Diverse variola virus (smallpox) strains were widespread in northern Europe in the Viking Age.

Smallpox, one of the most devastating human diseases, killed between 300 million and 500 million people in the 20th century alone. We recovered viral sequences from 13 northern European individuals, including 11 dated to ~600-1050 CE, overlapping the Viking Age, and reconstructed near-complete variola virus genomes for four of them. The samples predate the earliest confirmed smallpox cases by ~1000 years, and the sequences reveal a now-extinct sister clade of the modern variola viruses that were in circulation before the eradication of smallpox. We date the most recent common ancestor of variola virus to ~1700 years ago. Distinct patterns of gene inactivation in the four near-complete sequences show that different evolutionary paths of genotypic host adaptation resulted in variola viruses that circulated widely among humans.

Impaired activation of IFN-gamma+CD4+ T cells in peripheral blood of patients with dilated cardiomyopathy.

Viral persistence and autoantibodies are pathogenic components in patients with idiopathic dilated cardiomyopathy (DCM). The aim was to evaluate T-cell function in DCM using different flow cytometry based detection techniques. Following stimulation, the frequency of IFN-gamma-producing CD4+ T cells was significantly lower in patients compared with controls. In contrast, the frequency of IL-4 producing CD4+ T cells was no different. In supernatants of cultured PBMC, IFN-gamma and IL-10 were significantly lower in patients. In addition, lymphocyte proliferation was significantly lower in patients compared with controls, whereas major lymphocyte subsets were not different. IFN-gamma and IL-10 are key cytokines in the ability to mount protective immune responses and to maintain self-tolerance. A reduced activation of T-helper 1 (IFN-gamma producing) cells and a decreased capacity to produce IL-10, found in the present study, could explain parts of the autoimmune features seen in patients with DCM.

Lower levels of the host protective IL-10 in DCM--a feature of autoimmune pathogenesis?

OBJECTIVES: To investigate whether cytokine patterns differ with respect to heart failure (HF) etiology, and to study how cytokine concentrations relate to hemodynamic alterations. METHODS: Plasma levels of interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor alpha (TNF-alpha) and high sensitive-CRP (hs-CRP) were analysed with enzyme-linked-immunosorbent serologic assay and turbidimetry in 45 healthy subjects and 89 patients with HF, of whom 65 were diagnosed with dilated cardiomyopathy (DCM) and 24 had ischemic heart disease (IHD). RESULTS: IL-6, IL-10 and hs-CRP were significantly higher in patients with HF as compared to healthy controls. The IL-10 was significantly lower in patients with DCM as compared to IHD, also when adjusting for clinical variables. Diastolic filling pressure correlated with IL-6, IL-10 and hs-CRP while heart rate (HR) correlated with IL-6 and TNF-alpha. CONCLUSIONS: Proinflammatory cytokines are elevated in patients with HF and display a positive correlation with filling pressures and HR. Most significant, the regulatory and protective cytokine IL-10 was much lower in patients with DCM as compared to IHD, indicating a differentiation in cytokine patterns with respect to HF etiology.

Cardiac reserve in the transplanted heart: effect of a graft polymorphism in the beta1-adrenoceptor.

BACKGROUND: Polymorphism of the beta1-adrenoceptor (beta1-AR) affects outcome and beta-blocker efficacy in patients with heart failure. We studied the influence of the beta1-AR Ser49Gly polymorphism on cardiac reserve in transplanted hearts. METHODS: Beta1-AR polymorphism was determined by allelic discrimination analysis. Patients were divided into two groups: either homozygous for Ser49 (n = 15) or with Gly49 in one or both alleles (Gly49; n = 5). Patients underwent a maximal bicycle exercise test and echocardiographic evaluation at rest and during low-dose dobutamine stress. RESULTS: Patients with Gly49 grafts had better physical endurance (144 +/- 26 vs 112 +/- 31 W, p = 0.03), a trend toward better chronotropic reserve (deltaHR 64 +/- 13 vs 47 +/- 16 bpm, p = 0.056) during exercise, and lower resting heart rate (82 +/- 7 vs 90 +/- 7 bpm, p = 0.04) than those homozygous for Ser49. There were no significant differences in left ventricular ejection fraction (LVEF), with the exception of a decrease in cardiac reserve in patients with the Gly49 variants at the lowest dose of dobutamine (deltaLVEF -4.4 +/- 1.5 vs 2.2 +/- 5.8%, p = 0.04). Doppler myocardial tissue velocities of early relaxation were increased in patients with the Gly49 variants compared with patients homozygous for Ser49, both at rest (14.5 +/- 3.2 vs 10.4 +/- 2.0 cm/s, p = 0.03) and during the lowest dose of dobutamine (15.0 +/- 3.7 vs 10.9 +/- 2.5 cm/s, p = 0.04). CONCLUSIONS: Heart transplant patients with the beta1-AR Gly49 variants had a lower heart rate, and better stress endurance and diastolic function compared with patients homozygous for Ser49. They also showed a trend toward better chronotropic reserve. These results provide a possible explanation for differences in cardiac reserve among patients with heart transplants.

Ser49Gly of beta1-adrenergic receptor is associated with effective beta-blocker dose in dilated cardiomyopathy.

OBJECTIVE: Our objective was to evaluate the influence of polymorphisms at codons 49 and 389 of the beta1-adrenergic receptor (beta1-AR) on the response to beta-blockers and outcome in patients with dilated cardiomyopathy. METHODS: We genotyped both codons of the beta1-AR in 375 patients with dilated cardiomyopathy and 492 control subjects. RESULTS: Neither of the polymorphisms was associated with susceptibility for dilated cardiomyopathy. In a retrospective analysis of patients receiving beta-blockers, there was a significant association between long-term survival rate and codon 49 (P = .014) but not codon 389 (P = .08). Despite a similar mean heart rate (69 beats/min), patients with the Ser49 genotype tended to have higher doses of beta-blockade compared with Gly49 carriers (P = .065). In patients receiving a low dose of beta-blockade (< or = 50% of targeted full dose), the 5-year mortality rate was lower among Gly49 carriers than Ser49 patients (risk ratio [RR], 0.24; 95% confidence interval [CI], 0.07-0.80; P = .020). In patients receiving high doses of beta-blockers, there was no significant difference in outcome between genotypes (P = .20), which was attributable to a better outcome for Ser49 patients treated with a high dose of beta-blockade as compared with a low dose. Gly49 carriers had a similar survival rate with different doses of beta-blockers. With low-dose beta-blockers, both codon 49 (RR, 0.26; 95% CI, 0.08-0.89; P = .029) and codon 389 (RR, 2.42; 95% CI, 1.04-5.63, P = .039) were related to 5-year mortality rate. CONCLUSION: In patients with heart failure, the influence of codon 49 on the outcome and effect of beta-blockers appeared to be more pronounced than that of codon 389. The more common Ser49Ser genotype responded less beneficially to beta-blockade and would motivate genotyping to promote higher doses for the best outcome effect.

The myocardium-protective Gly-49 variant of the beta 1-adrenergic receptor exhibits constitutive activity and increased desensitization and down-regulation.

The beta(1)-adrenergic receptor (beta(1)AR) is a major mediator of catecholamine effects in human heart. Patients with heart failure who were hetero- or homozygous for the Gly-49 variant of the beta(1)AR (Gly-49-beta(1)AR) showed improved long-term survival as compared with those with the Ser-49 genotype. Here, the functional consequences of this polymorphism were studied in cells expressing either variant. The Gly-49-beta(1)AR demonstrated characteristic features of constitutively active receptors. In cells expressing the Gly-49-beta(1)AR, both basal and agonist-stimulated adenylyl cyclase activities were higher than in cells expressing the Ser-49 variant (Ser-49-beta(1)AR). The Gly-49-beta(1)AR was more sensitive to the inhibitory effect of the inverse agonist metoprolol and displayed increased affinity for agonists. Isoproterenol potency for adenylyl cyclase activation was higher on membranes expressing the Gly-49-beta(1)AR than on those expressing the Ser-49-beta(1)AR. After incubation with saturating concentrations of catecholamines or sustained stimulation, the Gly-49 variant showed a much higher desensitization, which largely prevailed over constitutive activity in terms of cAMP accumulation. The Gly-49-beta(1)AR also displayed a more profound agonist-promoted down-regulation than the Ser-49 variant. The stronger regulation of the Gly-49-beta(1)AR could explain the beneficial effect of the Gly-49 genotypes on survival, further supporting the concept that beta(1)AR desensitization is protective in heart failure.