Quantification of myocardial fibrosis using noninvasive T2-mapping magnetic resonance imaging: Preclinical models of aging and pressure overload

Noninvasive imaging of cardiac fibrosis is important for early diagnosis and intervention in chronic heart diseases. Here, we investigated whether noninvasive, contrast agent-free MRI T₂-mapping can quantify myocardial fibrosis in preclinical models of aging and pressure overload. Myocardial fibrosis and remodeling were analyzed in two animal models: (i) aging (15-month-old male CF-1 mice vs. young 6- to 8-week-old mice), and (ii) pressure overload (PO; by transverse aortic constriction in 4- to 5-month-old male C57BL/6 mice vs. sham-operated for 14 days). In vivo T₂-mapping was performed by acquiring data during the isovolumic and early diastolic phases, with a modified respiratory and ECG-triggered multiecho TurboRARE sequence on a 7-T MRI. Cine MRI provided cardiac morphology and function. A quantitative segmentation method was developed to analyze the in vivo T₂-maps of hearts at midventricle, apex, and basal regions. The cardiac fibrosis area was analyzed ex vivo by picro sirius red (PSR) staining. Both aged and pressure-overloaded hearts developed significant myocardial contractile dysfunction, cardiac hypertrophy, and interstitial fibrosis. The aged mice had two phenotypes, fibrotic and mild-fibrotic. Notably, the aged fibrotic subgroup and the PO mice showed a marked decrease in T₂ relaxation times (25.3 ± 0.6 in aged vs. 29.9 ± 0.7 ms in young mice, p = 0.002; and 24.3 ± 1.7 in PO vs. 28.7 ± 0.7 ms in shams, p = 0.05). However, no significant difference in T₂ was detected between the aged mild-fibrotic subgroup and the young mice. Accordingly, an inverse correlation between myocardial fibrosis percentage (FP) and T₂ relaxation time was derived (R² = 0.98): T₂ (ms) = 30.45 – 1.05 × FP. Thus, these results demonstrate a statistical agreement between T₂-map–quantified fibrosis and PSR staining in two different clinically relevant animal models. In conclusion, T₂-mapping MRI is a promising noninvasive contrast agent-free quantitative technique to characterize myocardial fibrosis.     

Efficacy of new insect growth regulators against mosquito larvae in dairy wastewater lagoons

Four new insect growth regulators (IGRs) and a slow-release formulation of a currently-used IGR were evaluated for the control of Culex peus and Cx. quinquefasciatus in dairy wastewater lagoons. The IGR AC-291898 (CME 13406) proved highly efficacious, producing 100% control for one week and about 98% control for two weeks at the rate of 0.05 lb AI/acre (0.056 kg/ha). The IGR XRD-473 produced similar results at this rate. The effective rate of these two compounds seems to be in the range of 0.05 to 0.1 lb AI/acre (0.056-0.11 kg/ha). A granular formulation of S-31183 (0.5 G) applied at 0.05 lb AI/acre (0.056 kg/ha) yielded mediocre reduction whereas fenoxycarb EC 1 at up to 0.25 lb AI/acre (0.28 kg/ha) and methoprene 4% slow release pellets at up to 1.0 lb AI/acre (1.12 kg/ha) produced little or no control of Culex in the dairy wastewater lagoons. These compounds need to be applied at higher rates or suitable formulations will have to be developed to achieve satisfactory control.     

Moderate acute rejection detected during annual catheterization in pediatric heart transplant recipients.

BACKGROUND: Acute rejection commonly occurs within the first year after heart transplantation, and then decreases in frequency with time. Recently, the long-term utility of endomyocardial biopsy during routine annual catheterization has been questioned. The purpose of this study was to retrospectively review the prevalence of biopsy-proven rejection during routine annual catheterization in our patient population, determine whether biopsies late after transplant are useful, and identify factors that correlate with late unsuspected rejection. METHODS: Biopsy results from the annual catheterization were evaluated from 1986 to August 2000. The prevalence of moderate rejection was evaluated and compared with the patient's immunosuppressive regimen; the prevalence of late rejection; and how late rejection correlated with recipient age, number of first-year rejections and presence of sub-therapeutic cyclosporine. RESULTS: A total of 1108 biopsies were performed in 269 children with a mean follow-up of 5 +/- 3 years (median 5 years, range 1 to 11 years). Three-drug immunosuppressive therapy, including steroids, was used in 93 patients. There was a persistent 8% to 10% prevalence of moderate rejection at up to 10 years post-transplantation. Moderate rejection was more likely in patients: (1). on 3-drug immunosuppressive therapy; (2). with a recipient age >1 year; and (3). with a relatively lower cyclosporine level. CONCLUSIONS: These data suggest that continued surveillance of pediatric transplant patients for acute rejection is indicated for long-term follow-up.     

In-vitro susceptibility of cefoperazone-susceptible and -resistant gram-negative rods to cefoperazone plus sulbactam,other beta-lactams,aminoglycosides and quinolone

Summary We compared thein-vitro activity of cefoperazone-sulbactam (2 : 1), other -lactams, aminoglycosides and ciprofloxacin against cefoperazone-susceptible and -resistant nosocomial gram-negative bacilli. Resistant isolates includingPseudomonas aeruginosa were susceptible to cefoperazone-sulbactam; the susceptible isolates had modestly increased susceptibility to the combination. Sulbactam, by itself, was poorly active. Among others tested, ciprofloxacin and imipenem were the most active. No inoculum effect was seen with cefoperazone-sulbactam and this drug combination had a prolonged post-antibiotic effect. Cefoperazone-sulbactam is an attractive candidate for evaluation in the treatment of nosocomial infections due to aerobic gram-negative bacilli.

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In-vitro-Empfindlichkeit cefoperazon-sensibler und -resistenter gramnegativer Stäbchen gegenüber Cefoperazon plus Sulbactam, anderen -Laktamen, Aminoglykosiden und Chinolon

Zusammenfassung Wir führten Vergleichsuntersuchungen zurIn-vitro-Aktivität von Cefoperazon-Sulbactam (2 : 1), anderen -Laktamen, Aminoglykosiden und Ciprofloxacin gegen cefoperazon-empfindliche und -resistente nosokomiale Isolate gramnegativer Bazillen durch. Resistente Isolate einschließlichPseudomonas aeruginosa waren empfindlich gegenüber Cefoperazon-Sulbactam; empfindliche Isolate sprachen auf die Kombination etwas besser an. Sulbactam allein wies nur geringe Aktivität auf. Unter den übrigen geprüften Substanzen waren Ciprofloxacin und Imipenem am wirksamsten. Mit Cefoperazon-Sulbactam war kein Inoculum-Effekt festzustellen. Die Kombination hatte einen anhaltenden postantibiotischen Effekt. Cefoperazon-Sulbactam ist eine interessante Substanzkombination, die in der Therapie nosokomialer Infektionen durch aerobe gramnegative Bazillen erprobt werden sollte.

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This study was presented at the 89th Annual Meeting of the American Society for Microbiology held in New Orleans, Louisiana during May 14–18, 1989.     

Glial cell-induced endothelial morphogenesis is inhibited by interfering with extracellular signal-regulated kinase signaling.

PURPOSE: Tumor vasculature provides the infrastructure by which malignant tissue can be nourished; therefore, targeting angiogenesis may be an effective means of treating cancer. We showed previously that SNB19 glioblastoma cells modulate bovine retinal endothelial cells in cocultures to form capillary-like network structures, that matrix metalloproteinase-9 (MMP-9) expression is critical for endothelial morphogenesis, and that MMP-9 expression in glioblastoma cells is regulated by extracellular signal-regulated kinase-1 (ERK-1). In the present study, we investigated whether interfering with the activation of this mitogen-activated protein (MAP) kinase would repress MMP-9 synthesis and inhibit capillary formation. EXPERIMENTAL DESIGN: Cocultures of bovine retinal endothelial and SNB19 cells were analyzed for MMP-9 secretion, and phospho- and total ERK levels. These cocultures were treated with PD98059, a specific inhibitor of MAP/ERK kinase 1, or transfected with dominant-negative ERK-1 mutant containing expression vector. Alterations in capillary-like structure formation, and actin cytoskeleton and secretion of vascular endothelial growth factor (VEGF), MMP-9, and tissue inhibitor of metalloproteinase-1 were determined by immunofluorescence, gelatin zymography, and Western blotting. RESULTS: We found that inhibition of the ERK-1/2 pathway with PD98059 abrogated glial cell-mediated capillary formation by the endothelial cells and reduced the levels of MMP-9 in the coculture. Strikingly, the abrogation of MAP kinase signaling by a dominant-negative ERK-1 mutant inhibited glial-induced capillary network formation by reducing VEGF levels and MMP-9 activity and increasing the levels of tissue inhibitor of metalloproteinase-1. Inhibition of ERK activity also disrupted the formation of the actin cytoskeleton, a prerequisite for endothelial cell migration. CONCLUSION: The mechanism underlying activation of ERK is involved in reorganization of the actin cytoskeleton, and induction of VEGF and MMP-9, thereby stimulating endothelial cell morphogenesis. These studies clearly provide experimental evidence that ERK inhibition diminishes glial-induced endothelial-cell morphogenesis; therefore, interfering with ERK signaling may be a viable approach to target angiogenesis.     

Rigid and flexible docking studies on PPAR-γ agonists: key interactions for a better antihyperglycemic activity and in silico pharmacodynamic activity versus experimental in vivo activity

We report both automated rigid and flexible ligand docking simulations performed on fifty peroxisome proliferator-activated receptor (PPAR-γ) agonists, namely, glitazones. The binding conformations and binding affinities of these agonists were obtained by the use of the Autodock 4.1 with Lamarckian genetic algorithm (LGA). All the 50 flexible docks are considered as well-docked as all of them were bound to the ligand binding domain of PPAR-γ. The predicted binding affinity values (pKa) were found to have some degree of correlation with their experimental in vivo activity values. The head group hydrogen bond interactions via H323 and H449 histidine residues were found to play a significant role. The results obtained will be valuable in designing newer selective PPAR-γ agonists.