Multidimensional CT approach to predict hemodynamics in pulmonary hypertension.

AIM: Computed tomographic pulmonary angiography (CTPA) allows an excellent visualization of heart chambers and vessels, which may be associated with hemodynamic status in pulmonary hypertension, obviating the need for repetitive right heart catheterization (RHC). In this study, we aimed to evaluate the capacity of CTPA to predict severe hemodynamics and to correlate with clinical status and events. MATERIAL AND METHODS: Retrospective study with 51 patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) in whom a CTPA and RHC were performed within 6 months. The primary endpoint was to evaluate the CTPA performance to predict severe hemodynamics, defined as the best mPAP threshold with clinical impact. Secondary endpoints were the correlation of CTPA measurements with clinical outcomes. RESULTS: The right ventricle (RV) and right atrium (RA) areas, RV-free wall thickness, septal angle and pulmonary artery diameter assessed by CTPA revealed a good capacity to predict severe hemodynamic status. A CTPA model, incorporating both an RV area above 23 cm2 and an RA area above 21 cm2, increased the prediction capacity to detect severe hemodynamic status. The presence of both parameters above the threshold predicted severe PH with a 100% specificity and a 52% sensitivity and conveyed a 5-fold increased risk of mortality during follow-up. CTPA-altered parameters were directly associated with higher NT-proBNP levels and worse WHO-FC at baseline and follow-up. CONCLUSION: In this pilot study, a CTPA model was able to predict severe PH hemodynamic status and worse clinical events during follow-up.

Development of inhaled moxifloxacin-metformin formulation as an alternative for pulmonary tuberculosis treatment.

Resistant M. tuberculosis strains threaten pulmonary tuberculosis (P-TB) control since they limit drug options. Drug repositioning and new development strategies are urgently required to overcome resistance. Studies have already shown the beneficial role of the oral antidiabetic metformin as an anti-tuberculosis adjuvant drug. This work aimed to develop an inhalatory dry powder co-formulation of metformin and moxifloxacin to figure out a future option for P-TB treatment. Pre-formulation evaluations indicated the physicochemical compatibility of constituents, demonstrating powder crystallinity and acceptable drug content. Eight moxifloxacin-metformin dry powder formulations were produced by spray drying, and solid-state characterizations showed partial amorphization, ascribed to moxifloxacin. Four formulations containing L-leucine exhibited micromeritic and in vitro deposition profiles indicating pulmonary delivery suitability, like spherical and corrugated particle surface, geometric diameters < 5 µm, high emitted doses (>85 %), and mass median aerodynamic diameters between 1-5 µm. The use of a second spray dryer model further optimized the aerodynamic properties and yield of the best formulation, demonstrating the influence of the equipment used on the product obtained. Moreover, the final formulation showed high in vitro cell tolerability and characteristics in permeability studies indicative of good drug retention in the lungs.

Chronic Aerobic Training at Different Volumes in the Modulation of Macrophage Function and in vivo Infection of BALB/c Mice by Leishmania major.

Physical inactivity is one of the main causes of chronic diseases; however, strenuous exercise can induce immunosuppression. Several studies suggest that moderate amounts of exercise lead to a Th1 response, favoring the resolution of infections caused by intracellular microorganisms, while high volumes of exercise tend to direct the response to Th2, favoring infection by them. Leishmaniasis is a parasitic disease promoted by parasites of the Leishmania genus, with clinical manifestations that vary according to the species of the parasite and the immune response of the host. The experimental Leishmania major-BALB/C mouse model provides a good model for the resistance (Th1 response) or susceptibility (Th2 response) that determines the progression of this infection. The aim of this study was to evaluate the effect of aerobic training at different volumes on modulation of in vitro macrophage infection by L. major, as well as to assess the effect of high volume (HV) aerobic training on the development of L. major in vivo in BALB/c mice. Uninfected animals were submitted to various exercise volumes: none (SED), light (LV), moderate (MV), high (HV), very high (VHV), and tapering (TAP). The macrophages of these animals were infected by L. major and the LV and MV groups showed a decrease in the infection factor, while the VHV showed an increase in the infection factor, when treated with LPS. The cytokine concentration pattern measured in the supernatants of these macrophages suggested a predominant Th1 response profile in the LV and MV groups, while the Th2 profile predominated in the VHV and TAP groups. Groups of BALB/C mice infected with L. major were subjected to high volume (iHV) or non-periodized high volume (iNPHV) exercise or kept sedentary (iSED). The exercised animals suffered a significant increase in injuries caused by the parasites. The animals in the group submitted to high volume exercise (iHV) showed visceralization of the infection. These data strongly suggest that a very high volume of aerobic training increased the susceptibility of BALB/C mice to L. major infection, while moderate distribution of training loads promoted immunological balance, better controlling the infection by this parasite.

Impact of markers of endothelial injury and hypercoagulability on systemic lupus erythematosus.

We have explored the relationship between possible hemostatic changes and clinical manifestation of the systemic lupus erythematosus (SLE) as a function of greater or lesser disease activity according to Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) criteria. Endothelial injury and hypercoagulability were investigated in patients with SLE by measuring thrombomodulin (TM), D-dimer (DDi) and thrombin generation (TG) potential. A total of 90 participants were distributed into three groups: 1) women with SLE presenting with low disease activity (laSLE) (SLEDAI-2K ≤ 4), 2) women with SLE presenting with moderate to high disease activity (mhaSLE) (SLEDAI-2K > 4), and 3) a control group comprising healthy women. Levels of TM and DDi were higher both in the laSLE and mhaSLE groups compared to controls and in mhaSLE compared to the laSLE group. With respect to TG assay, lagtime and endogen thrombin potential, low concentrations of tissue factor provided the best results for discrimination among groups. Analysis of these data allow us to conclude that TM, DDi and TG are potentially useful markers for discriminating patients with very active from those with lower active disease. Higher SLE activity may cause endothelial injury, resulting in higher TG and consequently a hypercoagulability state underlying the picture of thrombosis common in this inflammatory disease.

Differences for T-Cell Subtypes in Aspiration Biopsies of Patients With Kidney Transplant Under Polyclonal and Monoclonal Immunosuppressive Treatments.

Thymoglobulin, or antithymocyte globulin (ATG), and anti-interleukin 2α (IL-2α) chain receptor antibody (IL-2αRAb) achieve comparable good results in kidney transplantation notwithstanding different actions on immune cells. Previously, we reported the usefulness of flow cytometry (FC) analysis of lymphocyte subsets present in peripheral blood sample (PBL) and fine-needle aspiration biopsies (FNABs) for clinical surveillance, as, FC reaches very high predictive positive values for acute rejection diagnosis. Now we report an FC study on 2 kidney transplantation (KT) groups under ATG (n = 19) and IL-2αRAb (n = 24) treatment. Both groups were further treated with calcineurin inhibitors mycophenolate mofetil (MMF) and prednisone. PBL and FNAB samples were collected on day 7 post-KT, stained for several T- and B-lymphocyte subsets, and acquired using FACScan. Statistical analysis were done by Mann-Whitney U test. FNAB results showed a significant downregulation by ATG of CD3 (P < .001), CD4 (P = .009), CD4CD29 (P = .003), and CD2 (P ≤ .001) and significant upregulation of death receptor (DR) (P = .03), CD3CD69 (P < .001), and CD3CD25 (P < .0001) as compared to groups treated with IL-2αRAb. For PBL, the same trend was seen for CD3, CD4, CD2, CD3CD25, CD3CD69, CD4CD29, and DR plus a downregulation of CD45RO (P = .001) and an upregulation of CD4CD45RA (P < .0001) in IL-2αRAb. This study shows that among stable KTs, ATG as compared to IL-2αRAb induces a significant downregulation of a subset of T-memory (CD4CD29) cells but an upregulation of antigen-experienced cells (CD45RO). Further, ATG decreases CD2, CD3, CD4, and naïve (CD45RA) and stimulates T cells as translated by CD3CD69 and DR. As it should be expected from an IL-2αRAb agent, CD25 cells were virtually eliminated.

Evaluation of potential biomarkers for the diagnosis and monitoring of Systemic Lupus Erythematosus using the Cytometric Beads Array (CBA).

BACKGROUND: Systemic Lupus Erythematosus (SLE) is an autoimmune, multisystemic disease. Currently diagnosis depends on complex criteria developed by the American College of Rheumatology. Moreover, the lack of specific biomarkers also challenges the diagnosis. METHODS: Inflammatory biomarkers such as IL-8, IP-10, MIG, MIP-1α and RANTES were measured in serum samples from SLE patients and subjects in control groups (patients with other autoimmune diseases and healthy individuals). Forty-six SLE patients (22 patients with low activity, SLEDAI-2 K ≤ 4, 24 patients with moderate/high activity, SLEDAI-2 K > 4), 42 patients with other autoimmune diseases (OAD group), and 8 healthy volunteers participated in this study. RESULTS: MIG (p < .001) and RANTES (p < .001) concentrations in SLE patients and healthy controls, and IP-10 concentrations in SLE patients with different disease activities (low activity, p < .01, moderate/high activity, p < .05) differed significantly. IL-8 (p < .001) and MIP-1α (p < .001) concentrations in SLE patients differed from those in patients from the OAD group. IL-8 (p < .05), IP-10 (p < .01), MIG (p < .05), MIP-1α (p < .001), and RANTES (p < .05) were correlated with SLE activity; their concentrations in SLE patients with low and moderate/high activity differed significantly. CONCLUSIONS: Given the findings of this study, one can envision the possibility of future use of some of these cytokines to assist in the screening of SLE patients, or even in monitoring disease activity.

Paradoxical response to carbonic anhydrase inhibitors in patients with intraretinal cystoid spaces.

Background: Intraretinal cystoid spaces (IRCS) are fluid-filled spaces seen in some retinal dystrophies and often treated with carbonic anhydrase inhibitors. The purpose of this study is to report an unexpected bilateral improvement in the IRCS after discontinuation of therapy. Material and Methods: We identified from our records 23 patients with retinal dystrophy and IRCS who had been treated with topical and/or oral carbonic anhydrase inhibitors. All subjects had regular follow-up with OCT and previous genetic testing. Results: We identified four (17%) patients who experienced a bilateral and symmetrical paradoxical improvement in IRCS size and visual acuity after discontinuation of carbonic anhydrase inhibitors. Two were mutations in RS1, one in CLN3 and another in NR2E3. All patients were followed for at least three years (range 39-63 months). None had systemic abnormalities. Conclusions: Patients with IRCS may exhibit a paradoxical response after discontinuation of carbonic anhydrase inhibitors. Although the pathophysiology of these phenomena is unclear, stopping treatment may be an option in patients who cease to improve or get worse on treatment.

Species distribution and antifungal susceptibility of 358 Trichosporon clinical isolates collected in 24 medical centres.

OBJECTIVES: To provide species distribution and antifungal susceptibility profiles of 358 Trichosporon clinical isolates collected from 24 tertiary-care hospitals. METHODS: Species identification was performed by sequencing the IGS1 region of rDNA. Antifungal susceptibility testing for amphotericin B, fluconazole, voriconazole and posaconazole followed the Clinical and Laboratory Standards Institute reference method. Tentative epidemiologic cutoff values (97.5% ECVs) of antifungals for Trichosporon asahii were also calculated. RESULTS: Isolates were cultured mostly from urine (155/358, 43.3%) and blood (82/358, 23%) samples. Trichosporon asahii was the most common species (273/358, 76.3%), followed by T. inkin (35/358, 9.7%). Isolation of non-T. asahii species increased substantially over the last 11 years [11/77 (14.2%) from 1997 to 2007 vs. 74/281, (26.3%) from 2008 to 2018, p0.03]. Antifungal susceptibility testing showed high amphotericin B minimum inhibitory concentrations against Trichosporon isolates, with higher values for T. faecale. The ECV for amphotericin B and T. asahii was set at 4 µg/mL. Among the triazole derivatives, fluconazole was the least active drug. The ECVs for fluconazole and posaconazole against T. asahii were set at 8 and 0.5 µg/mL, respectively. Voriconazole showed the strongest in vitro activity against the Trichosporon isolates; its ECV for T. asahii was set at 0.25 µg/mL after 48 hours' incubation. CONCLUSIONS: Trichosporon species diversity has increased over the years in human samples, and antifungal susceptibility profiles were species specific. Trichosporon asahii antifungal ECVs were proposed, which may be helpful to guide antifungal therapy.

Epidemiology, risk factors and outcomes of multi-drug-resistant bloodstream infections in haematopoietic stem cell transplant recipients: importance of previous gut colonization.

BACKGROUND: Bloodstream infections (BSI) are a major complication in the early phase of a haematopoietic stem cell transplant (HSCT). AIM: To describe the incidence and risk factors for BSI occurring in the pre-engraftment phase of HSCT, and its impact on mortality. METHODS: Clinical variables of 232 HSCT patients were analysed retrospectively between 2014 and 2015. Univariate Cox regression analyses were performed to test the association between each covariate and the outcome. Covariates with P < 0.10 on univariate analysis were included in a multiple Cox regression analysis using a backward elimination method. FINDINGS: The cumulative incidence of BSI was 25.4%, mainly caused by Gram-negative bacteria (GNB) (55.2%). Approximately 40.5% of the patients had gut colonization by multi-drug-resistant (MDR) bacteria (vancomycin-resistant enterococcus and carbapenem-resistant GNB). Among patients colonized by MDR GNB, 20% developed an overt BSI due to MDR bacteria with the same pattern of sensitivity. Of the 13 deaths related to infection, 10 were patients with BSI caused by MDR GNB. The independent risk factors for BSI were gut colonization by MDR bacteria including GNB (P < 0.001) and duration of neutropenia >10 days (P = 0.005), and those associated with BSI caused by MDR bacteria were age >62 years (P = 0.03), use of total parenteral nutrition (TPN) (P < 0.001) and previous gut colonization by MDR GNB (P = 0.002). CONCLUSIONS: Previous gut colonization by MDR was an independent risk factor for BSI, together with TPN and age, and had an impact on outcome. These findings suggest that gut decolonization may be a potential strategy to prevent BSI.