The effects of losartan or angiotensin II receptor antagonists on cartilage: a systematic review.

OBJECTIVE: The aim of this study is to analyze the latest evidence on the effects of losartan or Ang II receptor antagonists on cartilage repair, with a focus on their clinical relevance. DESIGN: The PubMed, Embase, and Cochrane Library databases were searched up to November 12th 2021 to evaluate the effects of losartan or Ang II receptor antagonists on cartilage repair in in vitro studies and in vivo animal studies. Study design, sample characteristics, treatment type, duration, and outcomes were analyzed. The risk of bias and the quality of the eligible studies were assessed using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) risk of bias assessment tool and Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES). RESULTS: A total of 12 studies were included in this systematic review. Of the 12 eligible studies, two studies were in vitro human studies, three studies were in vitro animal studies, one study was an in vitro human and animal study, and six studies were in vivo animal studies. The risk bias and quality assessments were predominantly classified as moderate. Since meta-analysis was difficult due to differences in treatment type, dosage, route of administration, and method of outcome assessment among the eligible studies, qualitative evaluation was conducted for each study. CONCLUSIONS: Both in vitro and in vivo studies provide evidence to demonstrate beneficial effects of Ang II receptor antagonists on osteoarthritis and cartilage defect models across animal species.

Emergence of a Magnetostructural Dipolar Glass in the Quadruple Perovskite Dy_{1-δ}Mn_{7+δ}O_{12}.

We show that a polar, pseudo-Jahn-Teller instability exists for the underbonded rare-earth A-site cations in the quadruple perovskite Dy_{1-δ}Mn_{7+δ}O_{12}, which leads to the spontaneous formation of a dipolar glass. This observation alone expands the applicability of pseudo-Jahn-Teller physics in perovskite-derived materials, for which it is typically confined to B-site cations. We demonstrate that the dipolar glass order parameter is coupled to a ferrimagnetic order parameter via strain, leading to a first order magnetostructural phase transition that can be tuned by magnetic field. This phenomenology may emerge in a broad range of perovskite-derived materials in which A-site cation ordering and octahedral tilting are mutually tied to meet the criteria of structural stability.

Evaluation of apocynin in vitro on high glucose-induced oxidative stress on tenocytes.

AIMS: The purpose of this study was to evaluate the in vitro effects of apocynin, an inhibitor of nicotinamide adenine dinucleotide phosphate oxidase (NOX) and a downregulator of intracellular reactive oxygen species (ROS), on high glucose-induced oxidative stress on tenocytes. METHODS: Tenocytes from normal Sprague-Dawley rats were cultured in both control and high-glucose conditions. Apocynin was added at cell seeding, dividing the tenocytes into four groups: the control group; regular glucose with apocynin (RG apo+); high glucose with apocynin (HG apo+); and high glucose without apocynin (HG apo-). Reactive oxygen species production, cell proliferation, apoptosis and messenger RNA (mRNA) expression of NOX1 and 4, and interleukin-6 (IL-6) were determined in vitro. RESULTS: Expression of NOX1, NOX4, and IL-6 mRNA in the HG groups was significantly higher compared with that in the RG groups, and NOX1, NOX4, and IL-6 mRNA expression in the HG apo+ group was significantly lower compared with that in the HG apo- group. Cell proliferation in the RG apo+ group was significantly higher than in the control group and was also significantly higher in the HG apo+ group than in the HG apo- group. Both the ROS accumulation and the amounts of apoptotic cells in the HG groups were greater than those in the RG groups and were significantly less in the HG apo+ group than in the HG apo- group. CONCLUSION: Apocynin reduced ROS production and cell death via NOX inhibition in high-glucose conditions. Apocynin is therefore a potential prodrug in the treatment of diabetic tendinopathy.Cite this article: Bone Joint Res 2020;9(1):23-28.

Evidence for the weakly coupled electron mechanism in an Anderson-Blount polar metal.

Over 50 years ago, Anderson and Blount proposed that ferroelectric-like structural phase transitions may occur in metals, despite the expected screening of the Coulomb interactions that often drive polar transitions. Recently, theoretical treatments have suggested that such transitions require the itinerant electrons be decoupled from the soft transverse optical phonons responsible for polar order. However, this decoupled electron mechanism (DEM) has yet to be experimentally observed. Here we utilize ultrafast spectroscopy to uncover evidence of the DEM in LiOsO3, the first known band metal to undergo a thermally driven polar phase transition (Tc ≈ 140 K). We demonstrate that intra-band photo-carriers relax by selectively coupling to only a subset of the phonon spectrum, leaving as much as 60% of the lattice heat capacity decoupled. This decoupled heat capacity is shown to be consistent with a previously undetected and partially displacive TO polar mode, indicating the DEM in LiOsO3.

Efficacy of programmed intermittent bolus epidural analgesia in thoracic surgery: a randomized controlled trial.

BACKGROUND: Continuous epidural infusion (CEI) has some disadvantages, such as increased local anesthetic consumption and limited area of anesthetic distribution. Programmed intermittent bolus (PIB) is a technique of epidural anesthesia in which boluses of local anesthetic are automatically injected into the epidural space. The usefulness of PIB in thoracic surgery remains unclear. In this study, we aimed to compare the efficacies of PIB epidural analgesia and CEI in patients undergoing thoracic surgery. METHODS: This randomized prospective study was approved by the Institutional Review Board. The study included 42 patients, who were divided into CEI (n = 21) and PIB groups (n = 21). In the CEI group, patients received continuous infusion of the local anesthetic at a rate of 5.1 mL/90 min. In the PIB group, a pump delivered the local anesthetic at a dose of 5.1 mL every 90 min. The primary endpoints were the frequency of patient-controlled analgesia (PCA) and the total dose of local anesthetic until 36 h following surgery. Student's t-test, the chi-square test, and the Mann-Whitney U test were used for statistical analyses. RESULTS: The mean number of PCA administrations and total amount of local anesthetic were not significantly different between the two groups up to 24 h following surgery. However, the mean number of PCA administrations and total amount of local anesthetic at 24-36 h after surgery were significantly lower in the PIB group than in the CEI group (median [lower-upper quartiles]: 0 [0-2.5] vs. 2 [0.5-5], P = 0.018 and 41 [41-48.5] vs. 47 [43-56], P = 0.035, respectively). Hypotension was significantly more frequent in the PIB group than in the CEI group at 0-12 h and 12-24 h (3.3% vs. 0.5%, P = 0.018 and 7.9% vs. 0%, P = 0.017, respectively). CONCLUSION: PIB can reduce local anesthetic consumption in thoracic surgery. However, it might result in adverse events, such as hypotension. TRIAL REGISTRATION: This randomized prospective study was approved by the Institutional Review Board (IRB No. 15-9-06) of the Fukuoka University Hospital, Fukuoka, Japan, and was registered in the clinical trials database UMIN ( ID 000019904 ) on 24 November 2015. Written informed consent was obtained from all patients.

Evolution of the Magnetic Excitations in NaOsO_{3} through its Metal-Insulator Transition.

The temperature dependence of the excitation spectrum in NaOsO_{3} through its metal-to-insulator transition (MIT) at 410 K has been investigated using resonant inelastic x-ray scattering at the Os L_{3} edge. High-resolution (ΔE∼56 meV) measurements show that the well-defined, low-energy magnons in the insulating state weaken and dampen upon approaching the metallic state. Concomitantly, a broad continuum of excitations develops which is well described by the magnetic fluctuations of a nearly antiferromagnetic Fermi liquid. By revealing the continuous evolution of the magnetic quasiparticle spectrum as it changes its character from itinerant to localized, our results provide unprecedented insight into the nature of the MIT in NaOsO_{3} [J. G. Vale, S. Calder, C. Donnerer, D. Pincini, Y. G. Shi, Y. Tsujimoto, K. Yamaura, M. M. Sala, J. van den Brink, A. D. Christianson, and D. F. McMorrow, Phys. Rev. B 97, 184429 (2018)PRBMDO2469-995010.1103/PhysRevB.97.184429].

Fibrinolysis in Living Donor Liver Transplantation Recipients Evaluated Using Thromboelastometry: Impact on Mortality.

BACKGROUND: Inadequate hemostasis during living donor liver transplantation (LDLT) is mainly due to coagulopathy but may also include fibrinolysis. The purpose of this study was to determine the incidence of fibrinolysis and assess its relevance to mortality in LDLT. METHODS: The incidence and prognosis of fibrinolysis were retrospectively studied in 76 patients who underwent LDLT between April 2010 and February 2013. Fibrinolysis was evaluated and defined by maximum lysis (ML) >15% within a 60-minute run time using thromboelastometry (ROTEM). RESULTS: Fibrinolysis was observed in 19 of the 76 (25%) patients before the anhepatic (pre-anhepatic) phase and was developed in 24 (32%) patients during and after the anhepatic (post-anhepatic) phase. In these 43 patients who had fibrinolysis, spontaneous recovery occurred in 29 patients (73%) within 3 hours after reperfusion of the liver graft. Recovery with tranexamic acid was noted in 2 patients with fibrinolysis in the post-anhepatic phase. Thrombosis in the portal vein and liver artery was noted in 14 patients, and the incidence was significantly greater in patients with post-anhepatic fibrinolysis than in those with pre-anhepatic fibrinolysis (P = .0017). Fibrinolysis that developed in the pre-anhepatic phase was associated with increased 30-day and 6-month mortalities (P = .0003 and .0026, respectively). CONCLUSIONS: Fibrinolysis existed and developed in a large percentage of patients during LDLT. Thrombosis in the portal vein and hepatic artery was more common in patients with fibrinolysis in the post-anhepatic phase. Fibrinolysis that developed in the pre-anhepatic phase was associated with increased 30-day and 6-month mortalities.

Spin-Orbit Coupling Controlled J=3/2 Electronic Ground State in 5d

Entanglement of spin and orbital degrees of freedom drives the formation of novel quantum and topological physical states. Here we report resonant inelastic x-ray scattering measurements of the transition metal oxides Ca_{3}LiOsO_{6} and Ba_{2}YOsO_{6}, which reveals a dramatic spitting of the t_{2g} manifold. We invoke an intermediate coupling approach that incorporates both spin-orbit coupling and electron-electron interactions on an even footing and reveal that the ground state of 5d^{3}-based compounds, which has remained elusive in previously applied models, is a novel spin-orbit entangled J=3/2 electronic ground state. This work reveals the hidden diversity of spin-orbit controlled ground states in 5d systems and introduces a new arena in the search for spin-orbit controlled phases of matter.

Enhanced spin-phonon-electronic coupling in a 5d oxide.

Enhanced coupling of material properties offers new fundamental insights and routes to multifunctional devices. In this context 5d oxides provide new paradigms of cooperative interactions that drive novel emergent behaviour. This is exemplified in osmates that host metal-insulator transitions where magnetic order appears intimately entwined. Here we consider such a material, the 5d perovskite NaOsO3, and observe a coupling between spin and phonon manifested in a frequency shift of 40 cm(-1), the largest measured in any material. The anomalous modes are shown to involve solely Os-O interactions and magnetism is revealed as the driving microscopic mechanism for the phonon renormalization. The magnitude of the coupling in NaOsO3 is primarily due to a property common to all 5d materials: the large spatial extent of the ion. This allows magnetism to couple to phonons on an unprecedented scale and in general offers multiple new routes to enhanced coupled phenomena in 5d materials.

The charge carrier localization in the cubic perovskite BaOsO3 revealed by an optical study.

We present the optical conductivity spectra for the newly discovered cubic perovskite structure BaOsO3 at various temperatures. The compound exhibits metallic behaviour above 50 K, but becomes non-metallic below 50 K. However, below 550 cm(-1), neither the typical Drude response nor an energy gap is observed in optical conductivity spectra from 300 K to 10 K. A broad peak centred at about 550 cm(-1) is observed in the real part of optical conductivity σ1(ω). The structure could be well reproduced by the localization modified Drude model. The life time of the carrier, deduced from σ1(ω) in terms of the localization modified Drude model, decreases with T varying from 300 K to 100 K, then increases slightly at 10 K. The study indicates that the compound is at the boundary of metal-insulator transition.

New members of layered oxychloride perovskites with square planar coordination: Sr2MO2Cl2 (M = Mn, Ni) and Ba2PdO2Cl2.

New members of Ruddlesden-Popper type layered oxychloride compounds, Sr2MO2Cl2 (M = Mn, Ni) and Ba2PdO2Cl2, were synthesized under high-pressure conditions. Synchrotron XRD analysis revealed that all the phases adopt the tetragonal space group I4/mmm, where two-dimensional sheets composed of corner-sharing MO4/PdO4 squares were separated by rock-salt SrCl/BaCl layers.

Infrared evidence of a Slater metal-insulator transition in NaOsO3.

The magnetically driven metal-insulator transition (MIT) was predicted by Slater in the fifties. Here a long-range antiferromagnetic (AF) order can open up a gap at the Brillouin electronic band boundary regardless of the Coulomb repulsion magnitude. However, while many low-dimensional organic conductors display evidence for an AF driven MIT, in three-dimensional (3D) systems the Slater MIT still remains elusive. We employ terahertz and infrared spectroscopy to investigate the MIT in the NaOsO3 3D antiferromagnet. From the optical conductivity analysis we find evidence for a continuous opening of the energy gap, whose temperature dependence can be well described in terms of a second order phase transition. The comparison between the experimental Drude spectral weight and the one calculated through Local Density Approximation (LDA) shows that electronic correlations play a limited role in the MIT. All the experimental evidence demonstrates that NaOsO3 is the first known 3D Slater insulator.

Diastolic dysfunction of the left ventricle is associated with pulmonary edema after renal transplantation.

BACKGROUND: Post-operative pulmonary complications are associated with high mortality and graft loss in renal transplantation recipients. Left ventricular diastolic dysfunction is not uncommon in patients with chronic renal failure, including those with preserved left ventricular systolic function. The purpose of this study was to determine the relationship between left ventricular diastolic dysfunction and incidence of post-operative pulmonary edema in renal transplantation recipients with preserved left ventricular systolic function. METHODS: Pre-operative left ventricular function and incidence of pulmonary edema were retrospectively studied in 209 patients who underwent living-donor renal transplantation between January 2010 and October 2012. Left ventricular systolic and diastolic functions were evaluated by ejection fraction and E/E' ratio, retrospectively, using transthoracic echocardiography. Pulmonary edema was defined by evidence of pulmonary congestion on the chest X-ray together with PaO2 /FiO2 ratio < 300 mmHg. RESULTS: Eleven out of 190 (5.8%) renal transplantation patients with preserved left ventricular systolic function developed post-operative pulmonary edema. Patients with pulmonary edema had a significantly higher geometric mean (95% confidence interval) of E/E' ratio than those without pulmonary edema [17.8 (14.1-22.5) vs. 11.1 (10.6-11.7), P = 0.001]. CONCLUSION: Pre-operative left ventricular diastolic dysfunction correlated with the development of post-operative pulmonary edema in renal transplantation recipients. Meticulous intraoperative volume therapy is important to avoid post-operative pulmonary edema in such patients.

Magnetically driven metal-insulator transition in NaOsO3.

The metal-insulator transition (MIT) is one of the most dramatic manifestations of electron correlations in materials. Various mechanisms producing MITs have been extensively considered, including the Mott (electron localization via Coulomb repulsion), Anderson (localization via disorder), and Peierls (localization via distortion of a periodic one-dimensional lattice) mechanisms. One additional route to a MIT proposed by Slater, in which long-range magnetic order in a three dimensional system drives the MIT, has received relatively little attention. Using neutron and x-ray scattering we show that the MIT in NaOsO(3) is coincident with the onset of long-range commensurate three dimensional magnetic order. While candidate materials have been suggested, our experimental methodology allows the first definitive demonstration of the long predicted Slater MIT.

In vivo function of immune inhibitory molecule B7-H4 in alloimmune responses.

B7 ligands deliver both costimulatory and coinhibitory signals to the CD28 family of receptors on T lymphocytes, the balance between which determines the ultimate immune response. Although B7-H4, a recently discovered member of the B7 family, is known to negatively regulate T cell immunity in autoimmunity and cancer, its role in solid organ allograft rejection and tolerance has not been established. Targeting the B7-H4 molecule by a blocking antibody or use of B7-H4(-/-) mice as recipients of fully MHC-mismatched cardiac allografts did not affect graft survival. However, B7-H4 blockade resulted in accelerated allograft rejection in CD28-deficient recipients. B7-1/B7-2-double-deficient recipients are truly independent of CD28/CTLA-4:B7 signals and usually accept MHC-mismatched heart allografts. Blockade of B7-H4 in these mice also precipitated rejection, demonstrating regulatory function of this molecule independent of an intact CD28/CTLA-4:B7 costimulatory pathway. Accelerated allograft rejection was always accompanied by increased frequencies of alloreactive IFN-γ-, IL-4- and Granzyme B-producing splenocytes. Finally, intact recipient, but not donor, B7-H4 is essential for prolongation of allograft survival by blocking CD28/CTLA4:B7 pathway using CTLA4-Ig. These data are the first to provide evidence of the regulatory effects of B7-H4 in alloimmune responses in a murine model of solid organ transplantation.

Differential requirement of CD27 costimulatory signaling for naïve versus alloantigen-primed effector/memory CD8+ T cells.

CD8(+) memory T cells endanger allograft survival by causing acute and chronic rejection and prevent tolerance induction. We explored the role of CD27:CD70 T-cell costimulatory pathway in alloreactive CD8(+)/CD4(+) T-cell activation. CD27-deficient (CD27(-/-)) and wild-type (WT) B6 mice rejected BALB/c cardiac allografts at similar tempo, with or without depletion of CD4(+) or CD8(+) T cells, suggesting that CD27 is not essential during primary T-cell alloimmune responses. To dissect the role of CD27 in primed effector and memory alloreactive T cells, CD27(-/-) or WT mice were challenged with BALB/c hearts either 10 or 40 days after sensitization with donor-type skin grafts. Compared to WT controls, allograft survival was prolonged in day 40- but not day 10-sensitized CD27(-/-) recipients. Improved allograft survival was accompanied by diminished secondary responsiveness of memory CD8(+) T cells, which resulted from deficiency in memory formation rather than their lack of secondary expansion. Chronic allograft vasculopathy and fibrosis were diminished in CD27(-/-) recipients of class I- but not class II-mismatched hearts as compared to WT controls. These data establish a novel role for CD27 as an important costimulatory molecule for alloreactive CD8(+) memory T cells in acute and chronic allograft rejection.

NaV2O4: a quasi-1D metallic antiferromagnet with half-metallic chains.

NaV2O4 crystals were grown under high pressure using a NaCl flux, and the crystals were characterized with x-ray diffraction, electrical resistivity, heat capacity, and magnetization. The structure of NaV2O4 consists of double chains of edge-sharing VO6 octahedra. The resistivity is highly anisotropic, with the resistivity perpendicular to the chains more than 20 times greater than that parallel to the chains. Magnetically, the intrachain interactions are ferromagnetic and the interchain interactions are antiferromagnetic; 3D antiferromagnetic order is established at 140 K. First-principles electronic structure calculations indicate that the chains are half-metallic. Interestingly, the case of NaV2O4 seems to be a quasi-1D analogue of what was found for half-metallic materials.

Contribution of epoxyeicosatrienoic acids to the hypoxia-induced activation of Ca2+ -activated K+ channel current in cultured rat hippocampal astrocytes.

Brief hypoxia differentially regulates the activities of Ca(2+)-activated K(+) channels (K(Ca)) in a variety of cell types. We investigated the effects of hypoxia (<2% O(2)) on K(Ca) channel currents and on the activities of cytochrome P450 2C11 epoxygenase (CYP epoxygenase) in cultured rat hippocampal astrocytes. Exposure of astrocytes to hypoxia enhanced macroscopic outward K(Ca) current, increased the open state probability (NPo) of 71 pS and 161 pS single-channel K(Ca) currents in cell-attached patches, but failed to increase the NPo of both the 71 pS and 161 pS K(Ca) channel currents recorded from excised inside-out patches. The hypoxia-induced enhancement of macroscopic K(Ca) current was attenuated by pretreatment with tetraethylammonium (TEA, 1 mM) or during recording using low-Ca(2+) external bath solution. Exposure of astrocytes to hypoxia was associated with generation of superoxide as detected by staining of cells with the intracellular superoxide detection probe hydroethidine (HE), attenuation of the hypoxia-induced activation of unitary K(Ca) channel currents by superoxide dismutation with tempol, and as quantitated by high-pressure liquid chromatography/fluorescence assay using HE as a probe. In cultured astrocytes in which endogenous CYP epoxygenase activity has been inhibited with either miconazole or N-methylsulfonyl-6-(2-propargyloxyphenyl) hexanamide (MSPPOH) hypoxia failed to increase the NPo of both the 71 pS and 161 pS K(Ca) currents and generation of superoxide. Hypoxia increased the level of P450 epoxygenase protein and production of epoxyeicosatrienoic acids (EETs) from cultured astrocytes, as determined by immunohistochemical staining and LC/MS analysis, respectively. Exogenous 11,12-EET increased the NPo of both the 71 pS and 161 pS K(Ca) single-channel currents only in cell-attached but not in excised inside-out patches of cultured astrocytes. These findings indicate that hypoxia enhances the activities of two types of unitary K(Ca) currents in astrocytes by a mechanism that appears to involve CYP epoxygenase-dependent generation of superoxide and increased production or release of EETs.

Effect of coronary artery bypass grafting with gastroepiploic artery on gastric intramucosal pH and systemic inflammation.

BACKGROUND: The purpose of this study was to investigate the effect of coronary arterial bypass grafting (CABG) with gastroepiploic artery (GEA) on gastric intramucosal pH and systemic inflammation. DESIGN: retrospective study. SETTING: University hospital. PARTICIPANTS: 22 patients underwent CABG. INVESTIGATIONS: the GEA group (n=13) received CABG with the GEA graft. The non-GEA group (n=9) received conventional CABG without the GEA graft. MEASUREMENTS: gastric intramucosal pH (pHi) and carbon dioxide tension (PrCO(2)) were assessed by capnometric air tonometry. The difference between PrCO(2) and PaCO(2), PCO(2)-gap, was also determined. Systemic inflammatory responses were evaluated by serum interleukin-6 (IL-6) and leucocyte counts. Hemodynamics, oxygen delivery index (DO(2)I) and uptake index (VO(2)I) were monitored with catheters in the radial and pulmonary arteries (thermodilution). RESULTS: The duration of aortic cross-clamping and cardiopulmonary bypass was similar in both groups. Both groups did not show any significant difference in gastric pHi, PCO(2)-gap, systemic inflammation and hemodynamics. CONCLUSIONS: Our findings suggest that CABG using the GEA graft does not disturb gastric mucosal perfusion, and that laparotomy for the GEA graft does not aggravate systemic oxygen demand-supply imbalance or systemic inflammatory responses induced by hypothermic CPB. CABG with the GEA graft does not seem to pose an additional risk and is a safe technique compared with conventional CABG with regard to pHi and systemic inflammation.

Effect of low-dose milrinone on gastric intramucosal pH and systemic inflammation after hypothermic cardiopulmonary bypass.

OBJECTIVE: To investigate the usefulness of low-dose milrinone on gastric intramucosal pH (pHi) and systemic inflammation in patients undergoing hypothermic cardiopulmonary bypass (CPB). DESIGN: Prospective randomized study. SETTING: University hospital. PARTICIPANTS: Twenty patients scheduled for cardiac surgery. INTERVENTIONS: Ten patients were administered a low dose of milrinone, 0.25 microg/kg/min, from the initiation of CPB to 1 hour after admission to the intensive care unit. The other patients were administered saline. Supplemental inotropes and intravenous fluid were given to obtain adequate mean arterial blood pressure and pulmonary artery occlusion pressure. MEASUREMENTS AND RESULTS: Gastric pHi and carbon dioxide pressure (PCO2) were assessed by capnometric air tonometry. The difference between PCO2 and arterial carbon dioxide pressure (PaCO2), PCO2-gap, was also examined. Systemic inflammatory responses were evaluated by serum interleukin-6 and leukocyte counts. Hemodynamics, oxygen delivery index, and oxygen uptake index were monitored with catheters in the radial and pulmonary arteries (thermodilution). The hepatic venous blood flow and left ventricular flow were measured using transesophageal echocardiography. Milrinone prevented gastric intramucosal acidosis, detected as a decrease in pHi or an increase in PCO2-gap, without affecting hepatic venous blood flow. Increases in interleukin-6, leukocyte count, and oxygen uptake index, all of which developed after CPB, were significantly less in the milrinone group than in the control group. CONCLUSION: These results suggest that in patients undergoing hypothermic CPB, supplemental low-dose milrinone prevents gastric intramucosal acidosis and increases in some markers of systemic inflammation.