Ground Heave Due to Jet Grouting Near an Existing Structure

Renovations of the MBTA Copley Station in Boston included construction of a new elevator shaft to improve disabled access to the existing Green Line station. The site is immediately adjacent to the Eastern façade of the historic Old South Church. The construction work required excavation support including a perimeter secant pile wall and a jet-grouted base plug. Significant ground and structural movements were observed during jet grouting, mainly associated with soil displacements during grout injection. A three dimensional numerical model was developed, using the Plaxis 3D Foundation™ program, in order to test the hypothesis that the observed movements of the structure could be associated with the installation of the jet grout piles. The amount of volume expansion associated with installation of jet grout piles is estimated based by calibrating the model to measured ground movements. The finite element model results give a consistent explanation for the observed pattern of movements, including the heave of the church wall and lateral displacements at inclinometers located within the vicinity of the structure, measured at the time when damage occurred. The model assumes there is a vertical line of weakness in the masonry, representative of a pre-existing structural crack, as observed by structural investigations; and hence, confirms the underlying mechanical hypothesis for the source of ground movements

Predictors of Functional Outcomes following Operative Treatment of Acute Achilles Tendon Ruptures

Introduction: Previous studies involving operative management of Achilles tendon ruptures have attempted to determine if patient factors influence outcomes. No previous study has attempted to identify outcome predictors in patients exclusively undergoing surgical repair. The purpose of this study is to determine if any injury or patient variables were predictive of outcomes following operative management of Achilles ruptures. Methods: Patient demographics including age, sex, body mass index (BMI), comorbidities (diabetes mellitus, depression, anxiety), mechanism of injury (sports, non-sports), and date of injury were collected. Postoperative notes were reviewed to determine compliance. Patients completed the Foot & Ankle Ability Measure (FAAM)-Activities of Daily Living (ADL) and –Sports subscales, and visual analog scale (VAS) for pain. Multivariable regression analysis was performed, and regression coefficients with 95% confidence intervals and p-values were reported. Results: Female sex was associated with lower FAAM-Sports score (-10.11 [-19.73,-0.50]) and a lower Single Assessment Numeric Evaluation score from the FAAM-Sports subscale (-13.79 [-26.28,-1.30]; p=0.0325). History of anxiety was related to a lower FAAM-ADL score (-29.02 [-45.68, -12.36]; p=0.0009), FAAM-Sports score (-33.41 [-64.46, -2.37]; p=0.0368), and a higher VAS pain score (19.83 [4.43, 35.23]; p=0.0128). Age, BMI, a history of depression or diabetes mellitus, mechanism of injury, timing of repair, and patient compliance were not predictive. Discussion: Females and patients with anxiety have significantly poorer outcomes following Achilles tendon repair. Further study is indicated to determine whether these factors are also predictive of outcomes of Achilles ruptures treated non-surgically and how this may affect surgical indications in these patients

Priming in response to pro-inflammatory cytokines is a feature of adult synovial but not dermal fibroblasts

Background: It has been hypothesized that chronic inflammatory diseases such as rheumatoid arthritis (RA) may be caused by a failure of negative feedback mechanisms. This study sought to examine negative feedback mechanisms in fibroblast-like synoviocytes (FLS), one of the most abundant cell types in the joint. We hypothesized that prior exposure of healthy FLS to an inflammatory stimulus would attenuate their responses to a second inflammatory stimulus, in the same way that negative feedback mechanisms desensitize macrophages to repeated stimulation by lipopolysaccharide. We further hypothesized that such negative feedback mechanisms would be defective in FLS derived from the joints in RA.Methods: Synovial fibroblasts and dermal fibroblasts from non-inflamed joints and joints affected by RA and a fibroblast cell line from neonatal foreskin were stimulated twice with tumour necrosis factor (TNF) α or interleukin (IL)-1α, with a 24-h rest period between the two 24-h stimulations. Differences between response to the first and second dose of cytokine were examined by assessing secretion of inflammatory factors and intracellular signalling activity.Results: FLS from both non-inflamed joints and joints affected by RA mounted an augmented response to re-stimulation. This response was site-specific, as primary dermal fibroblasts did not alter their response between doses. The fibroblast priming was also gene-specific and transient. Assessment of signalling events and nuclear localization showed prolonged activation of nuclear factor (NF)-κB during the second stimulation.Conclusion: This study aimed to examine mechanisms of negative regulation of inflammatory responses in FLS. Instead, we found a pro-inflammatory stromal memory in FLS obtained from both non-inflamed joints and joints affected by RA. This suggests the joint is an area at high risk of chronic inflammation, and may provide a piece in the puzzle of how chronic inflammation is established in RA

The glucocorticoid dexamethasone inhibits HIF-1α stabilization and metabolic reprogramming in lipopolysaccharide-stimulated primary macrophages

Synthetic glucocorticoids are used to treat many chronic and acute inflammatory conditions. Frequent adverse effects of prolonged exposure toglucocorticoids include disturbances of glucose homeostasis caused by changes in glucose traffic and metabolism in muscle, liver, and adiposetissues. Macrophages are important targets for the anti-inflammatory actions of glucocorticoids. These cells rely on aerobic glycolysis to supportvarious pro-inflammatory and antimicrobial functions. Employing a potent pro-inflammatory stimulus in two commonly used model systems(mouse bone marrow-derived and human monocyte-derived macrophages), we showed that the synthetic glucocorticoid dexamethasone inhib-ited lipopolysaccharide-mediated activation of the hypoxia-inducible transcription factor HIF-1α, a critical driver of glycolysis. In both cell types,dexamethasone-mediated inhibition of HIF-1α reduced the expression of the glucose transporter GLUT1, which imports glucose to fuel aerobicglycolysis. Aside from this conserved response, other metabolic effects of lipopolysaccharide and dexamethasone differed between human andmouse macrophages. These findings suggest that glucocorticoids exert anti-inflammatory effects by impairing HIF-1α-dependent glucose uptakein activated macrophages. Furthermore, harmful and beneficial (anti-inflammatory) effects of glucocorticoids may have a shared mechanisticbasis, depending on the alteration of glucose utilization

Intermittent Surface Oxygenation Results in Similar Mitochondrial Protection and Maintenance of Aerobic Metabolism as Compared to Continuous Oxygenation during Hypothermic Machine Kidney Machine Perfusion

Short bubble and subsequent surface oxygenation is an innovative oxygenation technique and alternative for membrane oxygenation during hypothermic machine perfusion (HMP). The metabolic effect of the interruption of surface oxygenation for 4 h (mimicking organ transport) during HMP was compared to continuous surface and membrane oxygenation in a pig kidney ex situ preservation model. After 30 min of warm ischemia by vascular clamping, a kidney of a ±40 kg pig was procured and subsequently preserved according to one of the following groups: (1) 22-h HMP + intermittent surface oxygenation ( = 12); (2) 22-h HMP + continuous membrane oxygenation ( = 6); and (3) 22-h HMP + continuous surface oxygenation ( = 7). Brief perfusate O uploading before kidney perfusion was either obtained by direct bubble (groups 1, 3) or by membrane (group 2) oxygenation. Bubble oxygenation during minimum 15 min was as efficient as membrane oxygenation in achieving supraphysiological perfusate pO levels before kidney perfusion. Metabolic tissue analysis (i.e., lactate, succinate, ATP, NADH, and FMN) during and at the end of the preservation period demonstrated similar mitochondrial protection between all study groups. Short bubble and subsequent intermittent surface oxygenation of the perfusate of an HMP-kidney might be an effective and cheap preservation strategy to protect mitochondria, eliminating the need/costs of a membrane oxygenator and oxygen source during transport

Dexamethasone impairs the expression of antimicrobial mediators in lipopolysaccharide-activated primary macrophages by inhibiting both expression and function of interferon β

Glucocorticoids potently inhibit expression of many inflammatory mediators, and have been widely used to treat both acute and chronic inflammatory diseases for more than seventy years. However, they can have several unwanted effects, amongst which immunosuppression is one of the most common. Here we used microarrays and proteomic approaches to characterise the effect of dexamethasone (a synthetic glucocorticoid) on the responses of primary mouse macrophages to a potent pro-inflammatory agonist, lipopolysaccharide (LPS). Gene ontology analysis revealed that dexamethasone strongly impaired the lipopolysaccharide-induced antimicrobial response, which is thought to be driven by an autocrine feedback loop involving the type I interferon IFNβ. Indeed, dexamethasone strongly and dose-dependently inhibited the expression of IFNβ by LPS-activated macrophages. Unbiased proteomic data also revealed an inhibitory effect of dexamethasone on the IFNβ-dependent program of gene expression, with strong down-regulation of several interferon-induced antimicrobial factors. Surprisingly, dexamethasone also inhibited the expression of several antimicrobial genes in response to direct stimulation of macrophages with IFNβ. We tested a number of hypotheses based on previous publications, but found that no single mechanism could account for more than a small fraction of the broad suppressive impact of dexamethasone on macrophage type I interferon signaling, underlining the complexity of this pathway. Preliminary experiments indicated that dexamethasone exerted similar inhibitory effects on primary human monocyte-derived or alveolar macrophages.</p

Dominant suppression of inflammation via targeted mutation of the mRNA destabilizing protein tristetraprolin

In myeloid cells, the mRNA-destabilizing protein tristetraprolin (TTP) is induced and extensively phosphorylated in response to LPS. To investigate the role of two specific phosphorylations, at serines 52 and 178, we created a mouse strain in which those residues were replaced by nonphosphorylatable alanine residues. The mutant form of TTP was constitutively degraded by the proteasome and therefore expressed at low levels, yet it functioned as a potent mRNA destabilizing factor and inhibitor of the expression of many inflammatory mediators. Mice expressing only the mutant form of TTP were healthy and fertile, and their systemic inflammatory responses to LPS were strongly attenuated. Adaptive immune responses and protection against infection by Salmonella typhimurium were spared. A single allele encoding the mutant form of TTP was sufficient for enhanced mRNA degradation and underexpression of inflammatory mediators. Therefore, the equilibrium between unphosphorylated and phosphorylated TTP is a critical determinant of the inflammatory response, and manipulation of this equilibrium may be a means of treating inflammatory pathologies

Macrophage responses to lipopolysaccharide are modulated by a feedback loop involving prostaglandin E2, dual specificity phosphatase 1 and tristetraprolin

In many different cell types, pro-inflammatory agonists induce the expression of cyclooxygenase 2 (COX-2), an enzyme that catalyzes rate-limiting steps in the conversion of arachidonic acid to a variety of lipid signaling molecules, including prostaglandin E2 (PGE2). PGE2 has key roles in many early inflammatory events, such as the changes of vascular function that promote or facilitate leukocyte recruitment to sites of inflammation. Depending on context, it also exerts many important anti-inflammatory effects, for example increasing the expression of the anti-inflammatory cytokine interleukin 10 (IL-10), and decreasing that of the pro-inflammatory cytokine tumor necrosis factor (TNF). The tight control of both biosynthesis of, and cellular responses to, PGE2 are critical for the precise orchestration of the initiation and resolution of inflammatory responses. Here we describe evidence of a negative feedback loop, in which PGE2 augments the expression of dual specificity phosphatase 1, impairs the activity of mitogen-activated protein kinase p38, increases the activity of the mRNA-destabilizing factor tristetraprolin, and thereby inhibits the expression of COX-2. The same feedback mechanism contributes to PGE2-mediated suppression of TNF release. Engagement of the DUSP1-TTP regulatory axis by PGE2 is likely to contribute to the switch between initiation and resolution phases of inflammation

High-level IGF1R expression is required for leukemia-initiating cell activity in T-ALL and is supported by Notch signaling

Notch-driven expression of IGF1R promotes the growth, viability, and transplantability of T-ALL cells