Antibody-independent Classical Pathway-mediated Opsonophagocytosis of Type Ia, Group B Streptococcus

The opsonophagocytic requirements of human sera containing endogenous complement for a variety of type Ia, and group B streptococcal strains were defined. Significant reduction (>==90%) in colony-forming units was noted after a 40-min incubation for the highly encapsulated, mouse-passed prototype strain 090 by sera containing moderate to high concentrations of antibody to type Ia polysaccharide (mean, 16.5 mug/ml), whereas bacterial growth occurred in 25 sera with low levels of specific antibody (mean, 2.1 mug/ml). This absolute requirement for a critical amount of specific antibody in promoting opsonophagocytic killing of strain 090 was not found when 18 fresh clinical type Ia isolates were tested. In antibody-deficient and agammaglobulinemic sera, respectively, mean reductions in colony-forming units of 94 and 95% were seen for fresh clinical isolates, whereas strain 090 was not killed by polymorphonuclear leukocytes in the presence of these sera. All strains required a considerable amount of specific antibody for alternative pathway-mediated opsonophagocytosis. That opsonophagocytic killing of clinical type Ia isolates was mediated by the classical pathway in a nonantibody-dependent fashion was shown when MgEGTA chelation of agammaglobulinemic serum or use of serum deficient in C2 resulted in bacterial growth. The addition of C2 to C2-deficient serum restored bactericidal activity of this serum. These experiments indicate that substances other than the exposed surface of the type Ia capsular polysaccharide initiate classical pathway-mediated opsonophagocytosis of clinical isolates of type Ia, group B streptococci by human sera in the absence of immunoglobulin. Perhaps, a deficiency in classical complement pathway function is critical to the susceptibility of neonates to type Ia, group B streptococcal disease.     

Immunochemical analysis and immunogenicity of the type II group B streptococcal capsular polysaccharide.

The relationship between group B streptococcal (GBS) type-specific antisera and the type II-specific polysaccharide is evaluated from a structural and immunologic viewpoint. Although all GBS type-specific polysaccharides are composed of the same monosaccharides, the type II antigen is more complex structurally and contains these sugars in a molar ratio different from the other antigens. Type II polysaccharide has two side chains. One contains only sialic acid and is less susceptible to acid cleavage than sialic acid residues found on types III, Ia, and Ib polysaccharides. The other side chain is composed of galactose as the only sugar. Immunochemical studies demonstrate that the type II polysaccharide has several immunodeterminants. One of these determinants is likely to be the side-chain galactose, while sialic acid appears to comprise part of another immunodeterminant, more complex than sialic acid alone. A series of cross-reactions is demonstrated between the type II native antigen and antisera to serotypes Ia, III, and Ib by a sensitive radioactive antigen-binding assay, which account for additional, complex immunodeterminants. The strongest of these cross-reactions is with type Ia antiserum and the weakest with Ib antiserum. Since Ia and Ib polysaccharides differ in only one linkage, these findings suggest that the trisaccharide beta D-N-acetyl-glucosamine-p(1 leads to 3) beta D-galactose-p(1 leads to 4) beta D-glucose-p [[beta D-GlcNAcp(1 leads to 3) beta D-Galp(1 leads to 4)beta D-Glcap]] is the likely common site responsible for the interaction of the type II native polysaccharide and type Ia antiserum. Another cross-reaction is observed between type III antiserum and type II native antigen. Inhibition studies indicate that the most likely cross-reactive determinant in this case is [beta D-Galp(1 leads to 4)beta D-GlcNAcp]. Type II polysaccharide has been utilized in a human vaccine trial to test safety and immunogenicity. The polysaccharide is highly immunogenic, inducing an antibody response in 95% of recipients, and nontoxic, with side-effects confined to minimal local reactions. Despite the cross-reactions observed between type-specific antigens and antibody prepared by immunization of rabbits with whole bacteria, which suggest shared immunodeterminants, similar cross-reactions were not detected in human sera after immunization with purified type II polysaccharide.     

Biased selection and regression toward the mean in three Medicare HMO demonstrations: a survival analysis of enrollees and disenrollees

Mortality of aged Medicare enrollees in three demonstration health maintenance organizations (HMOs) was compared with that of three cohorts of local fee-for-service (FFS) beneficiaries as a measure of group differences in health status. Mortality of the HMO and FFS cohorts was tracked via life-table analysis for 6 years after enrollment to measure the persistence of health status differences existing at enrollment. After adjustment for age, sex, Medicaid-eligibility, and institutional status, HMO enrollee mortality was lower than FFS at all three plans in the first year after enrollment. Enrollee mortality at two plans increased to near FFS levels in year 2 and remained relatively stable thereafter. Enrollee mortality at the third plan increased toward FFS levels more gradually and was significantly below FFS levels for the first 5 years of follow-up. Mortality of disenrollees in the 2 years after disenrollment was significantly higher than that of the continuously enrolled in one plan and marginally significantly higher in a second. These findings suggest a pattern of favorable selection at enrollment, followed by different rates of decay in the favorable health status of enrollees. Other health status measures may exhibit different patterns, however. Selection effects may cause payments based on Medicare's AAPCC to be too high or low, in some cases for several years after enrollment.     

Predictive value of early and late residual 18F-fluorodeoxyglucose and 18F-fluorothymidine uptake using different SUV measurements in patients with non-small-cell lung cancer treated with erlotinib

Purpose

To evaluate the predictive value of early and late residual ¹⁸F-fluorodeoxyglucose (FDG) and ¹⁸F-fluorothymidine (FLT) uptake using different SUV measurements in PET in patients with advanced non-small-cell lung cancer (NSCLC) treated with erlotinib.

Methods

We retrospectively reviewed data from 30 patients with untreated stage IV NSCLC who had undergone a combined FDG PET and FLT PET scan at 1?week (early) and 6?weeks (late) after the start of erlotinib treatment. Early and late residual FDG and FLT uptake were measured in up to five lesions per scan with different quantitative standardized uptake values (SUV_max, SUV_2Dpeak, SUV_3Dpeak, SUV₅₀, SUV_A50, SUV_A41) and compared with short-term outcome (progression vs. nonprogression after 6?weeks of erlotinib treatment). Receiver-operating characteristics (ROC) curve analysis was used to determine the optimal cut-off value for detecting nonprogression after 6?weeks. Kaplan-Meier analysis and the log-rank test were used to evaluate the association between residual uptake and progression-free survival (PFS).

Results

Nonprogression after 6?weeks was associated with a significantly lower early and late residual FDG uptake, measured with different quantitative parameters. In contrast, nonprogression after 6?weeks was not associated with early and late residual FLT uptake. Furthermore, patients with a lower early residual FDG uptake measured in terms of SUV_max and SUV_2Dpeak had a significantly prolonged PFS (282?days vs. 118?days; p?=?0.022) than patients with higher values. Similarly, lower late residual FDG uptake and early residual FLT uptake measured in terms of SUV_3Dpeak, SUV_A50 and SUV_A41, and late FLT uptake measured in terms of SUV_3Dpeak and SUV_A50 was associated with an improved PFS.

Conclusion

Early and late residual FDG uptake, measured using different quantitative SUV parameters, are predictive factors for short-term outcome in patients with advanced NSCLC treated with erlotinib. Additionally, low residual FDG and FLT uptake early and late in the course of erlotinib treatment is associated with improved PFS.     

Non-invasive mechanical ventilation improves walking distance but not quadriceps strength in chronic respiratory failure

BACKGROUND: In patients with chronic respiratory failure (CRF) nocturnal mechanical ventilation (NMV) confers increased exercise tolerance. The hypothesis tested in the present study was that the increased exercise performance is associated with increased quadriceps strength. METHODS: In 28 patients with CRF due to chronic obstructive pulmonary disease and restrictive thoracic disease (post-tuberculosis-sequelae, scoliosis and obesity-hypoventilation) NMV was started. Before and after 2-month NMV the exercise tests, namely shuttle and 6-min walking distance, were performed. Furthermore, quadriceps strength was measured as the twitch tension elicited by magnetic stimulation the femoral nerve (TwQ) and the maximum voluntary contraction force (MVC). RESULTS: After 2 months therapy with NMV there was significant clinical and blood gas improvement. NMV significantly improved the walking distance by approximately 18% but there was no improvement in TwQ or MVC, the data could exclude a 15% improvement in TwQ with 82% confidence. CONCLUSION: The strength of quadriceps does not change after 2 months of effective NMV in patients with CRF despite a marked increase in endurance time. Factors other than quadriceps strength account for the improved performance.     

Glucocorticoid withdrawal schemes in chronic medical disorders. A systematic review.

This systematic review highlights the uncertainty about the safety and efficacy of glucocorticoid withdrawal in many chronic diseases, elucidating the need for further research in this area. The problem of glucocorticoid withdrawal seems to be good example for wide variation in physicians' approaches to weaning patients off glucocorticoids. This practice variation appears justified, given the well known extraordinary array of individual reactions to systemic glucocorticoid therapy [44], the obligation to individualize treatment, and scientific uncertainty. Moreover, only sparse information concerning health-related quality of life, well-being and symptoms, and socioeconomic sequelae after glucocorticoid withdrawal is available from published randomized trials. In conclusion, clinicians and patients need many more--and in a number of conditions, initial--high quality studies to assess the safety and efficacy of systemic glucocorticoid withdrawal schedules in chronic diseases.