Maridomycin, a New Macrolide Antibiotic: In Vivo Antibacterial Activity of 9-Propionylmaridomycin

The in vivo protecting activity of 9-propionylmaridomycin, a derivative of the new macrolide antibiotic, maridomycin, was compared with that of other macrolide antibiotics in mice infected with Staphylococcus aureus, Streptococcus pyogenes, and Diplococcus pneumoniae. The protective effect was almost similar to that afforded by several known macrolide antibiotics in mice infected intraperitoneally with certain strains of the gram-positive species described above. The skin lesion caused by intradermal challenge of S. aureus in mice also responded very effectively to treatment with 9-propionylmaridomycin.     

Maridomycin, a New Macrolide Antibiotic. In Vitro Antibacterial Activity of 9-Propionylmaridomycin

9-Propionylmaridomycin shows in vitro antibacterial activity against gram-positive bacteria and has some action on Neisseria gonorrhoeae and Vibrio cholerae, but is generally inactive against many gram-negative rods. This antibiotic exhibits strong activity against clinical isolates of Staphylococcus aureus which are highly resistant to erythromycin or oleandomycin, or both, but which are sensitive to josamycin and kitasamycin. Strains resistant to josamycin and kitasamycin were also found to be resistant to this antibiotic. A significant feature of 9-propionylmaridomycin is a lack in its ability to induce resistance induction in resistance-inducible strains of staphylococci to erythromycin. Several antibacterial features of 9-propionylmaridomycin such as the influence of medium pH, inoculum size, effect of addition of horse serum, development of resistance, cross resistance, and bacteriostatic activity were shown to be almost identical to those of josamycin and kitasamycin. The antibacterial activity of 9-propionylmaridomycin was stable in solutions at pH levels of 4, 7, and 9.     

Clinical,autoimmune, and genetic characteristics of adult-onset diabetic patients with GAD autoantibodies in Japan (Ehime Study)

OBJECTIVE: To characterize the clinical, autoimmune, and genetic features in Japanese adult-onset diabetic patients with GAD autoantibodies. RESEARCH DESIGN AND METHODS: GAD autoantibodies (GADab) were screened in 4,980 diabetic patients with age of onset >20 years in the hospital-based Ehime Study, and the GADab-positive (GADab(+)) patients were then divided into two groups according to their insulin secretion and compared with nondiabetic subjects. The insulin-deficient state was defined as <0.33 nmol/l serum C-peptide (CPR) at 2 h postprandial or 6 min after a 1-mg glucagon load. RESULTS: GADab was detected in 188 (3.8%) of the 4,980 diabetic patients tested. Of these patients, 72 (38.3%) were classified as insulin deficient, 97 (51.6%) were classified as non-insulin deficient, and 19 (10.1%) were unclassified. The GADab(+) insulin-deficient patients were characterized by young age at onset of diabetes, low BMI, low maximum BMI, and high levels of HbA(1c). The prevalence of IA-2 autoantibodies and thyrogastric autoantibodies in the GADab(+) insulin-deficient patients were significantly higher than those in the GADab(+) non-insulin-deficient patients (P < 0.05). GADab(+) patients with insulin deficiency had increased frequencies of HLA DRB1*0405-DQB1*0401, *0802-*0302, and *0901-*0303 haplotypes, whereas the frequency of only HLA DRB1*0405-DQB1*0401 was increased in the case of GADab(+) non-insulin-deficient patients. Of note is the fact that the GADab(+) non-insulin-deficient group did not differ from healthy control subjects with respect to type 1 diabetes protective haplotype HLA DRB1*1502-DQB1*0601. A total of 13% of the GADab(+) patients with diabetes had genotypes comprising the DRB1*1501-DQB1*0602 or *1502-*0601 and were characterized by old age at onset of diabetes, high BMI, resistance to the insulin-deficient state, low titer of GADab, and low frequency of other organ-specific autoantibodies. CONCLUSIONS: We conclude that GADab(+) non-insulin-deficient patients differ from GADab(+) patients with insulin deficiency with respect to clinical characteristics, humoral autoimmunity to other organ-specific autoantibodies, as well as HLA class II genes.     

Influence of fibrate treatment on malondialdehyde-modified LDL concentration

BACKGROUND: Drug therapy is considered essential to the clinical prevention of atherosclerotic lesions in patients with diabetes mellitus (DM). METHODS: To confirm the effects of fibrate therapy, we determined low-density lipoprotein (LDL) size by gradient gel electrophoresis and malondialdehyde-modified LDL (MDA-LDL) concentrations by enzyme-linked immunosolvent assay (ELISA) and clarified the association between apolipoprotein B (apo B) and MDA-LDL during the fibrate therapy. RESULTS: Mean MDA-LDL concentrations were higher in healthy men than in healthy women. There were no significant differences in mean MDA-LDL concentrations between age groups for males or females. According to the regression equation (y = 0.063x + 10.9) obtained for apo B and MDA-LDL concentrations with fibrate treatment, the apo B concentration in those may need to be decreased to 1260 mg/l to restore the MDA-LDL concentration to the control concentration (65 +/- 25 units/l). This slope of the apoB/MDA-LDL regression line was approximately half of that with no-drug treatment (y = 0.109x - 10.8). CONCLUSIONS: Fibrate therapy had an effect on reducing serum MDA-LDL concentration in diabetic patients.     

Apolipoprotein E in cerebrospinal fluid: relation to phenotype and plasma apolipoprotein E concentrations

BACKGROUND: Apolipoprotein (apo) E may be related to the development of Alzheimer disease, but data on apoE in cerebrospinal fluid (CSF) are limited. The aim of the present study was to measure apoE in CSF and relate its concentrations to apoE phenotype and CSF lipids. METHODS: We adapted an assay for CSF apoE sensitivity using an ELISA. It allowed us to measure CSF apoE with sufficient reproducibility and precision. RESULTS: The within- and between-run CVs were <7%, and the detection limit was 0.025 mg/L. No cross-reaction was found for other apolipoproteins. No significant differences related to sex or apoE phenotype were observed in the CSF apoE concentration. The mean CSF apoE concentration was significantly higher in the 0-5 year group (n = 6; 18.47 +/- 1.14 mg/L, mean +/- SD) than in the >5 year group (n = 34; 8.82 +/- 3.31 mg/L). The mean concentrations of total cholesterol (TC) and phospholipid (PL) in CSF were 2.68 +/- 2.16 and 6.50 +/- 2.84 mg/L (n = 52), respectively. Although no significant differences in TC or PL in the CSF were found with respect to sex or age, the concentrations in subjects with the apoE phenotype E4/E3 were significantly lower than in those with E3/E3 and E3/E2. The concentrations of apoE, TC, and PL in CSF did not correlate with those in plasma. The time-related fluctuations in CSF apoE were independent of those in total protein and IgG. CSF apoE was significantly correlated with TC and PL concentrations in the CSF, but not with the number of cells in the CSF. CONCLUSIONS: These findings support the idea that apoE and lipids are unable to cross the blood-brain barrier and that their concentrations in CSF may reflect production in central nervous tissue.Copyright 1999 American Association for Clinical Chemistry     

Natural killer type 2 bias in remission of multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease characterized by clinical relapse and remission. Because of the potential role of natural killer (NK) cells in the regulation of autoimmunity, we have examined cytokine profile and surface phenotype of NK cells in the peripheral blood of MS. Here we demonstrate that NK cells in the remission of MS are characterized by a remarkable elevation of IL-5 mRNA and a decreased expression of IL-12Rbeta2 mRNA, as well as a higher expression of CD95. Moreover, the NK cells from MS in remission produced much larger amounts of IL-5 than did those from controls after stimulation with phorbol myristate acetate (PMA) and ionomycin. These features are reminiscent of those of NK type 2 (NK2) cells that can be induced in a condition favoring functional deviation of T cells toward Th2. Remarkably, the NK cells lose the NK2-like property when relapse of MS occurs, but regain it after recovery. We also found that NK2 cells induced in vitro inhibit induction of Th1 cells, suggesting that the NK2-like cells in vivo may also prohibit autoimmune effector T cells. Taken together, it is possible that NK cells play an active role in maintaining the remission of MS.     

Prognostic value of combination of cardiac troponin T and B-type natriuretic peptide after initiation of treatment in patients with chronic heart failure

BACKGROUND: Recent studies have suggested that cardiac troponin T (cTnT) and troponin I may detect ongoing myocardial damage involved in the progression of chronic heart failure (CHF). This study was prospectively designed to examine whether the combination of cTnT, a marker for ongoing myocardial damage, and B-type natriuretic peptide (BNP), a marker for left ventricular overload, would effectively stratify patients with CHF after initiation of treatment. METHODS: We measured serum cTnT, plasma BNP, and left ventricular ejection fraction (LVEF) on admission for worsening CHF [New York Heart Association (NYHA) functional class III to IV] and 2 months after initiation of treatment to stabilize CHF (n = 100; mean age, 68 years). RESULTS: Mean (SD) concentrations of cTnT [0.023 (0.066) vs 0.063 (0.20) micro g/L] and BNP [249 (276) vs 753 (598) ng/L], percentage increased cTnT (>0.01 micro g/L; 35% vs 60%), NYHA functional class [2.5 (0.6) vs 3.5 (5)], and LVEF [43 (13)% vs 36 (12)%] were significantly (P <0.01) improved 2 months after treatment compared with admission. During a mean follow-up of 391 days, there were 44 cardiac events, including 12 cardiac deaths and 32 readmissions for worsening CHF. On a stepwise Cox regression analysis, increased cTnT and BNP were independent predictors of cardiac events (P <0.001). cTnT >0.01 micro g/L and/or BNP >160 ng/L 2 months after initiation of treatment were associated with increased cardiac mortality and morbidity rates. CONCLUSION: The combination of cTnT and BNP measurements after initiation of treatment may be highly effective for risk stratification in patients with CHF.     

Characterization of the uptake of organic anion transporter (OAT) 1 and OAT3 substrates by human kidney slices

The activities of renal multispecific organic anion transporters (OATs) 1 and 3 have not been fully evaluated in human kidneys. In the present study, the uptake of some organic anions was characterized in kidney slices from human intact renal cortical tissues: hOAT1 and hOAT3 substrates [p-aminohippurate (PAH) and 2,4-dichlorophenoxyacetate (2,4-D)] and hOAT3 substrates [benzylpenicillin (PCG), dehydroepiandrosterone sulfate (DHEAS), and estrone sulfate (ES)]. Despite large inter-batch differences, hOAT1 and hOAT3 mRNA levels correlated well, and there was a good correlation between the uptake of PAH and PCG by kidney slices. The uptake of organic anions by kidney slices was saturable with Km values of 31 to 48 microM for PAH, 0.73 to 4.9 microM for 2,4-D, 14 to 90 microM for PCG, and 9.2 to 11 microM for ES. These parameters were comparable with those for hOAT1 and/or hOAT3. The uptake of DHEAS consists of two saturable components with Km values of 2.2 to 3.9 and 1300 microM, and the Km value of the high-affinity component was close to that for hOAT3. Furthermore, PAH more potently inhibited the uptake of 2,4-D than that of PCG and DHEAS. PCG had a weaker effect on the uptake of PAH and 2,4-D than expected from its Km value. Taken together, it is likely that the uptake of PAH and 2,4-D is due to OAT1, and the uptake of PCG and ES and part of DHEAS uptake are due to OAT3 in human kidney slices. Human kidney slices are useful tools for characterizing the renal uptake of drugs.