Origin of New Lineages by Recombination and Mutation in Avian Infectious Bronchitis Virus from South America

The gammacoronavirus avian infectious bronchitis virus (IBV) is a highly contagious respiratory pathogen of primary economic importance to the global poultry industry. Two IBV lineages (GI-11 and GI-16) have been widely circulating for decades in South America. GI-11 is endemic to South America, and the GI-16 is globally distributed. We obtained full-length IBV genomes from Argentine and Uruguayan farms using Illumina sequencing. Genomes of the GI-11 and GI-16 lineages from Argentina and Uruguay differ in part of the spike coding region. The remaining genome regions are similar to the Chinese and Italian strains of the GI-16 lineage that emerged in Asia or Europe in the 1970s. Our findings support that the indigenous GI-11 strains recombine extensively with the invasive GI-16 strains. During the recombination process, GI-11 acquired most of the sequences of the GI-16, retaining the original S1 sequence. GI-11 strains with recombinant genomes are circulating forms that underwent further local evolution. The current IBV scenario in South America includes the GI-16 lineage, recombinant GI-11 strains sharing high similarity with GI-16 outside S1, and Brazilian GI-11 strains with a divergent genomic background. There is also sporadic recombinant in the GI-11 and GI-16 lineages among vaccine and field strains. Our findings exemplified the ability of IBV to generate emergent lineage by using the S gene in different genomic backgrounds. This unique example of recombinational microevolution underscores the genomic plasticity of IBV in South America.     

Trypanosoma cruzi trans-Sialidase Prevents Elicitation of Th1 Cell Response via Interleukin 10 and Downregulates Th1 Effector Cells

The trans-sialidases (TSs) from Trypanosoma cruzi, the agent of Chagas disease, are virulence factors shed to the bloodstream that induce strong alterations in the immune system. Here, we report that both enzymatically active TS (aTS) and its lectinlike isoform (iTS) disturb CD4 T cell physiology, inducing downregulation of Th1 cell functionality and in vivo cell expansion. By using ovalbumin-specific DO11.10 cells as tracers of clones developing the Th1 phenotype, we found that the infection induced significant amounts of gamma interferon (IFN-γ) but low levels of interleukin 2 (IL-2) and increased IL-4 production in vivo, in agreement with a mixed T helper response. The production of cytokines associated with the Th2 phenotype was prevented by passive transfer of anti-TS neutralizing antibodies. TSs also reduced the T cell receptor signaling as assayed by Zap-70 phosphorylation. TSs also reduced IL-2 and IFN-γ secretion, with a concomitant increase in IL-4 production and then an unbalancing of the CD4 T cell response toward the Th2 phenotype. This effect was prevented by using anti-IL-10 neutralizing antibodies or IL-10^−/− antigen-presenting cells, supporting the subversion of this regulatory pathway. In support, TSs stimulated IL-10 secretion by antigen-presenting cells during their interaction with CD4 T cells. When polarized cells were stimulated in the presence of TSs, the secretion of IL-2 and IFN-γ was strongly downregulated in Th1 cells, while IL-2 production was upregulated in Th2 cells. Although the Th1 response is associated with host survival, it may simultaneously induce extensive damage to infected tissues. Thus, by delaying the elicitation of the Th1 response and limiting its effector properties, TSs restrain the cell response, supporting T. cruzi colonization and persistence while favoring host survival.     

Donor‐specific anti‐HLA antibodies in pediatric renal transplant recipients with creeping creatinine: Prevalence,histological correlations,and impact on patient and graft survival

Donor‐specific anti‐HLA antibodies (DSA) causing CAMR are responsible for a high proportion of long‐term graft failures after RTX. We studied the prevalence of DSA in RTX children biopsied for creeping Cr, its relationship with NA, and patient and graft survival according to histopathology. Between 2008 and 2013, 92 children were biopsied at a median of 38 months post‐RTX. At biopsy, the prevalence of DSA was 49% and C4d 70%. NA rate was 45%, higher in adolescents (60%). Most frequent diagnoses were CAMR (72%) and interstitial fibrosis with tubular atrophy (IFTA) (28%). Forty‐five of 66 patients with CAMR (68%) had detectable DSA. Twenty‐one DSA‐negative patients with CAMR had histological damage (IFTA + C4d positivity). C4d was detected in 64 of 66 biopsies with CAMR. Recipients with IFTA alone had neither C4d, nor detectable DSA, and were adherent. Graft survival at five yr was 89% in patients with CAMR, 79% in those with CAMR + TCMR Banff I, 33% in those with CAMR + TCMR Banff II, and 96% in those with IFTA. ABMR and complement activation were frequent in children biopsied for creeping Cr. Recipients with DSA were more likely to be non‐adherent and have CAMR or CAMR + TCMR and worse graft survival.     

Delirium in palliative care

Delirium is highly prevalent in cancer patients with advanced disease. Frequently a preterminal event, the condition is a sign of significant physiologic disturbance, typically involving multiple medical etiologies including infection, organ failure, adverse medication effects, and in rare situations, paraneoplastic syndromes. Unfortunately, delirium is frequently unrecognized or misdiagnosed and, therefore, inappropriately treated or untreated in terminally ill patients. The clinical features of delirium are numerous and encompass a variety of neuropsychiatric symptoms common to other psychiatric disorders. Three clinical subtypes of delirium, based on arousal disturbance and psychomotor behavior, have been described: hyperactive, hypoactive, and mixed. The differential diagnosis for delirium includes depression, mania, psychosis, and dementia. Numerous instruments have been developed to aid the clinician in rapidly screening for the disorder. Standard management requires an investigation of the etiologies, correction of the contributing factors, and management of symptoms. Symptomatic and supportive therapies, including numerous pharmacologic approaches, are important, but several aspects of the use of neuroleptics and other agents in the management of delirium in the dying patient remain controversial.     

The 'immunological-synapse' at its APC side in relapsing and secondary-progressive multiple sclerosis: modulation by interferon-beta

Reciprocal interactions between T cells and antigen-presenting cells (APCs) within the 'Immunological-Synapse' (IS) govern immune cell autoreactivity in multiple sclerosis (MS). The present study examined the expression of a range of co-stimulatory molecules: CD40, CD54, CD80, CD86 and HLA-DR, on the cell-surface of CD14(+) peripheral blood monocytes (PBM) from relapsing-remitting (RR) and secondary-progressive (SP)-MS patients, prior to and during 1 year of Interferon (IFN)-beta-1a (Rebif(R)) therapy. Prior to treatment, patients from both MS subtypes expressed elevated CD80 and reduced CD40 levels in comparison to controls. CD86 expression was significantly reduced in SP compared to RR patients and controls. IFN-beta therapy led to a significant reduction in the expression of CD54 and CD80 in both groups of patients as well as to elevation of CD40 and CD86 expression in SP patients. These results confirm IFN-mediated modulation of the APC surface within the immunological-synapse and implicate CD80 and CD86 as targets for interventional therapies in MS as well as other Th1-mediated autoimmune diseases.     

Nonpeptide antagonists of AT1 receptor for angiotensin II delay the onset of acute respiratory distress syndrome

We have previously reported that losartan, a selective antagonist of AT1 receptors for angiotensin II (AII), strongly suppresses the activation of neutrophils by N-formylmethionyl-leucyl-phenylalanine (fMLP) through a mechanism that does not involve inhibition of AT1 receptors. Herein, we analyze whether losartan would prevent the development of the acute respiratory distress syndrome (ARDS) triggered by lung bacterial infection. We found that losartan (0.2-200 microg/kg/min) delays the onset of ARDS in Wistar rats challenged by i.t. instillation of Bordetella bronchiseptica. Although this effect was associated with a significant inhibition of lung-neutrophil recruitment, lung bacterial clearance was not impaired but rather, it was significantly improved. We also found that another nonpeptide AT1 receptor blocker, irbesartan, exerted similar effects to losartan, i.e., it was also able to inhibit neutrophil activation by fMLP and to delay the onset of ARDS in B. bronchiseptica-challenged rats. Neither the inhibitor of angiotensin-converting enzyme captopril, nor the nonselective peptide inhibitor of AII receptors saralasin reproduced these effects. Our data are consistent with the possibility that nonpeptide AT1 receptor blockers delay the onset of ARDS triggered by bacterial infection through a mechanism dependent, at least in part, on their ability to prevent neutrophil activation by N-formyl-peptides.     

Neuronal and astroglial alterations in the hippocampus of a mouse model for type 1 diabetes

The influence of diabetes mellitus on brain pathology is increasingly recognized. Previous contributions of our laboratory demonstrated in models of type 1 diabetes (nonobese diabetic and streptozotocin (STZ)-treated mice), a marked astrogliosis and neurogenesis deficit in hippocampus and increased expression of hypothalamic neuropeptides. In the present investigation, we further analyzed alterations of astroglia and neurons in the hippocampus of mice 1 month after STZ-induced diabetes. Results showed that these STZ-diabetic mice presented: (a) increased number of astrocytes positive for apolipoprotein-E (Apo-E), a marker of ongoing neuronal dysfunction; (b) abnormal expression of early gene products associated with neuronal activation, including a high number of Jun + neurons in CA1 and CA3 layers and dentate gyrus, and of Fos-expressing neurons in CA3 layer; (c) augmented activity of NADPH-diaphorase, linked to oxidative stress, in CA3 region. These data support the concept that uncontrolled diabetes leads to hippocampal pathology, which adjoin to changes in other brain structures such as hypothalamus and cerebral cortex.     

Monotherapy with Fluoroquinolone or Trimethoprim-Sulfamethoxazole for Treatment of Stenotrophomonas maltophilia Infections

The treatment of choice for Stenotrophomonas maltophilia is trimethoprim-sulfamethoxazole (SXT). Fluoroquinolones (FQs) have in vitro activity against S. maltophilia; however, there is limited published information on their effectiveness. The purpose of this study is to compare the effectiveness of FQs and SXT for the treatment of S. maltophilia. A retrospective review of 98 patients with S. maltophilia infections who received SXT or FQ monotherapy was conducted. Patients ≥18 years old with a positive culture for S. maltophilia and clinical signs of infection who received treatment for ≥48 h were included. Microbiological cure and clinical response were evaluated at the end of therapy (EOT). In-hospital mortality and isolation of nonsusceptible isolates were also evaluated. Thirty-five patients received SXT, and 63 patients received FQ; 48 patients received levofloxacin, and 15 patients received ciprofloxacin. The most common infection was pulmonary. The overall microbiological cure rate at EOT was 63%. Thirteen of 20 patients (65%) who received SXT and 23 of 37 patients (62%) who received FQ had microbiological cure at EOT (P = 0.832). The overall clinical success rate was 55%, 52% for those who received FQ and 61% for those who received SXT (P = 0.451). In-hospital mortality was 24%, with similar rates in the two groups (25% for FQ versus 22% for SXT; P = 0.546). Development of resistance on repeat culture was 30% for FQ and 20% for SXT (P = 0.426). Fluoroquinolone and SXT monotherapies may be equally effective for the treatment of S. maltophilia infections. Resistance was documented in subsequent isolates of S. maltophilia in both groups.     

Arterial wall structure and dynamics in type 2 diabetes mellitus methodological aspects and pathophysiological findings

Type 2 Diabetes Mellitus (DM), or adult-onset diabetes, is being considered as a new pandemic. Cardiovascular disease is the major cause of morbidity and mortality in type 2 DM, due to arterial structure and functional changes. Assessment of arterial structure and biomechanics, by non-invasive methods and parameters, can be used to detect early alterations related to DM. Three markers of vascular disease may help to a better evaluation of vascular dysfunction in type 2 DM patients: carotid intimamedia thickness (IMTc), arterial stiffness, assessed by pulse wave velocity (PWV), and endothelial function, evaluated through the brachial artery flow-mediated dilation (FMD). Among these parameters, IMTc is considered a marker of structural vessel wall properties, and arterial stiffness reflects functional wall properties. Endothelial function represents the arterial way to actively regulate its diameter (smooth muscle-dependent actions) and its visco-elastic properties (wall elasticity and viscosity). IMTc is increased in patients with type 2 DM and other independent risk factors, such as: age, hyperlipidemia and duration of DM. Subjects with DM have shown increased arterial stiffness. Type 2 DM is associated with reductions in FMD (endothelial dysfunction), which has already been reported to be inversely and strongly related to the extent of hyperglycemia. The underlying patho-physiological mechanisms are complex and remain to be fully elucidated. A complete understanding of the association between arterial alterations and early detection, and type 2 DM, may be critical for the primary prevention of DM-related macro-vascular disease.