Imbalance in A₂ and A₂B phenotype frequency of ABO group in South India

Background

The heterogeneity of A and B alleles results in weak variants of these antigens. Subgroups of A differ from each other quantitatively and qualitatively. The expected frequencies of A₁ and A₂ subtypes will be in Hardy-Weinberg equilibrium for the Mendelian inheritance of the allelic A₁ and A₂ genes. The frequency of A subgroups in the population from south India is not known. The aim of our study was to study the frequency of A subtypes and the prevalence of anti-A₁ antibody among this population.

Methods

Over a period of 3 years, patients’ blood group was typed using a standard tube technique. Anti-A₁ lectin studies were done for all patients with groups A and AB. Based on serological reactivity the samples were classified into A₁/A₁B, A₂/A₂B and weak A subgroups. The prevalence of A subgroups was determined. The significance of differences in proportions was analysed using the chi-square test.

Results

A total of 40,113 patients’ samples were typed for ABO, Rh group and A subgroups in our blood bank attached to a tertiary care hospital. Among 10,325 group A samples, 98.14% classified as A₁, 1.07% as A₂, and 0.01% as weak A; the remaining group A samples were from neonates and reacted poorly with anti A₁-lectin. The majority of AB samples (n=2,667) were of A₁B type (89.28%). However, the proportion of A₂B (8.99%) among AB samples was significantly higher than that of A₂ in group A samples (p < 0.0001). The prevalence of anti-A₁ antibodies among A₂ and A₂B samples was 1.8% and 3.75%, respectively, and none of them showed reactivity at 37°C.

Conclusion

The results of our study show a significantly higher proportion of A₂B subtypes than A₂ subgroups. A similar imbalance is seen in blacks and Japanese. The incidence of anti-A₁ antibodies is also higher among A₂B patients.     

β₂-glycoprotein I: a novel component of innate immunity

Sepsis is a systemic host response to invasive infection by bacteria. Despite treatment with antibiotics, current mortality rates are in the range of 20%-25%, which makes sepsis the most important cause of death in intensive care. Gram-negative bacteria are a prominent cause of sepsis. Lipopolysaccharide (LPS), one of the major constituents of the outer membrane of Gram-negative bacteria, plays a major role in activating the host's immune response by binding to monocytes and other cells. Several proteins are involved in neutralization and clearance of LPS from the bloodstream. Here, we provide evidence that β?-glycoprotein I (β?GPI) is a scavenger of LPS. In vitro, β?GPI inhibited LPS-induced expression of tissue factor and IL-6 from monocytes and endothelial cells. Binding of β?GPI to LPS caused a conformational change in β?GPI that led to binding of the β?GPI-LPS complex to monocytes and ultimately clearance of this complex. Furthermore, plasma levels of β?GPI were inversely correlated with temperature rise and the response of inflammatory markers after a bolus injection of LPS in healthy individuals. Together, these observations provide evidence that β?GPI is involved in the neutralization and clearance of LPS and identify β?GPI as a component of innate immunity.     

The effect of antecedent hypoglycaemia on β₂-adrenergic sensitivity in healthy participants with the Arg16Gly polymorphism of the β₂-adrenergic receptor

Aims/hypothesis  

Homozygosity for glycine at codon 16 (GlyGly) of the β₂-adrenergic receptor may alter receptor sensitivity upon chronic stimulation and has been implicated in the pathogenesis of hypoglycaemia unawareness. We compared the effect of antecedent hypoglycaemia on β₂-adrenergic receptor sensitivity between GlyGly participants and those with arginine 16 homozygosity (ArgArg) for the β₂-adrenergic receptor.     

Advanced glycation end products of human β₂ glycoprotein I modulate the maturation and function of DCs

In chronic disorders related to endothelial cell dysfunction, plasma β? glycoprotein I (β?GPI) plays a role as a target antigen of pathogenetic autoimmune responses. However, information is still lacking to clarify why β?GPI triggers autoimmunity. It is possible that posttranslational modification of the protein, such as nonenzymatic glycosylation, leads to the formation of advanced glycation end products (AGEs). The aim of our study was to explore whether glucose-modified β?GPI is able to interact and activate monocyte-derived immature dendritic cells (iDCs) from healthy human donors. SDS-PAGE and spectrofluorometric analyses indicated that β?GPI incubated with glucose was sugar modified, and that this modification likely consisted of AGE formation, resulting in AGE-β?GPI. AGE-β?GPI caused phenotypical and functional maturation of iDCs involving the activation of p38 MAPK, ERK, and NF-κB. It also induced on DCs a significant up-regulation of RAGE, the receptor for AGEs. Evidence for RAGE involvement comes from blocking experiments with an anti-RAGE mAb, confocal analysis, and coimmunoprecipitation experiments. AGE-β?GPI-stimulated DCs had increased allostimulatory ability and primed naive T lymphocytes toward a Th2 polarization. These findings might explain in part the interactive role of β?GPI, AGEs, and DCs in chronic disorders related to endothelial cell dysfunction.     

The antifibrinolytic function of factor XIII is exclusively expressed through α₂-antiplasmin cross-linking

Factor XIII (FXIII) generates fibrin-fibrin and fibrin-inhibitor cross-links. Our flow model, which is sensitive to cross-linking, was used to assess the effects of FXIII and the fibrinolytic inhibitor, α?-antiplasmin (α?AP) on fibrinolysis. Plasma model thrombi formed from FXIII or α?AP depleted plasma lysed at strikingly similar rates, 9-fold faster than pooled normal plasma (PNP). In contrast, no change was observed on depletion of PAI-1 or thrombin activatable fibrinolysis inhibitor (TAFI). Inhibition of FXIII did not further enhance lysis of α?AP depleted thrombi. Addition of PNP to FXIII or α?AP depleted plasmas normalized lysis. Lysis rate was strongly inversely correlated with total cross-linked α?AP in plasma thrombi. Reconstitution of FXIII into depleted plasma stabilized plasma thrombi and normalized γ-dimers and α-polymers formation. However, the presence of a neutralizing antibody to α?AP abolished this stabilization. Our data show that the antifibrinolytic function of FXIII is independent of fibrin-fibrin cross-linking and is expressed exclusively through α?AP.     

β₂ AR agonists in treatment of chronic heart failure: long path to translation

The main clinical manifestations of advanced chronic heart failure (CHF), e.g. in dilated cardiomyopathy (DCM), are reduced systolic and diastolic functions, increased arterial elastance and arterio-ventricular uncoupling, accompanied and exacerbated by an excessive sympathetic activation and extensive abnormalities in the βAR signaling. Loss of cardiomyocytes due to apoptosis is one mechanism that undoubtedly contributes to cardiac remodeling and functional deterioration associated with dilated cardiomyopathy (DCM). Research during the last decade on the single cardiomyocyte level strongly suggested that selective stimulation of β(1) AR activates the proapoptotic signaling pathways, while selective stimulation of β(2) AR is antiapoptotic, but its precise mechanisms remain to be elucidated. Extensive research in the rat model of DCM following induction of myocardial infarction (MI) showed that prolonged treatment with of β(2) AR agonist, fenoterol, in combination with a β(1) AR blocker, metoprolol, is more effective than β(1) AR blocker alone and as effective as β(1) AR blocker with ACE inhibitor with respect to survival and cardiac remodeling. This combined regimen of β(2) AR agonists and a β(1) AR blocker might be considered for clinical testing as alternative or adjunct therapy to currently acceptable CHF arsenal. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure."     

The effects of statin monotherapy and low-dose statin/ezetimibe on lipoprotein-associated phospholipase A₂

Background

Many of the pleiotropic effects of statins remain to be elucidated.

Hypothesis

Different statin regimens with similar lipid‐lowering efficacy may have different effects on biomarkers of atherothrombosis including lipoprotein‐associated phospholipase A₂ (Lp‐PLA₂).

Methods

After a 4‐week dietary lead‐in, 82 hypercholesterolemic patients were randomized to 1 of 2 treatment groups: atorvastatin 20 mg or atorvastatin/ezetimibe 5 mg/5 mg. After 8 weeks of drug treatment, the groups were compared for percent change in lipid parameters, Lp‐PLA₂, interleukin‐6 (IL‐6), monocyte chemoattractant protein‐1, and fibrinogen.

Results

Low‐density lipoprotein cholesterol (LDL‐C) lowering was comparable between the 2 groups (?47% ± 11% and ?49% ± 7% in the atorvastatin and combination groups, respectively). Although Lp‐PLA₂ was reduced in both groups, the reduction was greater in the atorvastatin group (?42% and ?9% [median], respectively, P = 0.03). Although IL‐6 was decreased only in the atorvastatin group, IL‐6 changes were not significantly different between the 2 groups. The changes in monocyte chemoattractant protein‐1 and fibrinogen were similar in each group.

Conclusions

Atorvastatin monotherapy was stronger at reducing plasma Lp‐PLA₂ than the low‐dose atorvastatin/ezetimibe combination after equivalent LDL‐C lowering. This result may provide evidence of potential statin effects beyond the lowering of LDL‐C. Copyright © 2011 Wiley Periodicals, Inc. This study was supported by a grant from the Ministry of Health and Welfare, Republic of Korea (A000385), a grant of the Seoul R&BD Program, Republic of Korea (10526), and a grant of the Korean Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A085136). The authors have no other funding, financial relationships, or conflicts of interest to disclose.

     

Pressure-induced reversible amorphization and an amorphous-amorphous transition in Ge₂Sb₂Te₅ phase-change memory material

Ge₂Sb₂Te₅ (GST) is a technologically very important phase-change material that is used in digital versatile disks-random access memory and is currently studied for the use in phase-change random access memory devices. This type of data storage is achieved by the fast reversible phase transition between amorphous and crystalline GST upon heat pulse. Here we report pressure-induced reversible crystalline-amorphous and polymorphic amorphous transitions in NaCl structured GST by ab initio molecular dynamics calculations. We have showed that the onset amorphization of GST starts at approximately 18 GPa and the system become completely random at approximately 22 GPa. This amorphous state has a cubic framework (c-amorphous) of sixfold coordinations. With further increasing pressure, the c-amorphous transforms to a high-density amorphous structure with trigonal framework (t-amorphous) and an average coordination number of eight. The pressure-induced amorphization is investigated to be due to large displacements of Te atoms for which weak Te–Te bonds exist or vacancies are nearby. Upon decompressing to ambient conditions, the original cubic crystalline structure is restored for c-amorphous, whereas t-amorphous transforms to another amorphous phase that is similar to the melt-quenched amorphous GST.     

RGS2 is a primary terminator of β₂-adrenergic receptor-mediated G(i) signaling

Two major β-adrenergic receptor (βAR) subtypes, β₁AR and β₂AR, are expressed in mammalian heart with β₁AR coupling to G_s and β₂AR dually coupling to G_s and G_i proteins. In many types of chronic heart failure, myocardial contractile response to both β₁AR and β₂AR stimulation is severely impaired. The dysfunction of βAR signaling in failing hearts is largely attributable to an increase in G_i signaling, because disruption of the G_i signaling restores myocardial contractile response to β₁AR as well as β₂AR stimulation. However, the mechanism terminating the β₂AR-G_i signaling remains elusive, while it has been shown activation of the G_i signaling is dependent on agonist stimulation and subsequent PKA-mediated phosphorylation of the receptor. Here we demonstrate that regulator of G protein signaling 2 (RGS2) is a primary terminator of the β₂AR-G_i signaling. Specifically, prolonged absence of agonist stimulation for 24 h impairs the β₂AR-G_i signaling, resulting in enhanced β₂AR- but not β₁AR-mediated contractile response in cultured adult mouse cardiomyocytes. Increased β₂AR contractile response is accompanied by a selective upregulation of RGS2 in the absence of alterations in other major cardiac RGS proteins (RGS3–5) or G_s, G_i or βAR subtypes. Administration of a βAR agonist, isoproterenol (ISO, 1.0 nM), prevents RGS2 upregulation and restores the β₂AR-G_i signaling in cultured cells. Furthermore, RGS2 ablation, similar to βAR agonist stimulation, sustains the β₂AR-G_i signaling in cultured cells, whereas adenoviral overexpression of RGS2 suppresses agonist-activated β₂AR-G_i signaling in cardiomyocytes and HEK293 cells. These findings not only define RGS2 as a novel negative regulator of the β₂AR-G_i signaling but also provide a potential novel target for the treatment of chronic heart failure.     

The effects of laropiprant, a selective prostaglandin D₂ receptor 1 antagonist, on the antiplatelet activity of clopidogrel or aspirin

Laropiprant (LRPT) is being developed in combination with Merck's extended-release niacin (ERN) formulation for the treatment of dyslipidemia. LRPT, an antagonist of the prostaglandin PGD? receptor DP1, reduces flushing symptoms associated with ERN. LRPT also has affinity for the thromboxane A? receptor TP (approximately 190-fold less potent at TP compared with DP1). Aspirin and clopidogrel are two frequently used anti-clotting agents with different mechanisms of action. Since LRPT may potentially be co-administered with either one of these agents, these studies were conducted to assess the effects of steady-state LRPT on the antiplatelet activity of steady-state clopidogrel or aspirin. Bleeding time at 24 h post-dose (trough) was pre-specified as the primary pharmacodynamic endpoint in both studies. Two separate, double-blind, randomized, placebo-controlled, crossover studies evaluated the effects of multiple-dose LRPT on the pharmacodynamics of multiple-dose clopidogrel or aspirin. Healthy subjects were randomized to once-daily oral doses of LRPT 40?mg or placebo to LRTP co-administered with clopidogrel 75?mg or aspirin 81 mg for 7 days with at least a 21-day washout between treatments. In both studies, bleeding time and platelet aggregation were assessed 4 and 24 hours post-dose on Day 7. Comparability was declared if the 90% confidence interval for the estimated geometric mean ratio ([LRPT+clopidogrel]/clopidogrel alone or [LRPT+aspirin]/aspirin alone) for bleeding time at 24 hours post-dose on Day 7 was contained within (0.66, 1.50). Concomitant daily administration of LRPT 40?mg with clopidogrel 75?mg or aspirin 81?mg resulted in an approximate 4-5% increase in bleeding time at 24 hours after the last dose vs. bleeding time after treatment with clopidogrel or aspirin alone, demonstrating that the treatments had comparable effects on bleeding time. Percent inhibition of platelet aggregation was not significantly different between LRPT co-administered with clopidogrel or aspirin vs. clopidogrel or aspirin alone at 24 hours post-dose at steady state. At 4 hours after the last dose, co-administration of LRPT 40?mg resulted in 3% and 41% increase in bleeding time vs. bleeding time after treatment with aspirin or clopidogrel alone, respectively. Co-administration of LPRT with clopidogrel or aspirin was generally well tolerated in healthy subjects. Co-administration of multiple doses of LRPT 40?mg and clopidogrel 75?mg or aspirin 81?mg had no clinically important effects on bleeding time or platelet aggregation.