Human immunodeficiency virus-associated changes in signal transduction

It is well established that the activation of T lymphocytes by mitogen/antigen is accompanied by a rise in intracellular free calcium ([Ca²⁺]_i), changes in membrane potential, metabolism of inositol phospholipid, and activation of protein kinase C. Theseearly events of signal transduction culminate inlate events of lymphocyte activation, namely, DNA synthesis, lymphokine production, and cellular proliferation. In this study we examined the effect of human immunodeficiency virus (HIV) on changes in membrane potential and [Ca²⁺]_i levels. The membrane potentials were markedly decreased (depolarized) in T cell lines infected with HIV (H9/HTLV IIIb) and did not respond normally to phytohemagglutinin (PHA) or anti-T3 (anti-CD3) monoclonal antibody compared to uninfected H9 cell line. The basal [Ca²⁺]_i levels in H9/HTLV IIIb cells were increased in comparison to those in H9 cells; however, there was very little further increase in [Ca²⁺]_i in H9/HTLV IIIb cells following activation with PHA or anti-T3 monoclonal antibody. This is in contrast to a significant rise in [Ca²⁺]_i in H9 cells following similar stimulation. These data demonstrate abnormalities in the plasma membrane potential and [Ca²⁺]_i levels in chronically infected T cells with HIV. These abnormalities in signal transduction of the T-cell activation pathway could be responsible for T-cell dysfunction in patients with HIV infection.     

Attenuation of Aluminum Chloride-Induced Neuroinflammation and Caspase Activation Through the AKT/GSK-3β Pathway by Hesperidin in Wistar Rats

Hesperidin, a flavanoglycone abundantly present in citrus fruits, is reported to have antioxidant, anti-inflammatory, and neuroprotective properties. Previous reports from our laboratory indicated the neuroprotective effect of hesperidin against aluminum chloride (AlCl₃)-induced memory loss, acetylcholine esterase hyperactivity, oxidative stress, and enhanced expression of amyloid β protein biosynthesis-related markers. However, their role on AlCl₃-induced inflammation, caspase activation, Tau pathology, altered Akt/GSK 3β signaling pathway, and Aβ clearance marker has not yet been fully elucidated. Intraperitonial injection of AlCl₃ (100 mg/kg body weight) for 60 days significantly elevated the expressions of insulin-degrading enzyme (IDE), cyclin-dependent kinase 5 (CDK 5), and phosphoTau (pTau); inflammatory markers such as glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule 1 (Iba-1), NF-kB, cyclooxygenase-2 (COX-2), interleukin (IL)-1β, IL-4, IL-6, tumor necrosis factor-alpha (TNF-α), inducible nitric oxide synthase (iNOS); and apoptotic markers including cytosolic cytochrome c (cyto c), caspase-3, caspase-8, and caspase-9, and lowered expressions of mitochondrial cyto c, phospho-Akt (pAkt) and phospho-glycogen synthase kinase-3β (pGSK-3β) in the hippocampus and cortex. Co-administration of hesperidin to AlCl₃ rats for 60 days significantly ameliorated the aluminum-induced pathological changes. The behavioral studies also supported the above findings. Our results imply that treatment with hesperidin might be a potent option for treating the symptoms of cognitive impairment in Alzheimer’s disease by targeting its most prominent hallmarks.     

Anticoagulation for coexisting bioprosthetic aortic valve thrombosis and anticoagulant-related bleeding: “A double edge sword”

The choice of anticoagulant agents for newly implanted bioprosthetic valve varies significantly, particularly in the presence of postoperative atrial fibrillation with increasing use of nonvitamin K oral anticoagulation (NOACs) in recent years. We reported a challenging case with a coexisting bioprosthetic aortic valve thrombosis and significant anticoagulant-related bleeding. Clinical management strategy and brief literature review were presented.     

Eczema and Sensitization to Common Allergens in the United States: A Multiethnic,Population‐Based Study

The relationship between food and environmental allergens in contributing to eczema risk is unclear on a multiethnic population level. Our purpose was to determine whether sensitization to specific dietary and environmental allergens as measured according to higher specific immunoglobulin E (IgE) levels is associated with eczema risk in children. National Health and Nutrition Examination Survey participants ages 1 to 17 years were asked whether they had ever received a diagnosis of eczema from a physician (n = 538). Total and specific serum IgE levels for four dietary allergens (egg, cow's milk, peanut, and shrimp) and five environmental allergens (dust mite, cat, dog, Aspergillus, and Alternaria) were measured. Logistic regression was used to examine the association between eczema and IgE levels. In the United States, 10.4 million children (15.6%) have a history of eczema. Eczema was more common in black children (p < 0.001) and in children from families with higher income and education (p = 0.01). The median total IgE levels were higher in children with a history of eczema than in those without (66.4 vs 50.6 kU/L, p = 0.004). In multivariate analysis adjusted for age, race, sex, family income, household education, and physician‐diagnosed asthma, eczema was significantly associated with sensitization to cat dander (odds ratio [OR] = 1.2, 95% confidence interval [CI] 1.05, 1.4, p = 0.009) and dog dander (OR = 1.5, 95% CI, 1.2, 1.7, p < 0.001). After correction for multiple comparisons, only sensitization to dog dander remained significant. U.S. children with eczema are most likely to be sensitized to dog dander. Future prospective studies should further explore this relationship.     

Vibrio cholerae-Induced Inflammation in the Neonatal Mouse Cholera Model

Vibrio cholerae is the causative agent of the acute diarrheal disease of cholera. Innate immune responses to V. cholerae are not a major cause of cholera pathology, which is characterized by severe, watery diarrhea induced by the action of cholera toxin. Innate responses may, however, contribute to resolution of infection and must be required to initiate adaptive responses after natural infection and oral vaccination. Here we investigated whether a well-established infant mouse model of cholera can be used to observe an innate immune response. We also used a vaccination model in which immunized dams protect their pups from infection through breast milk antibodies to investigate innate immune responses after V. cholerae infection for pups suckled by an immune dam. At the peak of infection, we observed neutrophil recruitment accompanied by induction of KC, macrophage inflammatory protein 2 (MIP-2), NOS-2, interleukin-6 (IL-6), and IL-17a. Pups suckled by an immunized dam did not mount this response. Accessory toxins RtxA and HlyA played no discernible role in neutrophil recruitment in a wild-type background. The innate response to V. cholerae deleted for cholera toxin-encoding phage (CTXϕ) and part of rtxA was significantly reduced, suggesting a role for CTXϕ-carried genes or for RtxA in the absence of cholera toxin (CTX). Two extracellular V. cholerae DNases were not required for neutrophil recruitment, but DNase-deficient V. cholerae caused more clouds of DNA in the intestinal lumen, which appeared to be neutrophil extracellular traps (NETs), suggesting that V. cholerae DNases combat NETs. Thus, the infant mouse model has hitherto unrecognized utility for interrogating innate responses to V. cholerae infection.