Training during a sensitive period in development may have greater effects on brain structure and behavior than training later in life. Musicians are an excellent model for investigating sensitive ...periods because training starts early and can be quantified. Previous studies suggested that early training might be related to greater amounts of white matter in the corpus callosum, but did not control for length of training or identify behavioral correlates of structural change. The current study compared white-matter organization using diffusion tensor imaging in early- and late-trained musicians matched for years of training and experience. We found that early-trained musicians had greater connectivity in the posterior midbody/isthmus of the corpus callosum and that fractional anisotropy in this region was related to age of onset of training and sensorimotor synchronization performance. We propose that training before the age of 7 years results in changes in white-matter connectivity that may serve as a scaffold upon which ongoing experience can build.
Many human cancers are dramatically accelerated by chronic inflammation. However, the specific cellular and molecular elements mediating this effect remain largely unknown. Using a murine model of ...pancreatic intraepithelial neoplasia (PanIN), we found that KrasG12D induces expression of functional IL-17 receptors on PanIN epithelial cells and also stimulates infiltration of the pancreatic stroma by IL-17-producing immune cells. Both effects are augmented by associated chronic pancreatitis, resulting in functional in vivo changes in PanIN epithelial gene expression. Forced IL-17 overexpression dramatically accelerates PanIN initiation and progression, while inhibition of IL-17 signaling using genetic or pharmacologic techniques effectively prevents PanIN formation. Together, these studies suggest that a hematopoietic-to-epithelial IL-17 signaling axis is a potent and requisite driver of PanIN formation.
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•IL-17+ T cells are recruited to the pancreas in response to Kras and inflammation•IL-17A overexpression accelerates PanIN initiation and progression•Inhibition of IL-17 signaling effectively prevents PanIN initiation and progression•Kras activates expression of functional IL-17 receptors on PanIN epithelium
McAllister et al. show that KrasG12D induces IL-17 receptors expression on PanIN epithelial cells and stimulates infiltration of IL-17-producing immune cells in a murine PanIN model, the latter of which is confirmed in human PanIN and that inhibition of IL-17 signaling prevents pancreatic neoplasia initiation.
As contemporary wildfire activity intensifies across the western United States, there is increasing recognition that a variety of forest management activities are necessary to restore ecosystem ...function and reduce wildfire hazard in dry forests. However, the pace and scale of current, active forest management is insufficient to address restoration needs. Managed wildfire and landscape-scale prescribed burns hold potential to achieve broad-scale goals but may not achieve desired outcomes where fire severity is too high or too low. To explore the potential for fire alone to restore dry forests, we developed a novel method to predict the range of fire severities most likely to restore historical forest basal area, density, and species composition in forests across eastern Oregon. First, we developed probabilistic tree mortality models for 24 species based on tree characteristics and remotely sensed fire severity from burned field plots. We applied these estimates to unburned stands in four national forests to predict post-fire conditions using multi-scale modeling in a Monte Carlo framework. We compared these results to historical reconstructions to identify fire severities with the highest restoration potential. Generally, we found basal area and density targets could be achieved by a relatively narrow range of moderate-severity fire (roughly 365-560 RdNBR). However, single fire events did not restore species composition in forests that were historically maintained by frequent, low-severity fire. Restorative fire severity ranges for stand basal area and density were strikingly similar for ponderosa pine (Pinus ponderosa) and dry mixed-conifer forests across a broad geographic range, in part due to relatively high fire tolerance of large grand (Abies grandis) and white fir (Abies concolor). Our results suggest historical forest conditions created by recurrent fire are not readily restored by single fires and landscapes have likely passed thresholds that preclude the effectiveness of managed wildfire alone as a restoration tool.
Activation of the peripheral innate immune system stimulates the secretion of CNS cytokines that modulate the behavioral symptoms of sickness. Excessive production of cytokines by microglia, however, ...may cause long-lasting behavioral and cognitive complications. The purpose of this study was to determine if minocycline, an anti-inflammatory agent and purported microglial inhibitor, attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia.
In the first set of experiments the effect of minocycline pretreatment on LPS-induced microglia activation was assessed in BV-2 microglia cell cultures. In the second study, adult (3-6 m) BALB/c mice received an intraperitoneal (i.p.) injection of vehicle or minocycline (50 mg/kg) for three consecutive days. On the third day, mice were also injected (i.p.) with saline or Escherichia coli LPS (0.33 mg/kg) and behavior (i.e., sickness and anhedonia) and markers of neuroinflammation (i.e., microglia activation and inflammatory cytokines) were determined. In the final study, adult and aged BALB/c mice were treated with the same minocycline and LPS injection regimen and markers of neuroinflammation were determined. All data were analyzed using Statistical Analysis Systems General Linear Model procedures and were subjected to one-, two-, or three-way ANOVA to determine significant main effects and interactions.
Minocycline blocked LPS-stimulated inflammatory cytokine secretion in the BV-2 microglia-derived cell line and reduced LPS-induced Toll-like-receptor-2 (TLR2) surface expression on brain microglia. Moreover, minocycline facilitated the recovery from sickness behavior (i.e., anorexia, weight loss, and social withdrawal) and prevented anhedonia in adult mice challenged with LPS. Furthermore, the minocycline associated recovery from LPS-induced sickness behavior was paralleled by reduced mRNA levels of Interleukin (IL)-1beta, IL-6, and indoleamine 2, 3 dioxygenase (IDO) in the cortex and hippocampus. Finally, in aged mice, where exaggerated neuroinflammation was elicited by LPS, minocycline pretreatment was still effective in markedly reducing mRNA levels of IL-1beta, TLR2 and IDO in the hippocampus.
These data indicate that minocycline mitigates neuroinflammation in the adult and aged brain and modulates the cytokine-associated changes in motivation and behavior.
Background The Venous Thromboembolism Prevention Study (VTEPS) Network is a consortium of 5 tertiary referral centers established to examine venous thromboembolism (VTE) in plastic surgery patients. ...We report our midterm analyses of the study's control group to evaluate the incidence of VTE in patients who receive no chemoprophylaxis, and validate the Caprini Risk Assessment Model (RAM) in plastic surgery patients. Study Design Medical record review was performed at VTEPS centers for all eligible plastic surgery patients between March 2006 and June 2009. Inclusion criteria were Caprini score ≥3, surgery under general anesthesia, and postoperative hospital admission. Patients who received chemoprophylaxis were excluded. Dependent variables included symptomatic deep vein thrombosis (DVT) or pulmonary embolism (PE) within the first 60 postoperative days and time to DVT or PE. Results We identified 1,126 historic control patients. The overall VTE incidence was 1.69%. Approximately 1 in 9 (11.3%) patients with Caprini score >8 had a VTE event. Patients with Caprini score >8 were significantly more likely to develop VTE when compared with patients with Caprini score of 3 to 4 (odds ratio OR 20.9, p < 0.001), 5 to 6 (OR 9.9, p < 0.001), or 7 to 8 (OR 4.6, p = 0.015). Among patients with Caprini score 7 to 8 or Caprini score >8, VTE risk was not limited to the immediate postoperative period (postoperative days 1-14). In these high-risk patients, more than 50% of VTE events were diagnosed in the late (days 15-60) postoperative period. Conclusions The Caprini RAM effectively risk-stratifies plastic and reconstructive surgery patients for VTE risk. Among patients with Caprini score >8, 11.3% have a postoperative VTE when chemoprophylaxis is not provided. In higher risk patients, there was no evidence that VTE risk is limited to the immediate postoperative period.
The increasing number of older adults has seen a corresponding growth in those affected by neurovascular diseases, including stroke and dementia. Since cures are currently unavailable, major efforts ...in improving brain health need to focus on prevention, with emphasis on modifiable risk factors such as promoting physical activity. Moderate‐intensity continuous training (MICT) paradigms have been shown to confer vascular benefits translating into improved musculoskeletal, cardiopulmonary and cerebrovascular function. However, the time commitment associated with MICT is a potential barrier to participation, and high‐intensity interval training (HIIT) has since emerged as a more time‐efficient mode of exercise that can promote similar if not indeed superior improvements in cardiorespiratory fitness for a given training volume and further promote vascular adaptation. However, randomised controlled trials (RCTs) investigating the impact of HIIT on the brain are surprisingly limited. The present review outlines how the HIIT paradigm has evolved from a historical perspective and describes the established physiological changes including its mechanistic bases. Given the dearth of RCTs, the vascular benefits of MICT are discussed with a focus on the translational neuroprotective benefits including their mechanistic bases that could be further potentiated through HIIT. Safety implications are highlighted and components of an optimal HIIT intervention are discussed including practical recommendations. Finally, statistical effect sizes have been calculated to allow prospective research to be appropriately powered and optimise the potential for detecting treatment effects. Future RCTs that focus on the potential clinical benefits of HIIT are encouraged given the prevalence of cognitive decline in an ever‐ageing population.
figure legend: Summary of the integrated mechanisms and functional adaptations underpinning high‐intensity interval training‐induced neuroprotection High‐intensity interval training (HIIT) represents a more time‐efficient mode of exercise that can potentiate cardiorespiratory fitness and further enhance neuroprotection compared to more traditional moderate‐intensity continuous training paradigms. While the precise mechanisms remain unclear, prolonged exposure to the mechanical forces associated with the intermittency of HIIT‐induced sinusoidal hyperaemia can promote complex changes in the cerebral pressure, strain and shear stress phenotype to induce functional–structural adaptation of the vascular wall subsequent to endothelial cell mechanotransduction. Redox activation of complex intracellular signalling cascades can translate into molecular, haemodynamic and structural adaptations that ultimately enhance neuroprotection. Establishing these mechanisms more clearly will provide an evidence base for the prescription and future optimisation of HIIT interventions that have arguably more potential to promote healthy ageing by delaying stroke, cognitive decline and dementia. Digits below each of the integrated functionally adaptive benefits proposed (bottom of figure) highlight sample size estimates (number of participants/patients required to achieve adequate statistical power) to inform the design of future randomised control trials.
Fibrosis is a serious consequence of Crohn's disease (CD), often necessitating surgical resection. We examined the hypothesis that IL-13 may promote collagen accumulation within the CD muscle ...microenvironment.
Factors potentially modulating collagen deposition were examined in intestinal tissue samples from fibrotic (f) CD and compared with cancer control (C), ulcerative colitis (UC) and uninvolved (u) CD. Mechanisms attributable to IL-13 were analysed using cell lines derived from uninvolved muscle tissue and tissue explants.
In fCD muscle extracts, collagen synthesis was significantly increased compared to other groups, but MMP-2 was not co-ordinately increased. IL-13 transcripts were highest in fCD muscle compared to muscle from other groups. IL-13 receptor (R) α1 was expressed by intestinal muscle smooth muscle, nerve and KIR(+) cells. Fibroblasts from intestinal muscle expressed Rα1, phosphorylated STAT6 in response to IL-13, and subsequently down-regulated MMP-2 and TNF-α-induced MMP-1 and MMP-9 synthesis. Cells with the phenotype KIR(+)CD45(+)CD56(+/-)CD3(-) were significantly increased in fCD muscle compared to all other groups, expressed Rα1 and membrane IL-13, and transcribed high levels of IL-13. In explanted CD muscle, these cells did not phosphorylate STAT6 in response to exogenous IL-13.
The data indicate that in fibrotic intestinal muscle of Crohn's patients, the IL-13 pathway is stimulated, involving a novel population of infiltrating IL-13Rα1(+), KIR(+) innate lymphoid cells, producing IL-13 which inhibits fibroblast MMP synthesis. Consequently, matrix degradation is down-regulated and this leads to excessive collagen deposition.
Certificate of Need (CON) laws, currently in place in 35 US states, require certain health care providers to obtain a certification of their economic necessity from a state board before opening or ...undertaking a major expansion. We conduct the first systematic review and cost-effectiveness analysis of these laws.
We review 90 articles to summarize the evidence on how certificate of need laws affect regulatory costs, health expenditures, health outcomes, and access to care. We use the findings from the systematic review to conduct a cost-effectiveness analysis of CON.
The literature provides mixed results, on average finding that CON increases health expenditures and overall elderly mortality while reducing heart surgery mortality. Our cost-effectiveness analysis estimates that the costs of CON laws somewhat exceed their benefits, although our estimates are quite uncertain.
The literature has not yet reached a definitive conclusion on how CON laws affect health expenditures, outcomes, or access to care. While more and higher quality research is needed to reach confident conclusions, our cost-effectiveness analysis based on the existing literature shows that the expected costs of CON exceed its benefits.
As compared to developed countries, a much higher proportion of entrepreneurs within base-of-the-pyramid (BOP) markets operate unregistered businesses. Prior research has suggested that the primary ...cause of such informal activity in these settings is the general failure of ‘weak’ institutions to provide sufficient resources to warrant formalization. We attempt to extend such thinking by deconstructing the discrete and inter-related effects of formal business registration on the level of resources obtained by entrepreneurs from financial, labor, and legal institutions within BOP markets. Using a multi-method approach involving 299 entrepreneurs within Guatemala City, our results suggest that being seen as a ‘legitimate’, registered business can actually lead to both increased resource provision and resource appropriation. More specifically, adhering to the norms and rules prescribed by regulatory institutions within weak legal environments can convey positive signals of stability and profitability that both attract the desired attention from formal institutional actors, as well as unwanted attention from criminals.
•We interview and survey 299 entrepreneurs in Guatemala about being a registered vs. informal business.•Being registered makes it easier to obtain the financial capital needed for growth.•Being registered also comes with increased challenges related to extortion and theft.•Legitimacy can lead to both resource provision and appropriation in environments where strong and weak institutions co-exist.
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