Matched sizes of activating and inhibitory receptor/ligand pairs are required for optimal signal integration by human Natural Killer cells

It has been suggested that receptor-ligand complexes segregate or co-localise within immune synapses according to their size, and this is important for receptor signaling. Here, we set out to test the importance of receptor-ligand complex dimensions for immune surveillance of target cells by human Natural Killer (NK) cells. NK cell activation is regulated by integrating signals from activating receptors, such as NKG2D, and inhibitory receptors, such as KIR2DL1. Elongating the NKG2D ligand MICA reduced its ability to trigger NK cell activation. Conversely, elongation of KIR2DL1 ligand HLA-C reduced its ability to inhibit NK cells. Whereas normal-sized HLA-C was most effective at inhibiting activation by normal-length MICA, only elongated HLA-C could inhibit activation by elongated MICA. Moreover, HLA-C and MICA that were matched in size co-localised, whereas HLA-C and MICA that were different in size were segregated. These results demonstrate that receptor-ligand dimensions are important in NK cell recognition, and suggest that optimal integration of activating and inhibitory receptor signals requires the receptor-ligand complexes to have similar dimensions

Association between skin diseases and severe bacterial infections in children: case-control study

BACKGROUND: Sepsis or bacteraemia, however rare, is a significant cause of high mortality and serious complications in children. In previous studies skin disease or skin infections were reported as risk factor. We hypothesize that children with sepsis or bacteraemia more often presented with skin diseases to the general practitioner (GP) than other children. If our hypothesis is true the GP could reduce the risk of sepsis or bacteraemia by managing skin diseases appropriately. METHODS: We performed a case-control study using data of children aged 0–17 years of the second Dutch national survey of general practice (2001) and the National Medical Registration of all hospital admissions in the Netherlands. Cases were defined as children who were hospitalized for sepsis or bacteraemia. We selected two control groups by matching each case with six controls. The first control group was randomly selected from the GP patient lists irrespective of hospital admission and GP consultation. The second control group was randomly sampled from those children who were hospitalized for other reasons than sepsis or bacteraemia. We calculated odds ratios and 95% confidence intervals (CI). A two-sided p-value less than 0.05 was considered significant in all tests. RESULTS: We found odds ratios for skin related GP consultations of 3.4 (95% CI: [1.1–10.8], p = 0.03) in cases versus GP controls and 1.4 (95% CI: [0.5–3.9], p = 0.44) in cases versus hospital controls. Children younger than three months had an odds ratio (cases/GP controls) of 9.2 (95% CI: [0.81–106.1], p = 0.07) and 4.0 (95% CI: [0.67–23.9], p = 0.12) among cases versus hospital controls. Although cases consulted the GP more often with skin diseases than their controls, the probability of a GP consultation for skin disease was only 5% among cases. CONCLUSION: There is evidence that children who were admitted due to sepsis or bacteraemia consulted the GP more often for skin diseases than other children, but the differences are not clinically relevant indicating that there is little opportunity for GPs to reduce the risk of sepsis and/or bacteraemia considerably by managing skin diseases appropriately

Clinical presentation and predictors of outcome in patients with severe acute exacerbation of chronic obstructive pulmonary disease requiring admission to intensive care unit

BACKGROUND: Severe acute exacerbation of chronic obstructive pulmonary disease (AE-COPD) is a common reason for emergency room (ER) visit about which little has been documented from India. METHODS: Prospective study of the clinical presentation and predictors of outcome in 116 patients presenting with severe AE-COPD requiring admission to the medical intensive care unit between January 2000 and December 2004. RESULTS: Their mean age was 62.1 ± 9.8 years. There were 102 males. Mean duration of COPD was 7.2 ± 5.8 years. All males were smokers (22.3 ± 11.2 pack years); 35.2% smoked cigarettes and 64.8% smoked bidis. All women were exposed to domestic fuel. Associated co-morbid illnesses were present in 81 patients (69.8%); 53(45.7%) had one co-morbid illness and the remaining 28 (54.3%) had two or more co-morbid illnesses. Evidence of past pulmonary tuberculosis (PTB) was present in 28.4% patients; 5 patients who also had type II diabetes mellitus had active PTB. Arterial blood gas analysis revealed respiratory failure in 40 (33.8%) patients (type I 17.5% and type II 82.5%). Invasive mechanical ventilation was required in 18 patients. Sixteen (13.7%) patients died. Stepwise multivariate logistic regression analysis revealed need for invasive ventilation (OR 45.809, 95%CI 607.46 to 3.009;p < 0.001); presence of co-morbid illness (OR 0.126, 95%CI 0.428 to 0.037;p < 0.01) and hypercapnia (OR 0.114, 95%CI 1.324 to 0.010;p < 0.05) were predictors of death. CONCLUSION: Co-morbid conditions and metabolic abnormalities render the diagnosis of AE-COPD difficult and also contribute to mortality. High prevalence of past PTB and active PTB in patients with AE-COPD suggests an intriguing relationship between smoking, PTB and COPD which merits further study

The use of Traditional Medicine by Ghanaians in Canada

Peer reviewedPublisher PD

High Affinity Antigen Recognition of the Dual Specific Variants of Herceptin Is Entropy-Driven in Spite of Structural Plasticity

The antigen-binding site of Herceptin, an anti-human Epidermal Growth Factor Receptor 2 (HER2) antibody, was engineered to add a second specificity toward Vascular Endothelial Growth Factor (VEGF) to create a high affinity two-in-one antibody bH1. Crystal structures of bH1 in complex with either antigen showed that, in comparison to Herceptin, this antibody exhibited greater conformational variability, also called “structural plasticity”. Here, we analyzed the biophysical and thermodynamic properties of the dual specific variants of Herceptin to understand how a single antibody binds two unrelated protein antigens. We showed that while bH1 and the affinity-improved bH1-44, in particular, maintained many properties of Herceptin including binding affinity, kinetics and the use of residues for antigen recognition, they differed in the binding thermodynamics. The interactions of bH1 and its variants with both antigens were characterized by large favorable entropy changes whereas the Herceptin/HER2 interaction involved a large favorable enthalpy change. By dissecting the total entropy change and the energy barrier for dual interaction, we determined that the significant structural plasticity of the bH1 antibodies demanded by the dual specificity did not translate into the expected increase of entropic penalty relative to Herceptin. Clearly, dual antigen recognition of the Herceptin variants involves divergent antibody conformations of nearly equivalent energetic states. Hence, increasing the structural plasticity of an antigen-binding site without increasing the entropic cost may play a role for antibodies to evolve multi-specificity. Our report represents the first comprehensive biophysical analysis of a high affinity dual specific antibody binding two unrelated protein antigens, furthering our understanding of the thermodynamics that drive the vast antigen recognition capacity of the antibody repertoire

Genetic and Structural Basis for Selection of a Ubiquitous T Cell Receptor Deployed in Epstein-Barr Virus Infection

Despite the ∼1018 αβ T cell receptor (TCR) structures that can be randomly manufactured by the human thymus, some surface more frequently than others. The pinnacles of this distortion are public TCRs, which exhibit amino acid-identical structures across different individuals. Public TCRs are thought to result from both recombinatorial bias and antigen-driven selection, but the mechanisms that underlie inter-individual TCR sharing are still largely theoretical. To examine this phenomenon at the atomic level, we solved the co-complex structure of one of the most widespread and numerically frequent public TCRs in the human population. The archetypal AS01 public TCR recognizes an immunodominant BMLF1 peptide, derived from the ubiquitous Epstein-Barr virus, bound to HLA-A*0201. The AS01 TCR was observed to dock in a diagonal fashion, grasping the solvent exposed peptide crest with two sets of complementarity-determining region (CDR) loops, and was fastened to the peptide and HLA-A*0201 platform with residue sets found only within TCR genes biased in the public response. Computer simulations of a random V(D)J recombination process demonstrated that both TCRα and TCRβ amino acid sequences could be manufactured easily, thereby explaining the prevalence of this receptor across different individuals. Interestingly, the AS01 TCR was encoded largely by germline DNA, indicating that the TCR loci already comprise gene segments that specifically recognize this ancient pathogen. Such pattern recognition receptor-like traits within the αβ TCR system further blur the boundaries between the adaptive and innate immune systems

B cell depletion in autoimmune diabetes:insights from murine models

INTRODUCTION: The incidence of type 1 diabetes (T1D) is rising for reasons that largely elude us. New strategies aimed at halting the disease process are needed. One type of immune cell thought to contribute to T1D is the B lymphocyte. The first Phase II trial of B cell depletion in new onset T1D patients indicated that this slowed the destruction of insulin-producing pancreatic beta cells. The mechanistic basis of the beneficial effects remains unclear. AREAS COVERED: Studies of B cell depletion and deficiency in animal models of T1D. How B cells can influence T cell-dependent autoimmune diabetes in animal models. The heterogeneity of B cell populations and current evidence for the potential contribution of specific B cell subsets to diabetes, with emphasis on marginal zone B cells and B1 B cells. EXPERT OPINION: B cells can influence the T cell response to islet antigens and B cell depletion or genetic deficiency is associated with decreased insulitis in animal models. New evidence suggests that B1 cells may contribute to diabetes pathogenesis. A better understanding of the roles of individual B cell subsets in disease will permit fine-tuning of therapeutic strategies to modify these populations

Non-hispanic whites have higher risk for pulmonary impairment from pulmonary tuberculosis

<p>Abstract</p> <p>Background</p> <p>Disparities in outcomes associated with race and ethnicity are well documented for many diseases and patient populations. Tuberculosis (TB) disproportionately affects economically disadvantaged, racial and ethnic minority populations. Pulmonary impairment after tuberculosis (PIAT) contributes heavily to the societal burden of TB. Individual impacts associated with PIAT may vary by race/ethnicity or socioeconomic status.</p> <p>Methods</p> <p>We analyzed the pulmonary function of 320 prospectively identified patients with pulmonary tuberculosis who had completed at least 20 weeks standard anti-TB regimes by directly observed therapy. We compared frequency and severity of spirometry-defined PIAT in groups stratified by demographics, pulmonary risk factors, and race/ethnicity, and examined clinical correlates to pulmonary function deficits.</p> <p>Results</p> <p>Pulmonary impairment after tuberculosis was identified in 71% of non-Hispanic Whites, 58% of non-Hispanic Blacks, 49% of Asians and 32% of Hispanics (<it>p </it>< 0.001). Predictors for PIAT varied between race/ethnicity. PIAT was evenly distributed across all levels of socioeconomic status suggesting that PIAT and socioeconomic status are not related. PIAT and its severity were significantly associated with abnormal chest x-ray, <it>p </it>< 0.0001. There was no association between race/ethnicity and time to beginning TB treatment, <it>p </it>= 0.978.</p> <p>Conclusions</p> <p>Despite controlling for cigarette smoking, socioeconomic status and time to beginning TB treatment, non-Hispanic White race/ethnicity remained an independent predictor for disproportionately frequent and severe pulmonary impairment after tuberculosis relative to other race/ethnic groups. Since race/ethnicity was self reported and that race is not a biological construct: these findings must be interpreted with caution. However, because race/ethnicity is a proxy for several other unmeasured host, pathogen or environment factors that may contribute to disparate health outcomes, these results are meant to suggest hypotheses for further research.</p

Potent Antioxidant and Genoprotective Effects of Boeravinone G, a Rotenoid Isolated from Boerhaavia diffusa

Background and Aims: Free radicals are implicated in the aetiology of some gastrointestinal disorders such as gastric ulcer, colorectal cancer and inflammatory bowel disease. In the present study we investigated the antioxidant and genoprotective activity of some rotenoids (i.e. boeravinones) isolated from the roots of Boerhaavia diffusa, a plant used in the Ayurvedic medicine for the treatment of diseases affecting the gastrointestinal tract. Methods/Principal Findings: Antioxidant activity has been evaluated using both chemical (Electron Spin Resonance spectroscopy, ESR) and Caco-2 cells-based (TBARS and ROS) assays. DNA damage was evaluated by Comet assay, while pERK 1/2 and phospho-NF-kB p65 levels were estimated by western blot. Boeravinones G, D and H significantly reduced the signal intensity of ESR induced by hydroxyl radicals, suggesting a scavenging activity. Among rotenoids tested, boeravinone G exerted the most potent effect. Boeravinone G inhibited both TBARS and ROS formation induced by Fenton's reagent, increased SOD activity and reduced H 2O 2-induced DNA damage. Finally, boeravinone G reduced the levels of pERK 1 and phospho-NF-kB p65 (but not of pERK 2) increased by Fenton's reagent. Conclusions: It is concluded that boeravinone G exhibits an extraordinary potent antioxidant activity (significant effect in the nanomolar range). The MAP kinase and NF-kB pathways seem to be involved in the antioxidant effect of boeravinone G. Boeravinone G might be considered as lead compound for the development of drugs potentially useful against those pathologies whose aetiology is related to ROS-mediated injuries

Promoting Functional Health in Midlife and Old Age: Long-Term Protective Effects of Control Beliefs, Social Support, and Physical Exercise

Previous studies have examined physical risk factors in relation to functional health, but less work has focused on the protective role of psychological and social factors. We examined the individual and joint protective contribution of control beliefs, social support and physical exercise to changes in functional health, beyond the influence of health status and physical risk factors in middle-aged and older adults. Given that functional health typically declines throughout adulthood, it is important to identify modifiable factors that can be implemented to maintain functioning, improve quality of life, and reduce disability.We conducted a national longitudinal study, Midlife in the United States (MIDUS), with assessments in 1995-1996 and 2004-2006, and 3,626 community-residing adults, aged 32 to 84, were included in the analyses. Functional health (Physical Functioning subscale of the SF-36) and protective factors were measured at both occasions. While controlling for socio-demographic, health status, and physical risk factors (large waist circumference, smoking, and alcohol or drug problems), a composite of the three protective variables (control beliefs, social support, and physical exercise) at Time 1 was significantly related to functional health change. The more of these factors at Time 1, the better the health maintenance over 10 years. Among middle-aged and older adults, declines in health were significantly reduced with an increased number of protective factors.Age-related declines in health were reduced among those with more protective factors up to a decade earlier in life. Modifiable psychological, social, and physical protective factors, individually and in the aggregate, are associated with maintenance of functional health, beyond the damaging effects of physical risk factors. The results are encouraging for the prospect of developing interventions to promote functional health and for reducing public health expenditures for physical disability in later life