Two Vaccines for Staphylococcus aureus Induce a B-Cell- Mediated Immune Response

Staphylococcus aureus causes severe disease in humans for which no licensed vaccine exists. A novel S. aureus vaccine (SA4Ag) is in development, targeting the capsular polysaccharides (CPs) and two virulence-associated surface proteins. Vaccine-elicited antibody responses to CPs are efficacious against serious infection by other encapsulated bacteria. Studies of natural S. aureus infection have also shown a role for TH17 and/or TH1 responses in protection. Single-antigen vaccines, including CPs, have not been effective against S. aureus; a multiantigen vaccine approach is likely required. However, the impact of addition of protein antigens on the immune response to CPs has not been studied. Here, the immune response induced by a bivalent CP conjugate vaccine (to model the established mechanism of action of vaccine-induced protection against Gram-positive pathogens) was compared to the response induced by SA4Ag, which contains both CP conjugates and protein antigens, in cynomolgus macaques. Microengraving, flow cytometry, opsonophagocytic assays, and Luminex technology were used to analyze the B-cell, T-cell, functional antibody, and innate immune responses. Both the bivalent CP vaccine and SA4Ag induced cytokine production from naive cells and antigen-specific memory B-cell and functional antibody responses. Increases in levels of circulating, activated T cells were not apparent following vaccination, nor was a TH17 or TH1 response evident. However, our data are consistent with a vaccine-induced recruitment of T follicular helper (TFH) cells to lymph nodes. Collectively, these data suggest that the response to SA4Ag is primarily mediated by B cells and antibodies that abrogate important S. aureus virulence mechanisms.IMPORTANCEStaphylococcus aureus causes severe disease in humans for which no licensed vaccine exists. A novel vaccine is in development that targets multiple elements of the bacteria since single-component vaccines have not shown efficacy to date. How these multiple components alter the immune response raised by the vaccine is not well studied. We found that the addition of two protein components did not alter substantially the antibody responses raised with respect to function or mobilization of B cells. There was also not a substantial change in the activity of T cells, another part of the adaptive response. This study showed that protection by this vaccine may be mediated primarily by antibody protection.Pfizer Inc.National Cancer Institute (U.S.) (grant P30-CA14051

Secondary osteosarcoma arising after treatment for childhood hematologic malignancies

Secondary osteosarcoma arising after the treatment of hematologic malignancies other than Hodgkin's lymphoma is rare. We report two cases of secondary osteosarcoma arising after treatment for childhood hematologic malignancies (non-Hodgkin's lymphoma and lymphoblastic leukemia). A 10-year-old boy, at the age of 3, was diagnosed with non-Hodgkin's lymphoma. He received chemotherapy, radiation, and bone-marrow transplantation and then was in complete remission. At 6 years, he complained of increasing pain of the right thigh and was diagnosed with osteoblastic osteosarcoma. A 26-year-old man, at the age of 6, was diagnosed as having acute lymphoblastic leukemia (ALL). He received chemotherapy, radiation, and peripheral blood stem cell transplantation (PBSCT). At 11 years after PBSCT, he visited with the complaint of left lumbar swelling. He was diagnosed with chondroblastic osteosarcoma. In both cases alkaline phosphatase (ALP) had already increased prior to the onset of the symptom. We should rule out secondary osteosarcoma at the abnormal elevation of ALP during clinical follow-up of patients after treatment of childhood hematologic malignancies

Role of Misfolded N-CoR Mediated Transcriptional Deregulation of Flt3 in Acute Monocytic Leukemia (AML)-M5 Subtype

The nuclear receptor co-repressor (N-CoR) is a key component of the generic multi-protein complex involved in transcriptional control. Flt3, a key regulator of hematopoietic cell growth, is frequently deregulated in AML (acute myeloid leukemia). Here, we report that loss of N-CoR-mediated transcriptional control of Flt3 due to misfolding, contributes to malignant growth in AML of the M5 subtype (AML-M5). An analysis of hematopoietic genes in AML cells led to the identification of Flt3 as a transcriptional target of N-CoR. Flt3 level was inversely related to N-CoR status in various leukemia cells. N-CoR was associated with the Flt3 promoter in-vivo, and a reporter driven by the Flt3 promoter was effectively repressed by N-CoR. Blocking N-CoR loss with Genistein; an inhibitor of N-CoR misfolding, significantly down-regulated Flt3 levels regardless of the Flt3 receptor mutational status and promoted the differentiation of AML-M5 cells. While stimulation of the Flt3 receptor with the Flt3 ligand triggered N-CoR loss, Flt3 antibody mediated blockade of Flt3 ligand-receptor binding led to N-CoR stabilization. Genetic ablation of N-CoR potentiated Flt3 ligand induced proliferation of BA/F3 cells. These findings suggest that N-CoR-induced repression of Flt3 might be crucial for limiting the contribution of the Flt3 signaling pathway on the growth potential of leukemic cells and its deregulation due to N-CoR loss in AML-M5, could contribute to malignant growth by conferring a proliferative advantage to the leukemic blasts. Therapeutic restoration of N-CoR function could thus be a useful approach in restricting the contribution of the Flt3 signaling pathway in AML-M5 pathogenesis

Novel Structurally Designed Vaccine for S. aureus α-Hemolysin: Protection against Bacteremia and Pneumonia

Staphylococcus aureus (S. aureus) is a human pathogen associated with skin and soft tissue infections (SSTI) and life threatening sepsis and pneumonia. Efforts to develop effective vaccines against S. aureus have been largely unsuccessful, in part due to the variety of virulence factors produced by this organism. S. aureus alpha-hemolysin (Hla) is a pore-forming toxin expressed by most S. aureus strains and reported to play a key role in the pathogenesis of SSTI and pneumonia. Here we report a novel recombinant subunit vaccine candidate for Hla, rationally designed based on the heptameric crystal structure. This vaccine candidate, denoted AT-62aa, was tested in pneumonia and bacteremia infection models using S. aureus strain Newman and the pandemic strain USA300 (LAC). Significant protection from lethal bacteremia/sepsis and pneumonia was observed upon vaccination with AT-62aa along with a Glucopyranosyl Lipid Adjuvant-Stable Emulsion (GLA-SE) that is currently in clinical trials. Passive transfer of rabbit immunoglobulin against AT-62aa (AT62-IgG) protected mice against intraperitoneal and intranasal challenge with USA300 and produced significant reduction in bacterial burden in blood, spleen, kidney, and lungs. Our Hla-based vaccine is the first to be reported to reduce bacterial dissemination and to provide protection in a sepsis model of S. aureus infection. AT62-IgG and sera from vaccinated mice effectively neutralized the toxin in vitro and AT62-IgG inhibited the formation of Hla heptamers, suggesting antibody-mediated neutralization as the primary mechanism of action. This remarkable efficacy makes this Hla-based vaccine a prime candidate for inclusion in future multivalent S. aureus vaccine. Furthermore, identification of protective epitopes within AT-62aa could lead to novel immunotherapy for S. aureus infection

Preprocedural Mean Platelet Volume Level Is a Predictor of In-Stent Restenosis of the Superficial Femoral Artery Stents in Follow-Up

Background. The mean platelet volume (MPV), the most commonly used measure of the platelet size, is a cheap and easy-to-use marker of the platelet activation. We aimed to evaluate the relationship between preprocedural MPV and other hematologic blood count parameters and in-stent restenosis in patients with superficial femoral artery (SFA) stenting. Methods and Results. The consecutive 118 patients who successfully underwent endovascular stenting of the SFA were enrolled retrospectively in the study. The mean follow-up was 23 ± 12 months. The in-stent restenosis was observed in 42 patients (35.6%). There were no statistically significant differences between the restenosis group and no-restenosis group in terms of age, gender, and smoking (p=0.116, p=0.924, and p=0.428, resp.). In the restenosis group, the MPV level was markedly higher than that in the no-restenosis group, and it was statistically significant (p<0.001). According to the ROC curve analysis, the optimal cutoff value of the MPV to determine the restenosis was >8.7 fL, and the level of the MPV >8.7 fL was a strong predictor of the restenosis (p<0.001) in logistic regression analysis. Conclusions. The measurement of the preprocedural MPV levels may help to identify high-risk patients for development of the in-stent restenosis. These patients may benefit from an aggresive antiplatelet therapy and close follow-up

A simple discharge risk model for predicting 1-year mortality in hospitalised acute decompansated heart failure patients with reduced ejection fraction

WOS: 000431104400008PubMed: 28786775Objective: The risk stratification for prognosis in heart failure is very important for optimal disease management and decision making. The aim of this study was to establish a simple discharge 1-year mortality prediction model by integrating data obtained from demographic characteristics, clinical evaluation, laboratory biomarkers and echocardiographic evaluation of hospitalised heart failure with reduced ejection fraction (HFrEF) patients with acute decompensation. Methods and results: A risk score model was developed based on beta-coefficient number of variables in a multivariable logistic regression model which was created with the use of data on clinical, laboratory, imaging and therapeutic findings of 670 patients (65.4% males, 65 +/- 11 years) who was hospitalised with acute decompensated HFrEF. The mean left ventricular ejection fraction (LVEF) was 26 +/- 9%. Independent predictors of mortality were: age >= 75 years, sodium <130 mEq/L, hepatomegaly at admission, unable to use beta-blocker at discharge and LVEF 20%. The 1-year mortality rate was 7.8% in the study population. The existence of each predictor was scored as 1 point and the discharge risk score identified patients into low (0-1 points), intermediate (2-3 points) and high (4-5 points) risk individuals with 3, 15.6 and 44.4% 1-year mortality rates, respectively. The model performance evaluated by concordance index was 0.74. Conclusions: This simple discharge risk score model for hospitalised acute decompensated HFrEF patients using easily determined demographic characteristics, clinical signs, echocardiographic and laboratory data is a valuable and an easy risk assessment tool to use at point-of-care

Elevated B12 levels in systolic heart failure patients - associations with right heart failure and impaired prognosis

WOS: 00040100530143

Elevated levels of vitamin B12 in chronic stable heart failure: a marker for subclinical liver damage and impaired prognosis

WOS: 000434357200002PubMed: 29922067Background: Elevated vitamin B12 is a sign for liver damage, but its significance in chronic stable heart failure (HF) is less known. The present study investigated the clinical correlates and prognostic significance of vitamin B12 levels in stable systolic HF. Methods: A total of 129 consecutive patients with HF and 50 control subjects were enrolled. Data regarding demographics, clinical signs, therapeutic and conventional echocardiographic measurements were recorded for all patients. Right-sided HF was defined as the presence of at least one of the typical symptoms (ankle swelling) or specific signs (jugular venous distention or abdominojugular reflux) of right HF. Cox proportional hazards regression analyses were performed to determine the independent prognostic determinants of mortality. Results: Baseline B12 levels in HF patients (n=129) with and without right sided HF were significantly higher compared to healthy controls (n=50): Median 311 pg/mL and 235 pg/mL vs 198 pg/mL, respectively (P=0.005). Folic acid levels were similar between the study groups. Age, ejection fraction, left atrial size, estimated glomerular filtration rate, and direct and indirect bilirubin levels were significantly correlated to serum B12 level in univariate analysis. In multivariate analysis, independent correlates of B12 were direct bilirubin (R=0.51, P= 270 pg/mL had 80% sensitivity and 58% specificity for predicting all-cause mortality (area under the curve=0.672, 95% CI=0.562-0.781; P=0.003). However, in Cox regression analysis, only left atrial diameter, level of direct bilirubin, and the presence of abdominojugular reflux were independent predictors of death. Conclusion: Increased B12 in stable HF patients is associated with increased direct bilirubin due to right HF, indicating a cardiohepatic syndrome, but neither B12 nor folic acid are independently associated with mortality

their mother's maternal aunt with a female phenotype

Objective: To present a familial case of Swyer syndrome.Design: Case report.Setting: Academic medical center.Patient(s): Two sisters with a main complaint of primary amenorrhea and another case, their mother's maternal aunt with the same history of primary amenorrhea but married with no consanguinity and no children.Intervention(s): None.Main Outcome Measure(s): The patients were studied from clinical, endocrinologic, and genetic perspectives.Result(s): Chromosome analyses revealed a 46, XY male karyotype with no detectable mosaicism in both sisters and their mother's maternal aunt. Molecular studies of sex-determining region Y and molecular investigation undertaken for the two sisters revealed SRY negativity.Conclusion(s): Gonadal dysgenesis can also be inherited as an X-linked disorder, and evidence exists from familial studies of perhaps autosomal inheritance. (Fertil Steril (R) 2011; 95: 1786. e1-e3. (C) 2011 by American Society for Reproductive Medicine.