Nonlinear Mechanical Effect of Free Water on the Dynamic Compressive Strength and Fracture of High-Strength Concrete

It is well-known that the effect of interstitial fluid on the fracture pattern and strength of saturated high-strength concrete is determined by qualitatively different mechanisms at quasi-static and high strain rate loading. This paper shows that the intermediate range of strain rates (10⁻⁴ s⁻¹ < ε˙ < 10⁰ s⁻¹) is also characterized by the presence of a peculiar mechanism of interstitial water effect on the concrete fracture and compressive strength. Using computer simulations, we have shown that such a mechanism is the competition of two oppositely directed processes: deformation of the pore space, which leads to an increase in pore pressure; and pore fluid flow. The balance of these processes can be effectively characterized by the Darcy number, which generalizes the notion of strain rate to fluid-saturated material. We have found that the dependence of the compressive strength of high-strength concrete on the Darcy number is a decreasing sigmoid function. The parameters of this function are determined by both low-scale (capillary) and large-scale (microscopic) pore subsystems in a concrete matrix. The capillary pore network determines the phenomenon of strain-rate sensitivity of fluid-saturated concrete and logistic form of the dependence of compressive strength on strain rate. Microporosity controls the actual boundary of the quasi-static loading regime for fluid-saturated samples and determines localized fracture patterns. The results of the study are relevant to the design of special-purpose concretes, as well as the assessment of the limits of safe impacts on concrete structural elements.     

Perindopril arginine and amlodipine besylate for hypertension: a safety evaluation

Introduction: Controlling blood pressure is a global health priority; single-pill antihypertensive combinations may improve adherence, persistence, and outcomes.

Areas covered: A novel combination of perindopril arginine and amlodipine besylate was recently approved. A systematic review of the literature revealed its most common adverse effects as: peripheral edema (depending on the dose of amlodipine, but attenuated by perindopril), cough, dizziness and hypotension. Dose-dependent hyperkalemia, impairment of renal function (especially in renovascular hypertension), angioedema, and teratogenicity were derived from experience with other ACE-inhibitors.

Expert opinion: Substantial clinical trial experience with amlodipine or perindopril suggests that these two agents effectively lower blood pressure, and can reduce the risk of major adverse cardiovascular events, as in the Anglo-Scandinavian Cardiac Outcomes Trial. The incidence of adverse effects reported in clinical trials is lower than expected, likely due to exclusion of subjects previously exposed to its components; the nature of open-label, uncontrolled observational studies; and difficulty in recognizing and measuring cough and pedal edema. This new formulation of perindopril arginine protects its ethyl ester, without requiring physical separation from amlodipine in a single tablet, and is less hygroscopic than perindopril erbumine. These and other attributes may make this combination an attractive addition to the antihypertensive armamentarium.     

Sphingosine Kinase 1 Deficiency Confers Protection against Hyperoxia-Induced Bronchopulmonary Dysplasia in a Murine Model: Role of S1P Signaling and Nox Proteins

Bronchopulmonary dysplasia of the premature newborn is characterized by lung injury, resulting in alveolar simplification and reduced pulmonary function. Exposure of neonatal mice to hyperoxia enhanced sphingosine-1-phosphate (S1P) levels in lung tissues; however, the role of increased S1P in the pathobiological characteristics of bronchopulmonary dysplasia has not been investigated. We hypothesized that an altered S1P signaling axis, in part, is responsible for neonatal lung injury leading to bronchopulmonary dysplasia. To validate this hypothesis, newborn wild-type, sphingosine kinase1^−/− (Sphk1^−/−), sphingosine kinase 2^−/− (Sphk2^−/−), and S1P lyase^+/− (Sgpl1^+/−) mice were exposed to hyperoxia (75%) from postnatal day 1 to 7. Sphk1^−/−, but not Sphk2^−/− or Sgpl1^+/−, mice offered protection against hyperoxia-induced lung injury, with improved alveolarization and alveolar integrity compared with wild type. Furthermore, SphK1 deficiency attenuated hyperoxia-induced accumulation of IL-6 in bronchoalveolar lavage fluids and NADPH oxidase (NOX) 2 and NOX4 protein expression in lung tissue. In vitro experiments using human lung microvascular endothelial cells showed that exogenous S1P stimulated intracellular reactive oxygen species (ROS) generation, whereas SphK1 siRNA, or inhibitor against SphK1, attenuated hyperoxia-induced S1P generation. Knockdown of NOX2 and NOX4, using specific siRNA, reduced both basal and S1P-induced ROS formation. These results suggest an important role for SphK1-mediated S1P signaling–regulated ROS in the development of hyperoxia-induced lung injury in a murine neonatal model of bronchopulmonary dysplasia.Bronchopulmonary dysplasia (BPD) is a chronic lung disease occurring as a consequence of injury to the rapidly developing premature lungs of a preterm newborn infant.¹ Preterm neonates receive ventilator care and inhaled oxygen supplementation for variable periods after delivery; prolonged exposure of preterm lungs to hyperoxia results in inflammation, pulmonary edema, lung injury, and, ultimately, death.^2,3 BPD is characterized by decreased secondary septation of alveoli, resulting in the formation of enlarged simplified alveoli and reduced area for gas exchange.^4,5 More than 25% of premature infants with birth weights <1500 g develop BPD.^5,6 Infants with BPD have higher rehospitalization rates because of asthma, infection, pulmonary hypertension, and other respiratory tract ailments.^7,8 Many surviving neonatal BPD patients reaching adulthood show a sharp decline in lung capacity, indicating that the adverse effects of insult in the neonatal stage can be long lasting.^9,10 There is no effective treatment for BPD, and strategies to prevent BPD by administering gentler ventilation and other therapeutic approaches have not been effective.¹¹ The identification of novel signaling pathways linking hyperoxia-induced lung injury in neonatal BPD is necessary for new therapeutic approaches.Sphingolipids and their metabolites, such as ceramide, sphingosine, and sphingosine-1-phosphate (S1P), are important bioregulators, capable of modulating acute lung injury in a variety of lung disorders.^12–14 S1P plays an important role in vascular development and endothelial barrier function.^14,15 It is generated by the phosphorylation of sphingosine catalyzed by sphingosine kinases (SphKs) 1 and 2 and metabolized by S1P phosphatases and lipid phosphatases to yield sphingosine or by S1P lyase (S1PL; Sgpl1) that generates Δ2-hexadecenal and ethanolamine phosphate in mammalian cells.¹⁶ In addition to the previously mentioned enzymes, serine palmitoyltransferase (SPT) initiates the biosynthesis of sphingolipids by catalyzing condensation of serine and palmitoyl-CoA to form 3-ketosphinganine.¹⁷ S1P acts extracellularly and intracellularly, and most effects of extracellular S1P are mediated via a family of five highly specific G-protein–coupled S1P_1-5 receptors.^18,19 Significantly lower levels of S1P in plasma and lung tissues were reported in a murine model of lipopolysaccharide (LPS)–induced lung injury, most likely because of elevated expression of S1PL,²⁰ and infusion of S1P ameliorated LPS-induced acute lung injury in murine and canine models.^21,22 Taken together, these results suggest a protective role for S1P in LPS-mediated lung injury. Hyperoxia is also known to cause lung injury; however, the underlying pathological characteristics are not similar to those observed in the LPS-treated mouse model.^20,23The goal of the present study was, therefore, to elucidate the role of S1P in the development of lung injury and BPD in the murine neonatal model. Our results showed that hyperoxia-induced accumulation of S1P is detrimental and linked to BPD because SphK1-, but not SphK2-, deficient mice exhibited significantly less hyperoxia-induced reactive oxygen species (ROS) formation, lung injury, and BPD, such as morphological characteristics, whereas S1P lyase–deficient heterozygous mice showed the opposite. Furthermore, by using human lung microvascular endothelial cells (HLMVECs), we observed that exogenous S1P stimulated ROS production, and down-regulation of SphK1 with siRNA blocked hyperoxia-induced ROS generation. We also present herein evidence in support of an inflammatory role for S1P in BPD as it relates to increased expression of NADPH oxidase (NOX) proteins, such as NOX2 and NOX4, and the proinflammatory cytokine, IL-6.     

The K1 Capsular Polysaccharide from Acinetobacter baumannii Is a Potential Therapeutic Target via Passive Immunization

The emergence of extremely resistant and panresistant Gram-negative bacilli, such as Acinetobacter baumannii, requires consideration of nonantimicrobial therapeutic approaches. The goal of this report was to evaluate the K1 capsular polysaccharide from A. baumannii as a passive immunization target. Its structure was determined by a combination of mass spectrometric and nuclear magnetic resonance (NMR) techniques. Molecular mimics that might raise the concern for autoimmune disease were not identified. Immunization of CD1 mice demonstrated that the K1 capsule is immunogenic. The monoclonal antibody (MAb) 13D6, which is directed against the K1 capsule from A. baumannii, was used to determine the seroprevalence of the K1 capsule in a collection of 100 A. baumannii strains. Thirteen percent of the A. baumannii isolates from this collection were seroreactive to MAb 13D6. Opsonization of K1-positive strains, but not K1-negative strains, with MAb 13D6 significantly increased neutrophil-mediated bactericidal activity in vitro (P < 0.05). Lastly, treatment with MAb 13D6 3 and 24 h after bacterial challenge in a rat soft tissue infection model resulted in a significant decrease in the growth/survival of a K1-positive strain compared to that of a K1-negative strain or to treatment with a vehicle control (P < 0.0001). These data support the proof of principle that the K1 capsule is a potential therapeutic target via passive immunization. Other serotypes require assessment, and pragmatic challenges exist, such as the need to serotype infecting strains and utilize serotype-specific therapy. Nonetheless, this approach may become an important therapeutic option with increasing antimicrobial resistance and a diminishing number of active antimicrobials.     

The diversity of heart failure in a hospitalized population: the role of age

BackgroundThe prevalence of heart failure (HF) among hospitalized elderly patients is high and steadily growing. However, because most studies have focused mostly on young patients, little is known about the clinical characteristics, echocardiographic measures, prognostic factors, and outcome of hospitalized elderly HF patients.Methods and ResultsWe identified all HF patients aged ≥50 years who had undergone ≥1 echocardiography study and had been hospitalized during January 2000 to December 2009. A comparative analysis was performed between 3,897 “young” patients (aged 50–75 years) and 5,438 “elderly” patients (aged >75 years), followed for a mean 2.8 ± 2.6 years. Elderly HF patients were more often female (50% vs 35%; P < .0001) and had a higher prevalence of HF with preserved ejection fraction (64.8% vs 53%; P < .0001), more significant valvular disease (35.7% vs 32.5%; P < .0001), and lower rates of ischemic heart disease (65.5% vs 70.9%; P < .0001) and diabetes (34.4% vs 53.9%; P < .0001). Thirty-day and 1-year mortality rates were significantly higher among the elderly population (12.2% vs 6.9% [P < .0001] and 34.3% vs 21.2% [P < .0001], respectively). Prognostic markers differed significantly between age groups. Young-specific predictors were chronic renal failure, diastolic dysfunction, malignancy, and tricuspid regurgitation, whereas elderly-specific predictors were HF with reduced ejection fraction, chronic obstructive pulmonary disease, pulmonary hypertension, and mitral regurgitation.ConclusionsHospitalized elderly, compared with young, HF patients differed in prevalence of cardiac and noncardiac comorbid conditions, echocardiographic parameters, and predictors of short- and intermediate-term mortality. Identifying unique features in the elderly population may render age-tailored therapeutics.     

Conservative Treatment of Hemorrhoids: Results of an Observational Multicenter Study

Introduction

This study was conducted to determine the frequency of complaints in a cohort of patients with symptomatic hemorrhoidal disease (HD) treated with micronized purified flavonoid fraction (MPFF, Detralex). MPFF was selected for conservative treatment in this population owing to its proven effects on hemorrhoidal symptoms in a large number of patients.

Methods

This multicenter, non-interventional study was part of the international CHORUS survey (Chronic venous and HemORrhoidal diseases evalUation for improvement of Scientific knowledge), conducted in nine centers in different regions of Russia with the participation of 80 coloproctologists. The study enrolled consecutive patients with complaints of hemorrhoids. All were prescribed MPFF-based conservative treatment. The effect of treatment on HD clinical signs and symptoms was assessed at two follow-up visits performed 5–7 days and 25–30 days after enrollment. Surgical and minimally invasive treatment could be performed from day 7 onwards if required.

Results

A total of 1952 patients were enrolled. Over the entire period of observation, MPFF-based conservative treatment was effective in 1489 (76.3%) patients in eliminating the main clinical manifestations of disease, i.e., bleeding and prolapse of internal nodes. Invasive treatment was performed in 68 (3.5%) patients with grade IV hemorrhoids and was combined with MPFF conservative treatment in 395 (20.2%) patients with grades I–III hemorrhoids.

Conclusion

Conservative therapy with MPFF was beneficial for relieving hemorrhoidal symptoms in the majority of patients. MPFF-based treatment was most effective in patients with grade I and II hemorrhoids before irreversible degenerative changes in ligaments of the hemorrhoidal plexuses have occurred. It was also beneficial in preventing disease relapse in patients with more advanced HD and for promoting optimal conditions in the postoperative period.

Funding

Servier.