Safety and immunogenicity of a bivalent group B streptococcal conjugate vaccine for serotypes II and III

To determine whether 2 monovalent group B streptococcus (GBS) serotype II or III capsular polysaccharide (CPS)-tetanus toxoid (TT) conjugate vaccines combined in a single intramuscular dose would elicit immune responses comparable to those of monovalent vaccines, 75 healthy adults were randomized to receive GBS II-TT (3.6 micro g of CPS), GBS III-TT (12.5 micro g of CPS), or a bivalent mixture of GBS II-TT/III-TT vaccine (double-masked design). Vaccines were well tolerated. Four-fold or greater increases in GBS II or III CPS-specific IgG, respectively, were noted in postimmunization serum samples from 80%-90% of bivalent conjugate vaccine recipients, and these responses were similar to those of recipients of GBS II-TT or GBS III-TT monovalent vaccines. Immune serum samples promoted the opsonophagocytic killing of types II and III GBS in vitro. Unexpectedly, some recipients of these vaccines developed cross-reactive antibodies to the structurally similar heterologous polysaccharide. These results support the feasibility of a multivalent vaccine for the 5 prevalent invasive disease-causing GBS CPS serotypes.     

Deceleration time of early filling in patients with left ventricular systolic dysfunction: functional and prognostic independent value

Background Although diastolic function parameters have been mentioned as significant predictors of functional capacity and prognosis in patients with left ventricular (LV) systolic dysfunction, it has not been fully elucidated whether they keep an independent predictive value when multiple parameters from a wide variety of examinations are considered. Methods We prospectively studied 60 patients with New York Heart Association (NYHA) class II-IV chronic heart failure symptoms and LV ejection fraction <0.4. At the time of entry into the study, demographic data and functional class were obtained, and usual Doppler echocardiographic, radionuclide ventriculographic, cardiopulmonary exercise testing and hemodynamic variables were determined. Deceleration time of early filling (DT) and NYHA functional class were the only independent predictors of functional capacity as assessed by means of peak oxygen uptake (peak Vo₂). Mean follow-up was 21 ± 6 months, and event-free survival was defined as the absence of cardiac death, urgent cardiac transplantation, or hospital admission requiring inotropic or mechanical support. Results Multivariate Cox analysis showed that DT (P = .008), peak Vo₂ (P = .01), and NYHA class (P = .02) were independent predictors of event-free survival at 1 year. Patients in the lowest tertile of DT (<130 ms) had a significantly lower event-free survival than patients in the intermediate (44% vs 80%, P = .03) and in the highest tertile (44% vs 83%, P = .02). Patients with both a DT <130 milliseconds and a peak Vo₂ <14 mL/kg/min had the highest rate of events at 1 year (83% vs 22% for the remaining patients, relative risk 3.75, P < .001). Conclusions In patients with LV systolic dysfunction, DT is a powerful independent predictor of functional capacity and prognosis among a wide variety of variables. A shortened DT (<130 ms) identifies a subgroup of patients with a worse outcome, especially when combined with a reduced peak Vo₂ (<14 mL/kg/min). (Am Heart J 2002;143:1101-6.)     

Effect of inhibition of Na(+)/Ca(2+) exchanger at the time of myocardial reperfusion on hypercontracture and cell death

OBJECTIVE: There is recent evidence that Ca(2+) influx via reverse mode Na(+)/Ca(2+) exchange (NCX) at the time of reperfusion can contribute to cardiomyocyte hypercontracture. However, forward NCX is essential for normalization of [Ca(2+)](i) during reperfusion, and its inhibition may be detrimental. This study investigates the effect of NCX inhibition with KB-R7943 at the time of reperfusion on cell viability. METHODS: The effect of several concentrations of KB-R7943 added at reperfusion was studied in Fura-2 loaded quiescent cardiomyocytes submitted to 40 min of simulated ischemia (NaCN 2 mM, pH 6.4), and in rat hearts submitted to 60 min of ischemia. [Ca(2+)](i) and cell length were monitored in myocytes, and functional recovery and LDH release in isolated hearts. From these experiments an optimal concentration of KB-R7943 was identified and tested in pigs submitted to 48 min of coronary occlusion and 2 h of reperfusion. RESULTS: In myocytes, KB-R7943 at concentrations up to 15 microM reduced [Ca(2+)](i) rise and the probability of hypercontracture during re-energization (P<0.01). Nevertheless, in rat hearts, the effects of KB-R7943 applied during reperfusion after 60 min of ischemia depended on concentration and timing of administration. During the first 5 min of reperfusion, KB-R7943 (0.3-30 microM) induced a dose-dependent reduction in LDH release (half-response concentration 0.29 microM). Beyond 6 min of re-flow, KB-R7943 had no effect on LDH release, except at concentrations > or = 15 microM, which increased LDH. KB-R7943 at 5 microM given during the first 10 min of reflow reduced contractile dysfunction (P=0.011), LDH release (P=0.019) and contraction band necrosis (P=0.014) during reperfusion. Intracoronary administration of this concentration during the first 10 min of reperfusion reduced infarct size by 34% (P=0.033) in pigs submitted to 48 min of coronary occlusion. CONCLUSIONS: These results are consistent with the hypothesis that during initial reperfusion NCX activity results in net reverse mode operation contributing to Ca(2+) overload, hypercontracture and cell death, and that NCX inhibition during this phase is beneficial. Beyond this phase, NCX inhibition may impair forward mode-dependent Ca(2+) extrusion and be detrimental. These findings may help in the design of therapeutic strategies against lethal reperfusion injury, with NCX as the target.     

Safety and efficacy of off-pump coronary artery bypass grafting in chronic dialysis patients

Off-pump coronary artery bypass grafting (CABG) has been recently revived, because cardiopulmonary bypass (CPB) appears to worsen the multiple organ dysfunction after conventional CABG. To evaluate the safety and efficacy of the off-pump CABG in chronic dialysis patients, we compared the perioperative morbidity and mortality between 15 dialysis patients who underwent off-pump CABG at our center over the past 8 years with that of a concurrent group of 19 patients who underwent conventional CABG. Patients were selected for off-pump CABG only when complete revascularization was technically feasible. We found that off-pump CABG is as safe and effective as conventional CABG in selected dialysis patients. It might even be beneficial, because it is associated with less hematocrit drop and blood product use, a lower catabolic rate, and fewer dialysis requirements after surgery. However, the impact of off-pump technique on the long-term clinical outcome and resource utilization in renal patients requires further investigation.     

Self-competence and self-liking in the prediction of change in bulimic symptoms

OBJECTIVE: To examine the relationship of self-competence and self-liking (two distinct dimensions of self-esteem) to bulimic symptoms. METHOD: Two separate longitudinal studies were conducted on undergraduate women from two universities (Study 1, N=129; Study 2, N=406). Measures of self-competence, self-liking, and bulimic symptoms were administered on two occasions, separated by several weeks. RESULTS: Self-competence demonstrated a stronger relationship than self-liking to change in bulimic symptoms over time. DISCUSSION: These findings have significant theoretic implications for the construct of self-esteem and implications for risk for and treatment of bulimia.     

MHC class I-deficient metastatic tumor variants immunoselected by T lymphocytes originate from the coordinated downregulation of APM components

Previous reports from our group indicated that the MHC class I phenotype of metastatic lung colonies produced by a mouse fibrosarcoma tumor clone (B9) were, depending on the immune status of the host, MHC class I negative in immunocompetent mice and MHC class I positive in immunodeficient athymic nude/nude mice. Now we report the identification of the molecular alterations responsible for the changes of MHC class I molecules in both situations. Metastatic nodes were analyzed for the mRNA level of H-2 class I and beta2-microglobulin genes, and several gene components of the major histocompatibility complex (MHC) class I antigen-processing machinery (APM). These included the genes coding for the low-molecular-weight proteins LMP2, LMP7, LMP10, the transporter associated with antigen processing (TAP-1, TAP-2), and calnexin, calreticulin, tapasin, PA-28-alpha, PA-28-beta, ERP-59 and ER-60. Analyses with RT-PCR showed that TAP-1, TAP2, LMP-2, LMP7, LMP10, tapasin and calnexin mRNA specific for these genes was absent in metastases produced in immunocompetent mice. In contrast, similar techniques with mRNA preparations obtained from metastatic nodes from immunodeficient mice showed that the mRNA expression level of these genes was highly positive. Interestingly, the MHC class I-positive or negative phenotypes of the metastatic colonies correlated with in vivo immunogenicity. H-2 positive metastasis grew more slowly than the H-2 negative ones when injected intrafootpat in syngeneic immunocompetent animals and were finally rejected. These results provide evidence of the role of T cells in immune surveillance against tumors and identify a mechanism targeted by antitumor T lymphocytes to generate MHC class I-negative tumor escape variants.     

Human papillomavirus type 16 and 18 L1 protein peptide binding to VERO and HeLa cells inhibits their VLPs binding

Human papillomaviruses (HPVs) are the cause of epithelial lesions, HPV type 16 and type 18 being associated with the development of anogenital cancer. The L1 Major Capsid Protein (L1) represents about 90% of total HPV protein and is involved in virus-host cell interaction, but little is known about this binding process. L1 sequences from HPV types 16 and 18 were synthesized in 56 20-mer peptides, covering the entire protein, HPLC-purified, (125)I-radiolabeled and tested in VERO and HeLa cell-binding assays to identify those peptides with high specific binding activity. Peptides 18283 (residues 54-77) and 18294 (274-308) from HPV16 L1, as well as 18312 (59-78) and 18322 (259-278) from HPV18 L1, presented high specific target cell binding activity. Peptide 18283 and 18294 affinity constants were 300 and 600 nM, respectively. Enzyme cell treatment before binding assay indicated that VERO and HeLa cell peptide receptor is a surface-exposed protein. There was a 60% reduction in peptide 18283 binding to heparin lyase-treated cells. Cross-linking assays showed that these proteins molecular weights were around 69 and 54 kDa. Peptides 18283 and 18294 specifically inhibited HPV-16 VLP binding to HeLa cells. According to the L1- and VLP-reported structure, both peptides are close on the VLP-surface, belonging to the outer surface broad pockets suggested as being potential receptor sites. Furthermore, it has been reported that a conserved motif from peptide 18294 is the target for neutralizing antibodies. These results suggest that such binding sequences are used by the virus as cell-binding regions.     

14C]-lycopene and [14C]-labeled polar products are differentially distributed in tissues of F344 rats prefed lycopene

Epidemiologic evidence suggests a possible role for lycopene-rich foods in the prevention of prostate cancer and cardiovascular disease. Despite active research in disease reduction, there is a paucity of information on the absorption, biodistribution and metabolism of lycopene. The aim of this study was to evaluate the biodistribution of 14C-lycopene (specific activity, 1.83 microCi/mg) and 14C-labeled products after an oral dose of 22 microCi of 14C-lycopene in male rats that had been prefed a lycopene-containing diet (0.25 g lycopene/ kg diet) for 30 d. The percentage of 14C excreted in feces and urine over the 168 h was 68%. Quantitatively, serum 14C levels were maintained between 3 and 24 h then decreased at 72 h (P < 0.05). At all time points the majority of tissue 14C was in the liver (approximately 72%), although total hepatic 14C decreased after 24 h. In a comparison of the extrahepatic tissue at 168 h, the 14C was greatest in adipose tissue followed by spleen and then adrenal; approximately 80% of the 14C in the liver was in the cis and all-trans configuration at all time points. At 3 h, the 14C in seminal vesicles was primarily in the all-trans plus 5-cis forms (70%), but by 168 h, 55% of 14C was present as 14C-polar products. Despite the presence of unlabeled lycopene in the prostate, the primary 14C form was in 14C-polar products (67-92%), even at 3 h. The percentage and amount of 14C-polar products in the dorsolateral prostate lobe increased from 3 to 24 h and then reached a plateau. The data suggest that lycopene may be metabolized differently among tissues in rats prefed lycopene.     

Isolated and Skeptical: Social Engagement and Trust in Information Sources Among Smokers

Our study compared indicators of social engagement and trust among current, former, and never smokers. Multinomial regression analyses of data from the 2005 U.S. Health Information National Trends Survey (n = 5586) were conducted to identify independent associations between social engagement, trust in health information sources, and smoking status. Never smokers (odds ratio (OR) = 2.08) and former smokers (OR = 2.48) were significantly more likely to belong to community organizations than current smokers. Never (OR = 4.59) and former smokers (OR = 1.96) were more likely than current smokers to attend religious services. Never smokers (OR = 1.38) were significantly more likely than current smokers to use the Internet. Former smokers (OR = 1.41) were more likely than current smokers to be married. Compared to current smokers, never smokers were significantly more likely to trust health care professionals (OR = 1.52) and less likely to trust the Internet (OR=0.59) for health information. Current smokers are less socially engaged and less trusting of information resources than non-smokers.