Randomized Clinical Trial Comparing Basal Insulin Peglispro and Insulin Glargine in Patients With Type 2 Diabetes Previously Treated With Basal Insulin: IMAGINE 5

OBJECTIVE To evaluate the efficacy and safety of basal insulin peglispro (BIL) versus insulin glargine in patients with type 2 diabetes (hemoglobin A1c [HbA1c] ≤9% [75 mmol/mol]) treated with basal insulin alone or with three or fewer oral antihyperglycemic medications. RESEARCH DESIGN AND METHODS This 52-week, open-label, treat-to-target study randomized patients (mean HbA1c 7.42% [57.6 mmol/mol]) to BIL ( n = 307) or glargine ( n = 159). The primary end point was change from baseline HbA1c to 26 weeks (0.4% [4.4 mmol/mol] noninferiority margin). RESULTS At 26 weeks, reduction in HbA1c was superior with BIL versus glargine (−0.82% [−8.9 mmol/mol] vs. −0.29% [−3.2 mmol/mol]; least squares mean difference −0.52%, 95% CI −0.67 to −0.38 [−5.7 mmol/mol, 95% CI −7.3 to −4.2; P < 0.001); greater reduction in HbA1c with BIL was maintained at 52 weeks. More BIL patients achieved HbA1c <7% (53 mmol/mol) at weeks 26 and 52 ( P < 0.001). With BIL versus glargine, nocturnal hypoglycemia rate was 60% lower, more patients achieved HbA1c <7% (53 mmol/mol) without nocturnal hypoglycemia at 26 and 52 weeks ( P < 0.001), and total hypoglycemia rates were lower at 52 weeks ( P = 0.03). At weeks 26 and 52, glucose variability was lower ( P < 0.01), basal insulin dose was higher ( P < 0.001), and triglycerides and aminotransferases were higher with BIL versus glargine ( P < 0.05). Liver fat content (LFC), assessed in a subset of patients ( n = 162), increased from baseline with BIL versus glargine ( P < 0.001), with stable levels between 26 and 52 weeks. CONCLUSIONS BIL provided superior glycemic control versus glargine, with reduced nocturnal and total hypoglycemia, lower glucose variability, and increased triglycerides, aminotransferases, and LFC

Quantitative variations in the expression of the mouse serum antigen Ss and its sex-limited allotype Slp

A radial immunodiffusion assay for quantitation of the Ss and Slp serum antigens is described. Significant differences between the mean serum concentrations of Ss and Slp were found among various inbred strains. Some of these differences have been shown to be associated with the H-2 haplotype. The quantitative difference between Slp levels associated with the H-2 a and H-2 S haplotypes has been used as a marker for the S region in the analysis of certain H-2 recombinant strains [A.TH, B10.S(7R), B10.S(9R), and B10.BSVS]. Male mice of two strains with the H-2 b haplotype have been shown to have significantly lower levels of Ss compared to males of the other strains tested. Male mice of every strain examined were found to have significantly higher levels of Ss in their serum than females of the same strain. The molecular relationship and developmental patterns of the Ss and Slp antigens have also been investigated using the radial immunodiffusion assay.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44121/1/10528_2004_Article_BF00485949.pd

The effects of periodontal therapy on serum antibody (IgG) levels to plaque microorganisms *

The influence of periodontal therapy on serum antibody titers to selected periodontal disease-associated microorganisms was assessed in 23 patients having chronic inflammatory periodontal disease (CIPD), The immunoglobulin G (IgG) titers were dÉtÉrmined by the micro ELISA technique in serum samples obtained prior to treatment; following a hygienic phase which included scaling, root planing, and oral hygiene instruction; following surgical treatment; and one year and two years following hygienic phase (maintenance phase). Considerable individual variability existed in the magnitude of immune response to specific bacterial preparations. Significant reductions in the mean antibody titers were seen to A. viscosus. S. sanguis. F. nucleatum, S, spuligena, B. gingivalis. B. interme-dius. B. melaninogeniem, T. vincentii , and T denticola by the end of the second year of maintenance. There was no consistent response to Capnucytophaga. When individual patient responses were examined. 6 of the 23 were found to have elevated titers to at least one of the microorganisms in the interval between pretreatment and the end of the hygienic phase; however, in all but one case, the titers at the end of the second year of maintenance were below pretreatment levels. Antibody levels to bacteria such as S. sanguis were modified during therapy. This would indicate that immune responses to microbes not generally considered to be “periodontal pathogens” may be modified by adjuvant activity associated with subgingival plaque or changes in the environment of the sulcus and that subsequent changes in titer do not necessarily reflect a role of that microorganism in the disease process.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75110/1/j.1600-051X.1988.tb02127.x.pd

The effect of periodontal therapy on lymphocyte blastogenesis to plaque associated microorganisms

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66105/1/j.1600-0765.1983.tb00340.x.pd

Immunodominant PstS1 antigen of mycobacterium tuberculosis is a potent biological response modifier for the treatment of bladder cancer

BACKGROUND: Bacillus Calmette Guérin (BCG)-immunotherapy has a well-documented and successful clinical history in the treatment of bladder cancer. However, regularly observed side effects, a certain degree of nonresponders and restriction to superficial cancers remain a major obstacle. Therefore, alternative treatment strategies are intensively being explored. We report a novel approach of using a well defined immunostimulatory component of Mycobacterium tuberculosis for the treatment of bladder cancer. The phosphate transport protein PstS1 which represents the phosphate binding component of a mycobacterial phosphate uptake system is known to be a potent immunostimulatory antigen of M. tuberculosis. This preclinical study was designed to test the potential of recombinant PstS1 to serve as a non-viable and defined immunotherapeutic agent for intravesical bladder cancer therapy. METHODS: Mononuclear cells (PBMCs) were isolated from human peripheral blood and stimulated with PstS1 for seven days. The activation of PBMCs was determined by chromium release assay, IFN-γ ELISA and measurement of lymphocyte proliferation. The potential of PstS1 to activate monocyte-derived human dendritic cells (DC) was determined by flow cytometric analysis of the marker molecules CD83 and CD86 as well as the release of the cytokines TNF-α and IL-12. Survival of presensitized and intravesically treated, tumor-bearing mice was analyzed by Kaplan-Meier curve and log rank test. Local and systemic immune response in PstS1-immunotherapy was investigated by anti-PstS1-specific ELISA, splenocyte proliferation assay and immunohistochemistry. RESULTS: Our in vitro experiments showed that PstS1 is able to stimulate cytotoxicity, IFN-γ release and proliferation of PBMCs. Further investigations showed the potential of PstS1 to activate monocyte-derived human dendritic cells (DC). In vivo studies in an orthotopic murine bladder cancer model demonstrated the therapeutic potential of intravesically applied PstS1. Immunohistochemical analysis and splenocyte restimulation assay revealed that local and systemic immune responses were triggered by intravesical PstS1-immunotherapy. CONCLUSION: Our results demonstrate profound in vitro activation of human immune cells by recombinant PstS1. In addition, intravesical PstS1 immunotherapy induced strong local and systemic immune responses together with substantial anti-tumor activity in a preclinical mouse model. Thus, we have identified recombinant PstS1 antigen as a potent immunotherapeutic drug for cancer therapy

Circulating endothelial cells are an early predictor in renal cell carcinoma for tumor response to sunitinib

<p>Abstract</p> <p>Background</p> <p>Tyrosine kinase inhibitors (TKI) have enriched the therapeutic options in patients with renal cell carcinoma (RCC), which frequently induce morphological changes in tumors. However, only little is known about the biological activity of TKI. Circulating endothelial cells (CEC) have been associated with endothelial damage and, hence, may serve as a putative marker for the biological activity of TKI. The main objective of our study was to evaluate the predictive value of CEC, monocytes, and soluble vascular endothelial growth factor receptor (sVEGFR)-2 in RCC patients receiving sunitinib treatment.</p> <p>Methods</p> <p>Analyses of CEC, monocytes, and sVEGFR-2 were accomplished for twenty-six consecutive patients with metastatic RCC who received treatment with sunitinib (50 mg, 4 wks on 2 wks off schedule) at our institution in 2005 and 2006.</p> <p>Results</p> <p>In RCC patients CEC are elevated to 49 ± 44/ml (control 8 ± 8/ml; P = 0.0001). Treatment with sunitinib is associated with an increase in CEC within 28 days of treatment in patients with a Progression free survival (PFS) above the median to 111 ± 61 (P = 0.0109), whereas changes in patients with a PFS below the median remain insignificant 69 ± 61/ml (P = 0.1848). Monocytes and sVEGFR2 are frequently altered upon sunitinib treatment, but fail to correlate with clinical response, defined by PFS above or below the median.</p> <p>Conclusions</p> <p>Sunitinib treatment is associated with an early increase of CEC in responding patients, suggesting superior endothelial cell damage in these patients as a putative predictive biomarker.</p

Differences in Immunoglobulin Light Chain Species Found in Urinary Exosomes in Light Chain Amyloidosis (AL)

Renal involvement is a frequent consequence of plasma cell dyscrasias. The most common entities are light chain amyloidosis, monoclonal immunoglobulin deposition disease and myeloma cast nephropathy. Despite a common origin, each condition has its own unique histologic and pathophysiologic characteristic which requires a renal biopsy to distinguish. Recent studies have shown urinary exosomes containing kidney-derived membrane and cytosolic proteins that can be used to probe the proteomics of the entire urinary system from the glomerulus to the bladder. In this study, we analyzed urine exosomes to determine the differences between exosomes from patients with light chain amyloidosis, multiple myeloma, monoclonal gammopathy of undetermined significance, and non-paraproteinemia related kidney disease controls. In patients with light chain amyloidosis, multiple myeloma and monoclonal gammopathy of undetermined significance, immunoreactive proteins corresponding to monomeric light chains were found in exosomes by western blot. In all of the amyloidosis samples with active disease, high molecular weight immunoreactive species corresponding to a decamer were found which were not found in exosomes from the other diseases or in amyloidosis exosomes from patients in remission. Few or no light chains monomeric bands were found in non-paraproteinemia related kidney disease controls. Our results showed that urinary exosomes may have tremendous potential in furthering our understanding of the pathophysiology and diagnosis of plasma cell dyscrasia related kidney diseases