only ever experience successful wound healing outcomes, some 1-3 % of those aged over 65 years will experience wound healing delay or perpetuation. These hard-to-heal wounds are comprised of degraded and dysfunctional extracellular matrix, yet the integrity of this structure is critical in the processes of normal wound healing. As such, extracellular matrix replacements have been devised that can replace dysfunctional extracellular matrix in hard-to-heal wounds with the aim of restoring normal wound healing processes. Here we evaluated a novel synthetic matrix protein for its ability to act as an acellular scaffold that can replace dysfunctional extracellular matrix. In this regard the synthetic protein demonstrated an ability to rapidly adsorb to the dermal surface, permit cell attachment and facilitate the cellular functions essential to wound healing. When applied to deep partial thickness wounds in a porcine animal model the matrix protein also demonstrated the ability to reduce wound duration. These data provide evidence that the synthetic matrix protein has the ability to function as an acellular scaffold for wound healing purposes.

Effectiveness of an acellular synthetic matrix in the treatment of hard-to-heal leg ulcers

Hard-to-heal leg ulcers are a major cause of morbidity in the elderly population. Despite improvements in wound care, some wounds will not heal and they present a significant challenge for patients and health care providers. A multi-centre cohort study was conducted to evaluate the effectiveness and safety of a synthetic, extracellular matrix protein as an adjunct to standard care in the treatment of hard-to-heal venous or mixed leg ulcers. Primary effectiveness criteria were (i) reduction in wound size evaluated by percentage change in wound area and (ii) healing assessed by number of patients healed by end of the 12 week study. Pain reduction was assessed as a secondary effectiveness criteria using VAS. A total of 45 patients completed the study and no difference was observed between cohorts for treatment frequency. Healing was achieved in 35·6% and wound size decreased in 93·3% of patients. Median wound area percentage reduction was 70·8%. Over 50% of patients reported pain on first visit and 87·0% of these reported no pain at the end of the study. Median time to first reporting of no pain was 14 days after treatment initiation. The authors consider the extracellular synthetic matrix protein an effective and safe adjunct to standard care in the treatment of hard-to-heal leg ulcers.

Architecture and affect

Invited Lecture for Interdisciplinary seminar, Yale School of Architecture. Seminar investigates architectural techniques of affect; topics included Adrian Stokes, Freud on aggression, Spinoza, German aesthetics, viscerality, Guattari and “concrete machines”; Other Invited guests: Peggy Deamer, Brian Massumi, Gary Genosko, Ernst Prelinger, Elizabeth Grosz, Ed Mitchell.

Capability presence in the newly internationalizing firm

We investigate the enablers of early internationalization of the firm. We posit that for firms to internationalize early in their lifecycles, sets of capabilities must be present at the firm’s formative stage and that these capabilities build upon routines that the founders bring into the new firm. These capabilities are aligned to establish a platform for internationalization unencumbered by the administrative heritage often observed in well-established firms. We model this phenomenon, testing it in a cross-national setting of early internationalizing firms in Australia and the United States. To do so, we draw upon a dynamic capabilities framing, conceptualizing and measuring the dynamic capabilities that founders apply in their early internationalization activities.

The newly internationalizing firm and its capabilities

In this paper we investigate the enablers of early internationalization of the firm. We posit that for firms to internationalize early in their lifecycles, sets of capabilities must be present at the firm’s formative stage and that these capabilities build upon routines that the founders bring into the new firm. These capabilities align to establish a platform for internationalization unencumbered by the administrative heritage often observed in well-established firms that constrains expansion overseas. We model this phenomenon, testing it in an Australian sample of early internationalizing firms. To do so, we draw upon a dynamic capabilities framing, conceptualizing and measuring the dynamic capabilities that founders apply in their early internationalization activities.

Re : Why optometry must work from urban and regional Aboriginal health services

We are writing to support the recent Viewpoint written by Anjou, Boudville and Taylor ‘Why optometry must work in Aboriginal Health Services in urban and regional Australia’.[1] We are a group of optometrists who provide optometric services within Aboriginal Health Services in urban and regional settings and we agree that access to optometry in Aboriginal Health Services should be supported and expanded in an effort to ‘close the gap’ for vision.

Engraftment outcomes after HPC co-culture with mesenchymal stromal cells and osteoblasts

Haematopoietic stem cell (HSC) transplantation is an established cell-based therapy for a number of haematological diseases. To enhance this therapy, there is considerable interest in expanding HSCs in artificial niches prior to transplantation. This study compared murine HSC expansion supported through co-culture on monolayers of either undifferentiated mesenchymal stromal cells (MSCs) or osteoblasts. Sorted Lineage− Sca-1+ c-kit+ (LSK) haematopoietic stem/progenitor cells (HPC) demonstrated proliferative capacity on both stromal monolayers with the greatest expansion of LSK shown in cultures supported by osteoblast monolayers. After transplantation, both types of bulk-expanded cultures were capable of engrafting and repopulating lethally irradiated primary and secondary murine recipients. LSKs co-cultured on MSCs showed comparable, but not superior, reconstitution ability to that of freshly isolated LSKs. Surprisingly, however, osteoblast co-cultured LSKs showed significantly poorer haematopoietic reconstitution compared to LSKs co-cultured on MSCs, likely due to a delay in short-term reconstitution. We demonstrated that stromal monolayers can be used to maintain, but not expand, functional HSCs without a need for additional haematopoietic growth factors. We also demonstrated that despite apparently superior in vitro performance, co-injection of bulk cultures of osteoblasts and LSKs in vivo was detrimental to recipient survival and should be avoided in translation to clinical practice.

Heparan sulfate proteoglycans and human breast cancer epithelial cell tumorigenicity

Heparan sulfate proteoglycans (HSPGs) are key components of the extracellular matrix that mediate cell proliferation, invasion, and cellular signaling. The biological functions of HSPGs are linked to their co-stimulatory effects on extracellular ligands (e.g., WNTs) and the resulting activation of transcription factors that control mammalian development but also associated with tumorigenesis. We examined the expression profile of HSPG core protein syndecans (SDC1–4) and glypicans (GPC1–6) along with the enzymes that initiate or modify their glycosaminoglycan chains in human breast cancer (HBC) epithelial cells. Gene expression in relation to cell proliferation was examined in the HBC cell lines MCF-7 and MDA-MB-231 following treatment with the HS agonist heparin. Heparin increased gene expression of chain initiation and modification enzymes including EXT1 and NDST1, as well as core proteins SDC2 and GPC6. With HS/Wnt interactions established, we next investigated WNT pathway components and observed that increased proliferation of the more invasive MDA-MB-231 cells is associated with activation of the Wnt signaling pathway. Specifically, there was substantial upregulation (>5-fold) of AXIN1, WNT4A, and MYC in MDA-MB-231 but not in MCF-7 cells. The changes in gene expression observed for HSPG core proteins and related enzymes along with the associated Wnt signaling components suggest coordinated interactions. The influence of HSPGs on cellular proliferation and invasive potential of breast cancer epithelial cells are cell and niche specific. Further studies on the interactions between HSPGs and WNT ligands may yield clinically relevant molecular targets, as well as new biomarkers for characterization of breast cancer progression.

The osteogenic transcription factor Runx2 regulates components of the fibroblast growth factor/proteoglycan signaling axis in osteoblasts

Heparan sulfate proteoglycans cooperate with basic fibroblast growth factor (bFGF/FGF2) signaling to control osteoblast growth and differentiation, as well as metabolic functions of osteoblasts. FGF2 signaling modulates the expression and activity of Runt-related transcription factor 2 (Runx2/Cbfa1), a key regulator of osteoblast proliferation and maturation. Here, we have characterized novel Runx2 target genes in osteoprogenitors under conditions that promote growth arrest while not yet permitting sustained phenotypic maturation. Runx2 enhances expression of genes related to proteoglycan-mediated signaling, including FGF receptors (e.g., FGFR2 and FGFR3) and proteoglycans (e.g., syndecans [Sdc1, Sdc2, Sdc3], glypicans [Gpc1], versican [Vcan]). Runx2 increases expression of the glycosyltransferase Exostosin-1 (Ext1) and heparanase, as well as alters the relative expression of N-linked sulfotransferases (Ndst1 = Ndst2 > Ndst3) and enzymes mediating O-linked sulfation of heparan sulfate (Hs2st > Hs6st) or chondroitin sulfate (Cs4st > Cs6st). Runx2 cooperates with FGF2 to induce expression of Sdc4 and the sulfatase Galns, but Runx2 and FGF2 suppress Gpc6, thus suggesting intricate Runx2 and FGF2 dependent changes in proteoglycan utilization. One functional consequence of Runx2 mediated modulations in proteoglycan-related gene expression is a change in the responsiveness of bone markers to FGF2 stimulation. Runx2 and FGF2 synergistically enhance osteopontin expression (>100 fold), while FGF2 blocks Runx2 induction of alkaline phosphatase. Our data suggest that Runx2 and the FGF/proteoglycan axis may form an extracellular matrix (ECM)-related regulatory feed-back loop that controls osteoblast proliferation and execution of the osteogenic program.

The role of the market sub-system and the socio-technical sub-system in innovation and firm performance : a dynamic capabilities approach

Organizational learning has been studied as a key factor in firm performance and internationalization. Moving beyond the past emphasis on market learning, we develop a more complete explanation of learning, its relationship to innovation, and their joint effect on early internationalization. We theorize that, driven by the founders’ international vision, early internationalizing firms employ a dual subsystem of dynamic capabilities: a market subsystem consisting of market-focused learning capability and marketing capability, and a socio-technical subsystem comprised of network learning capability and internally focused learning capability. We argue that innovation mediates the proposed relationship between the dynamic capability structure and early internationalization. We conduct case studies to develop the conceptual framework and test it in a field survey of early internationalizing firms from Australia and the United States. Our findings indicate a complex interplay of capabilities driving innovation and early internationalization. We provide theoretical and practical implications and offer insights for future research.

Understanding the abnormal brain activity in epilepsy as a potential predictor of the onset of an epileptic seizure

The Brain Research Institute (BRI) uses various types of indirect measurements, including EEG and fMRI, to understand and assess brain activity and function. As well as the recovery of generic information about brain function, research also focuses on the utilisation of such data and understanding to study the initiation, dynamics, spread and suppression of epileptic seizures. To assist with the future focussing of this aspect of their research, the BRI asked the MISG 2010 participants to examine how the available EEG and fMRI data and current knowledge about epilepsy should be analysed and interpreted to yield an enhanced understanding about brain activity occurring before, at commencement of, during, and after a seizure. Though the deliberations of the study group were wide ranging in terms of the related matters considered and discussed, considerable progress was made with the following three aspects. (1) The science behind brain activity investigations depends crucially on the quality of the analysis and interpretation of, as well as the recovery of information from, EEG and fMRI measurements. A number of specific methodologies were discussed and formalised, including independent component analysis, principal component analysis, profile monitoring and change point analysis (hidden Markov modelling, time series analysis, discontinuity identification). (2) Even though EEG measurements accurately and very sensitively record the onset of an epileptic event or seizure, they are, from the perspective of understanding the internal initiation and localisation, of limited utility. They only record neuronal activity in the cortical (surface layer) neurons of the brain, which is a direct reflection of the type of electrical activity they have been designed to record. Because fMRI records, through the monitoring of blood flow activity, the location of localised brain activity within the brain, the possibility of combining fMRI measurements with EEG, as a joint inversion activity, was discussed and examined in detail. (3) A major goal for the BRI is to improve understanding about ``when'' (at what time) an epileptic seizure actually commenced before it is identified on an eeg recording, ``where'' the source of this initiation is located in the brain, and ``what'' is the initiator. Because of the general agreement in the literature that, in one way or another, epileptic events and seizures represent abnormal synchronisations of localised and/or global brain activity the modelling of synchronisations was examined in some detail. References C. M. Michel, G. Thut, S. Morand, A. Khateb, A. J. Pegna, R. Grave de Peralta, S. Gonzalez, M. Seeck and T. Landis, Electric source imaging of human brain functions, Brain Res. 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Effects of a pediatric weight management program with and without active video games

Importance Active video games may offer an effective strategy to increase physical activity in overweight and obese children. However, the specific effects of active gaming when delivered within the context of a pediatric weight management program are unknown. Objective To evaluate the effects of active video gaming on physical activity and weight loss in children participating in an evidence-based weight management program delivered in the community. Design, Setting, and Participants Group-randomized clinical trial conducted during a 16-week period in YMCAs and schools located in Massachusetts, Rhode Island, and Texas. Seventy-five overweight or obese children (41 girls [55%], 34 whites [45%], 20 Hispanics [27%], and 17 blacks [23%]) enrolled in a community-based pediatric weight management program. Mean (SD) age of the participants was 10.0 (1.7) years; body mass index (BMI) z score, 2.15 (0.40); and percentage overweight from the median BMI for age and sex, 64.3% (19.9%). Interventions All participants received a comprehensive family-based pediatric weight management program (JOIN for ME). Participants in the program and active gaming group received hardware consisting of a game console and motion capture device and 1 active game at their second treatment session and a second game in week 9 of the program. Participants in the program-only group were given the hardware and 2 games at the completion of the 16-week program. Main Outcomes and Measures Objectively measured daily moderate-to-vigorous and vigorous physical activity, percentage overweight, and BMI z score. Results Participants in the program and active gaming group exhibited significant increases in moderate-to-vigorous (mean [SD], 7.4 [2.7] min/d) and vigorous (2.8 [0.9] min/d) physical activity at week 16 (P < .05). In the program-only group, a decline or no change was observed in the moderate-to-vigorous (mean [SD] net difference, 8.0 [3.8] min/d; P = .04) and vigorous (3.1 [1.3] min/d; P = .02) physical activity. Participants in both groups exhibited significant reductions in percentage overweight and BMI z scores at week 16. However, the program and active gaming group exhibited significantly greater reductions in percentage overweight (mean [SD], −10.9% [1.6%] vs −5.5% [1.5%]; P = .02) and BMI z score (−0.25 [0.03] vs −0.11 [0.03]; P < .001). Conclusions and Relevance Incorporating active video gaming into an evidence-based pediatric weight management program has positive effects on physical activity and relative weight.