T-Cell Memory Responses Elicited by Yellow Fever Vaccine are Targeted to Overlapping Epitopes Containing Multiple HLA-I and -II Binding Motifs

The yellow fever vaccines (YF-17D-204 and 17DD) are considered to be among the safest vaccines and the presence of neutralizing antibodies is correlated with protection, although other immune effector mechanisms are known to be involved. T-cell responses are known to play an important role modulating antibody production and the killing of infected cells. However, little is known about the repertoire of T-cell responses elicited by the YF-17DD vaccine in humans. In this report, a library of 653 partially overlapping 15-mer peptides covering the envelope (Env) and nonstructural (NS) proteins 1 to 5 of the vaccine was utilized to perform a comprehensive analysis of the virus-specific CD4+ and CD8+ T-cell responses. The T-cell responses were screened ex-vivo by IFN-γ ELISPOT assays using blood samples from 220 YF-17DD vaccinees collected two months to four years after immunization. Each peptide was tested in 75 to 208 separate individuals of the cohort. The screening identified sixteen immunodominant antigens that elicited activation of circulating memory T-cells in 10% to 33% of the individuals. Biochemical in-vitro binding assays and immunogenetic and immunogenicity studies indicated that each of the sixteen immunogenic 15-mer peptides contained two or more partially overlapping epitopes that could bind with high affinity to molecules of different HLAs. The prevalence of the immunogenicity of a peptide in the cohort was correlated with the diversity of HLA-II alleles that they could bind. These findings suggest that overlapping of HLA binding motifs within a peptide enhances its T-cell immunogenicity and the prevalence of the response in the population. In summary, the results suggests that in addition to factors of the innate immunity, "promiscuous" T-cell antigens might contribute to the high efficacy of the yellow fever vaccines. © 2013 de Melo et al

Tibiofibular syndesmosis in acute ankle fractures: additional value of an oblique MR image plane

Item does not contain fulltextOBJECTIVE: To evaluate the additional value of a 45� oblique MRI scan plane for assessing the anterior and posterior distal tibiofibular syndesmotic ligaments in patients with an acute ankle fracture. MATERIALS AND METHODS: Prospectively, data were collected for 44 consecutive patients with an acute ankle fracture who underwent a radiograph (AP, lateral, and mortise view) as well as an MRI in both the standard three orthogonal planes and in an additional 45� oblique plane. The fractures on the radiographs were classified according to Lauge-Hansen (LH). The anterior (ATIFL) and posterior (PTIFL) distal tibiofibular ligaments, as well as the presence of a bony avulsion in both the axial and oblique planes was evaluated on MRI. MRI findings regarding syndesmotic injury in the axial and oblique planes were compared to syndesmotic injury predicted by LH. Kappa and the agreement score were calculated to determine the interobserver agreement. The Wilcoxon signed rank test and McNemar's test were used to compare the two scan planes. RESULTS: The interobserver agreement (?) and agreement score [AS (\%)] regarding injury of the ATIFL and PTIFL and the presence of a fibular or tibial avulsion fracture were good to excellent in both the axial and oblique image planes (? 0.61-0.92, AS 84-95\%). For both ligaments the oblique image plane indicated significantly less injury than the axial plane (p?<?0.001). There was no significant difference in detection of an avulsion fracture in the axial or oblique plane, neither anteriorly (p?=?0.50) nor posteriorly (p?=?1.00). With syndesmotic injury as predicted by LH as comparison, the specificity in the oblique MR plane increased for both anterior (to 86\% from 7\%) and posterior (to 86\% from 48\%) syndesmotic injury when compared to the axial plane. CONCLUSION: Our results show the additional value of an 45� oblique MR image plane for detection of injury of the anterior and posterior distal tibiofibular syndesmoses in acute ankle fractures. Findings of syndesmotic injury in the oblique MRI plane were closer to the diagnosis as assumed by the Lauge-Hansen classification than in the axial plane. With more accurate information, the surgeon can better decide when to stabilize syndesmotic injury in acute ankle fractures

Craniectomy for Malignant Cerebral Infarction: Prevalence and Outcomes in US Hospitals

Randomized trials have demonstrated the efficacy of craniectomy for the treatment of malignant cerebral edema following ischemic stroke. We sought to determine the prevalence and outcomes related to this by using a national database.Patient discharges with ischemic stroke as the primary diagnosis undergoing craniectomy were queried from the US Nationwide Inpatient Sample from 1999 to 2008. A subpopulation of patients was identified that underwent thrombolysis. Two primary end points were examined: in-hospital mortality and discharge to home/routine care. To facilitate interpretations, adjusted prevalence was calculated from the overall prevalence and two age-specific logistic regression models. The predictive margin was then generated using a multivariate logistic regression model to estimate the probability of in-hospital mortality after adjustment for admission type, admission source, length of stay, total hospital charges, chronic comorbidities, and medical complications.After excluding 71,996 patients with the diagnosis of intracranial hemorrhage and posterior intracranial circulation occlusion, we identified 4,248,955 adult hospitalizations with ischemic stroke as a primary diagnosis. The estimated rates of hospitalizations in craniectomy per 10,000 hospitalizations with ischemic stroke increased from 3.9 in 1999-2000 to 14.46 in 2007-2008 (p for linear trend<0.001). Patients 60+ years of age had in-hospital mortality of 44% while the 18-59 year old group was found to be 24% (p = 0.14). Outcomes were comparable if recombinant tissue plasminogen activator had been administered.Craniectomy is being increasingly performed for malignant cerebral edema following large territory cerebral ischemia. We suspect that the increase in the annual incidence of DC for malignant cerebral edema is directly related to the expanding collection of evidence in randomized trials that the operation is efficacious when performed in the correct patient population. In hospital mortality is high for all patients undergoing this procedure

What Is Direct Allorecognition?

Direct allorecognition is the process by which donor-derived major histocompatibility complex (MHC)-peptide complexes, typically presented by donor-derived ‘passenger’ dendritic cells, are recognised directly by recipient T cells. In this review, we discuss the two principle theories which have been proposed to explain why individuals possess a high-precursor frequency of T cells with direct allospecificity and how self-restricted T cells recognise allogeneic MHCpeptide complexes. These theories, both of which are supported by functional and structural data, suggest that T cells recognising allogeneic MHC-peptide complexes focus either on the allopeptides bound to the allo-MHC molecules or the allo-MHC molecules themselves. We discuss how direct alloimmune responses may be sustained long term, the consequences of this for graft outcome and highlight novel strategies which are currently being investigated as a potential means of reducing rejection mediated through this pathway