From inflamm-aging to immune-paralysis: a slippery slope during aging for immune-adaptation

Aging is accompanied by many physiological changes including those in the immune system. These changes are designated as immunosenescence indicating that age induces a decrease in immune functions. However, since many years we know that some aspects are not decreasing but instead are increasing like the pro-inflammatory activity by the innate immune cells, especially by monocytes/macrophages. Recently it became evident that these cells may possess a sort of memory called trained memory sustained by epigenetic changes occurring long after even in the absence of the initiator aggressor. In this review we are reviewing evidences that such changes may occur in aging and describe the relationship between inflamm-aging and immunosenescence as an adaptation/remodelling process leading on one hand to increased inflammation and on the other to decreased immune response (immune-paralysis) mastered by the innate immune system. These changes may collectively induce a state of alertness which assure an immune response even if ultimately resulting in age-related deleterious inflammatory diseases.     

A study of HLA-A, B, C, and DR specificities in pigeon breeder's disease.

The frequencies of HLA-A, -B, and -C antigens were determined among 51 symptomatic pigeon breeders, 102 asymptomatic pigeon breeders, and 100 normal blood donors. The HLA-DR specificities were also studied in 32 symptomatic and 29 asymptomatic pigeon breeders. All subjects were white. Symptomatic subjects were defined by the development of respiratory symptoms or decreased pulmonary function after aerosol challenge with pigeon serum. Asymptomatic subjects were comparably exposed to pigeons but had no pulmonary signs or symptoms after aerosol challenge. No significant association was found between any of the tested HLA specificities and pigeon breeders. This lack of association and the observed paucity of multiplex families indicate that HLA complex genetic factors tested in this study do not favor the development of pigeon breeder's disease in exposed persons.     

Persistence of lymphocytic choriomeningitis virus at very low levels in immune mice

Lymphocytic choriomeningitis virus (LCMV), strain WE, is a non-cytopathic RNA virus that is highly adapted to its natural host, the mouse. Acute infection of adult mice leads to generalized virus spread, followed by cytotoxic T lymphocyte-mediated virus clearance below the detection levels of conventional assays within 2-3 weeks. Indirect evidence had suggested that virus or viral antigen might persist in the immune mouse. Here we demonstrate LCMV-WE persistence at low levels after infection with 10(2) or 10(6) plaque-forming units, shown as viral genome, viral antigen, and replicative virus using sensitive in vitro and in vivo assays. The finding that LCMV-WE persists in the face of apparently intact immune responses resembles the situation in some viral (hepatitis B and C, HIV) and bacterial (tuberculosis, leprosy) infections in humans; the results are relevant to the understanding not only of other murine and human persistent viral infections but also of protective immunological memory by "infection immunity."     

Threshold parameters of left main coronary artery stem stenosis based on intracoronary ultrasound examination

INTRODUCTION: The left main coronary stem (LMS) provides blood supply to the left ventricle, and its stenosis is associated with serious clinical consequences. The accurate assessment of LMS stenosis determines appropriate treatment and long term prognosis. So far no criteria have been established to correctly estimate the magnitude of problematic lesions as indicated by quantitative angiography (QCA). AIM: An attempt to establish intracoronary ultrasound (ICUS) threshold values of significant LMS stenosis. METHODS: The studied group consisted of 197 patients (mean age 69.72+/-8.51) who underwent percutaneous coronary intervention (PCI) of the left coronary artery. Group 1 (G1) consisted of 99 patients who had LMS diameter reduction (%DS) of less than 30%. Group 2 (G2) consisted of 77 patients with %DS between 30% and 50%, and the remaining 21 patients with %DS higher than 50% were classified as Group 3 (G3). The quantitative angiography (QCA) analysis included lumen diameter (Ldmin) which was LMS lumen diameter at the most stenotic segment as well as LMS diameter reduction (%DS). The parameters that were analysed during ICUS study included maximum plaque burden (%) (Pbmax), minimal lumen area (LAmin) and lumen stenosis (%LS) calculated according to the formula: (LAmin/LAref) x 100%. Additionally, correlations between the corresponding parameters measured using QCA and ICUS were investigated. RESULTS: Both diagnostic techniques showed the most advanced degree of atherosclerosis in G3. All the G3 patients and 5 G2 patients had MLD values less than or equal to 2 mm. In G1 LAmin values exceeded 9 mm(2) in all patients, whereas among G2 patients 12 (15.5%) had LAmin lower than 6 mm(2), 29 pts. (37.66%) within the range of 6-9 mm(2) and in the remaining 36 pts. (46.75%) it exceeded 9 mm(2). In G3 LAmin values in 17 pts. (80.95%) did not exceed 6 mm(2) and in the remaining 4 pts. (19.05%) were slightly higher. Lumen reduction higher than 50% was noted in all G3 patients and 3 G2 patients (in all these 3 G2 patients LAmin values were lower than 6 mm(2)). All G3 pts. and 3 G2 pts. with LAmin value <6 mm(2) and %LS >50% had angina and a positive stress ECG test. All of these patients (n=24) underwent LMS stent implantation. CONCLUSIONS: 1. Minimal lumen diameter of LMS < or = 2 mm in quantitative angiography indicates a very high probability of significant stenosis of this vessel. 2. Ultrasound data analysis shows that besides LMS lumen area (<9 mm(2)) stenosis significance is determined by lumen reduction of more than 50%.     

Non-linear adaptive controllers for an over-actuated pneumatic MR-compatible stepper

Pneumatics is one of the few actuation principles that can be used in an MR environment, since it can produce high forces without affecting imaging quality. However, pneumatic control is challenging, due to the air high compliance and cylinders non-linearities. Furthermore, the system’s properties may change for each subject. Here, we present novel control strategies that adapt to the subject’s individual anatomy and needs while performing accurate periodic gait-like movements with an MRI compatible pneumatically driven robot. In subject-passive mode, an iterative learning controller (ILC) was implemented to reduce the system’s periodic disturbances. To allow the subjects to intend the task by themselves, a zero-force controller minimized the interaction forces between subject and robot. To assist patients who may be too weak, an assist-as-needed controller that adapts the assistance based on online measurement of the subject’s performance was designed. The controllers were experimentally tested. The ILC successfully learned to reduce the variability and tracking errors. The zero-force controller allowed subjects to step in a transparent environment. The assist-as-needed controller adapted the assistance based on individual needs, while still challenged the subjects to perform the task. The presented controllers can provide accurate pneumatic control in MR environments to allow assessments of brain activation.     

The Influence of Recombinant Human Erythropoietin on Apoptosis and Cytokine Production of CD4+ lymphocytes from Hemodialyzed Patients

Recombinant human erythropoietin (rhEPO) treatment of hemodialyzed (HD) patients normalizes the altered phenotype of CD4⁺ lymphocytes and restores the balance of Th1/Th2 cytokines. We decided to test how the presence of rhEPO in cell culture modulates cytokine production of CD4⁺ lymphocytes in HD patients with stable hemoglobin level and expression of activation antigens of stimulated CD4⁺ lymphocytes similar to those observed in healthy individuals. We also tested whether the presence of rhEPO in cell culture protects stimulated CD4⁺ lymphocytes of HD patients from apoptosis. Peripheral blood mononuclear cells (PBMC) of HD patients were stimulated with an immobilized anti-CD3 antibody with or without addition of rhEPO. The percentage of apoptotic CD4⁺ lymphocytes and the level of Th1/Th2 cytokines in culture supernatants were measured with flow cytometry. HD patients showed a decrease in the percentage of apoptotic CD4⁺ cells after stimulation with the anti-CD3 antibody combined with rhEPO. The level of IFN-γ and IL-10 was increased while the level of TNF-α was decreased in the presence of rhEPO in cell culture from HD patients. These results confirm the role of rhEPO signaling in T lymphocytes of HD patients.