Patients with the most advanced rheumatoid arthritis remain with Th1 systemic defects after TNF inhibitors treatment despite clinical improvement

Systemic immune defects might reflect severely dysregulated control of chronic inflammation related to disease progression. Th17/Treg cell imbalance has been demonstrated to be involved in rheumatoid arthritis (RA) pathogenesis. Despite controversial results, a growing anti-inflammatory role in this process has been recently attributed to Th1 responses. The aim of the study was to estimate the extent of Th1/Th17/Treg imbalance in peripheral blood (PB) of patients with short- and long-term RA in relation to cytokine milieu and its reversal after therapy with methotrexate and/or TNF inhibitors, respectively. Patients with different duration of RA (median 6 vs. 120 months) in the active phase of RA were enrolled in this study. We performed flow cytometric analysis of PB Th1, Th17, and Treg populations together with estimation of serum cytokine concentrations using cytometric bead array. Disease activity was calculated on the basis of clinical and biochemical indices of inflammation (DAS28, ESR, CRP). All parameters were measured and correlated with each other before and after 6 months therapy. Elevated levels of circulating Th17 cells and IL-6 were found in all active patients, of which Th17 cells were down-regulated by the treatment. Significantly reduced Th1 and functional CTLA-4+ Treg cell frequencies as well as Th1 cytokines observed only in progressive RA seemed to be irreversible. Although therapy induced clinical improvement in almost all patients, those with advanced RA remained with signs of inflammation. Our report demonstrates that both the extent of systemic immune abnormalities and their restoration are dependent on duration of the active RA.     

N-acylhydrazone derivative ameliorates monocrotaline-induced pulmonary hypertension through the modulation of adenosine AA2R activity

Background

Pulmonary arterial hypertension (PAH) is a disease that results in right ventricular (RV) dysfunction. While pulmonary vascular disease is the primary pathological focus, RV hypertrophy and RV dysfunction are the major determinants of prognosis in PAH. The aim of this study was to investigate the effects of (E)-N′-(3,4-dimethoxybenzylidene)-4-methoxybenzohydrazide (LASSBio-1386), an N-acylhydrazone derivative, on the lung vasculature and RV dysfunction induced by experimental PAH.

Methods

Male Wistar rats were injected with a single dose (60 mg/kg, i.p.) of monocrotaline (MCT) and given LASSBio-1386 (50 mg/kg, p.o.) or vehicle for 14 days. The hemodynamic, exercise capacity (EC), endothelial nitric oxide synthase (eNOS), adenosine A_2A receptor (A_2AR), sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a), phospholamban (PLB) expression, Ca^2 +-ATPase activity and vascular activity of LASSBio-1386 were evaluated.

Results and conclusions

The RV systolic pressure was elevated in the PAH model and reduced from 49.6 ± 5.0 mm Hg (MCT group) to 27.2 ± 2.1 mm Hg (MCT + LASSBio-1386 group; P < 0.05). MCT administration also impaired the EC, increased the RV and pulmonary arteriole size, and promoted endothelial dysfunction of the pulmonary artery rings. In the PAH group, the eNOS, A_2AR, SERCA2a, and PLB levels were changed compared with the control; in addition, the Ca^2 +-ATPase activity was reduced. These alterations were related with MCT-injected rats, and LASSBio-1386 had favorable effects that prevented the development of PAH. LASSBio-1386 is effective at preventing endothelial and RV dysfunction in PAH, a finding that may have important implications for ongoing clinical evaluation of A_2AR agonists for the treatment of PAH.     

Long-term response to imatinib is not affected by the initial dose in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: final update from the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) study

The TOPS trial evaluated high- (800 mg/day; n = 319) versus standard-dose (400 mg/day; n = 157) imatinib in patients newly diagnosed with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase. Patients had a minimum follow-up of 42 months or discontinued early. Major molecular response (MMR) rates were similar between arms at (51.6 vs 50.2 % for 400 and 800 mg/day, respectively; P = 0.77) and by (75.8 vs 79.0 %; P = 0.4807) 42 months. There were no differences in event-free survival (EFS), progression-free survival (PFS), or overall survival (OS) between arms. The estimated rates of PFS on treatment and OS at 42 months were significantly higher in patients with MMR at 6, 12, and 18 months compared with those without MMR. Adverse events were more frequent with high-dose imatinib. Patients with ≤1 treatment interruption (vs >1) and those able to maintain imatinib ≥600 mg/day (vs <600 mg/day) in the first year of treatment had faster and higher response rates, but no improvement in EFS or PFS. Adherence to prescribed dose without interruption may be more important than initiation of therapy with higher doses of imatinib. Achievement of MMR correlated with long-term clinical outcomes.     

Enhancement in sustained friction and wear resistance of nanoporous aluminum oxide films obtained by controlled electrochemical oxidation process

The primary purpose of this study is to investigate the effect of the electrochemical parameters required in the anodic oxidation process on the friction and wear resistance of the obtained nanoporous aluminum oxide films. The wear resistance of the aluminum oxide films and the electrochemically polished Al1050 alloy were tested using a ball-on-disc tribometer having a corundum ball as counterbody in dry conditions. The friction coefficient graphs were recorded during wear tests at a 5 N normal force simulating the application of nanoporous aluminum oxide films in industrial areas requesting moderate wear resistance. The wear tracks formed on the tested surfaces were analyzed ex situ both qualitatively and quantitatively. Higher wear resistance is showed by nanoporous aluminum oxide films as compared with electro polished Al1050 alloy substrate.

The primary purpose of this study is to investigate the effect of the electrochemical parameters required in the anodic oxidation process on the friction and wear resistance of the obtained nanoporous aluminum oxide films.     

Clinical evaluation of hyponatremia and hypovolemia in critically ill adult neurologic patients: contribution of the use of cumulative balance of sodium

Purpose

Knowledge of the cumulative balance of sodium (CBS) is important for the diagnosis of salt disorders and water homeostasis and has the potential to predict hypovolemic status in acute neurological patients. However, an extensive application of the use of CBS is still lacking in the intensive care setting, where salt and water homeostasis represents a priority.

Methods

Records of consecutive series of acute neurological patients admitted to a neurointensive care unit over a 6-month period were retrospectively reviewed. CBS was calculated at the admission to the Emergency Department. Discrimination between cerebral salt-wasting syndrome (CSWS) and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) was performed on the basis of the classical criteria. Additionally, we used the findings of a negative CBS exceeding 2 mEq/kg for the diagnosis of CSWS. Two independent clinicians who were blinded to the CBS results performed diagnosis of the causes of hyponatremia and estimated the daily volemic status of the patients on the basis of clinical parameters. Logistic regression analysis was used to determine the independent prognostic factors of hypovolemia.

Results

Thirty-five patients were studied for a total of 418 days. Four patients (11.4 %) fitted the criteria of CSWS and three patients (8.5 %) had SIADH. The unavailability of the CBS led to a wrong diagnosis in three of the eight hyponatremic patients (37.5 %). The risk of developing hypovolemia in patients with negative CBS was 7.1 times higher (CI 3.86–13.06; p < 0.001). Multivariate analysis revealed that negative cumulative fluid balance, negative CBS >2 mEq/kg, and CVP ≤5 cmH₂O were independent prognostic factors for hypovolemia.

Conclusions

CBS is likely to be a useful parameter in the diagnosis of CSWS and a surrogate parameter for estimating hypovolemia in acute neurological patients.     

The choroid plexus stroma constitutes a sanctuary for paediatric B-cell precursor acute lymphoblastic leukaemia in the central nervous system

Despite current central nervous system-directed therapies for childhood B-cell precursor acute lymphoblastic leukaemia, relapse at this anatomical site still remains a challenging issue. Few reports have addressed the study of the specific cellular microenvironments which can promote the survival, quiescence, and therefore chemoresistance of B-cell precursor acute lymphoblastic leukaemia cells in the central nervous system. Herein, we showed by immunofluorescence and electron microscopy that in xenotransplanted mice, leukaemic cells infiltrate the connective tissue stroma of the choroid plexus, the brain structure responsible for the production of cerebrospinal fluid. The ultrastructural study also showed that leukaemia cells are able to migrate through blood vessels located in the choroid plexus stroma. In short-term co-cultures, leukaemic cells established strong interactions with human choroid plexus fibroblasts, mediated by an increased expression of ITGA4 (VLA-4)/ITGAL (LFA-1) and their ligands VCAM1/ICAM1. Upon contact with leukaemia cells, human choroid plexus fibroblasts acquired a cancer-associated fibroblast phenotype, with an increased expression of α-SMA and vimentin as well as pro-inflammatory factors. Human choroid plexus fibroblasts also have the capacity to reduce the proliferative index of leukaemic blasts and promote their survival and chemoresistance to methotrexate and cytarabine. The inhibition of VLA-4/VCAM-1 interactions using anti-VLA-4 antibodies, and the blockade of Notch signalling pathway by using a γ-secretase inhibitor partially restored chemotherapy sensitivity of leukaemia cells. We propose that the choroid plexus stroma constitutes a sanctuary for B-cell precursor acute lymphoblastic leukaemia cells in the central nervous system. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.     

Effect of adhesion boosters on indirect bracket bonding

Objective:To determine the influence of two adhesion boosters on shear bond strength and on the bond failure location of indirectly bonded brackets.Materials and Methods:Sixty bovine incisors were randomly divided into three groups (n  =  20), and their buccal faces were etched using 37% phosphoric acid. In group 1 (control), brackets were indirectly bonded using only Sondhi adhesive. In groups 2 and 3, the adhesion boosters Enhance Adhesion Booster and Assure Universal Bonding Resin, respectively, were applied before bonding with Sondhi. Maximum bond strength was measured with a universal testing machine, and the location of bond failure was evaluated using the Adhesive Remnant Index (ARI). One-way analysis of variance followed by the Tukey test (P < .05) was used to compare the shear bond strength among groups, and the differences in ARI scores were evaluated using the Kruskal-Wallis test (P < .05). The Pearson correlation coefficient was calculated to determine whether there was any correlation between bond strength and ARI scores.Results:The mean shear bond strength in group 3 was significantly higher (P < .01) than in the other groups. Evaluation of the locations of bond failure revealed differences (P < .05) among the three groups. There was a moderate correlation between bond strength and ARI scores within group 3 (r  =  0.5860, P < .01).Conclusion:In vitro shear bond strength was acceptable in all groups. The use of the Assure adhesion booster significantly increased both the shear bond strength of indirectly bonded brackets and the amount of adhesive that remained on the enamel after bracket debonding.