Jacksonville Harbor Deepening Project: St. Johns River Circulation and Salinity Modeling

Source: ICHE Conference Archive - https://mdi-de.baw.de/icheArchiv

Quantitative analysis of late gadolinium enhancement in hypertrophic cardiomyopathy: comparison of diagnostic performance in myocardial fibrosis between gadobutrol and gadopentetate dimeglumine

The purpose of this study was to compare different semi-automated late gadolinium enhancement (LGE) quantification techniques using gadobutrol and gadopentetate dimeglumine contrast agents with regard to the diagnosis of fibrotic myocardium in patients with hypertrophic cardiomyopathy (HCM). Thirty patients with HCM underwent two cardiac MRI protocols with use of gadobutrol and gadopentetate dimeglumine. Contrast-tonoise ratio (CNR) between LGE area and remote myocardium (CNRremote), between LGE area and left ventricular blood pool (CNRpool), and signal-to-noise ratio (SNR) in LGE were compared. The presence and quantity of LGE were determined by visual assessment. With signal threshold versus reference mean (STRM) based thresholds of 2 SD, 5 SD, and 6 SD above the mean signal intensity (SI) of reference myocardium, the full-width at half-maximum (FWHM) technique was used. The volume and segments of the LGE area were compared between the two types of contrast agents. LGE was present in 26 of 30 (86.6%) patients in both protocols. The CNRremote of fibrotic myocardium in gadobutrol and gadopentetate dimeglumine agents was 26.82 ± 14.24 and 21.46 ± 10.59, respectively (P < 0.05). The CNRpool was significantly higher in gadobutrol (9.32 ± 7.64 vs. 6.39 ± 6.11, P < 0.05). The SNR was higher in gadobutrol (33.36 ± 14.35 vs. 27.53 ± 10.91, P < 0.05). The volume of scar size in MR images acquired with gadobutrol were significantly higher than those with gadopentetate dimeglumine (P < 0.05), and the STRM of 5 SD technique showed the greatest agreement with visual assessment (ICC = 0.99) in both examinations. There was no significant difference in fibrotic segments of the fibrotic myocardium in the LGE area (P < 0.05). This study proved that the Gadobutrol was an effective contrast agent for LGE imaging with superior delineation of fibrotic myocardium as compared to gadopentetate dimeglumine. The 5 SD technique yields the closest approximation of the extent of LGE identified by visual assessment

Changes observed in radionuclide bone scans during and after teriparatide treatment for osteoporosis

# The Author(s) 2011. This article is published with open access at Springerlink.com Purpose Visual changes on radionuclide bone scans have been reported with teriparatide treatment. To assess this, serial studies were evaluated and quantified in ten postmenopausal women with osteoporosis treated with teriparatide (20 μg/day subcutaneous) who had 99m Tc-methylene diphosphonate (MDP) bone scans (baseline, 3 and 18 months, then after 6 months off therapy). Methods Women were injected with 600 MBq 99m Tc-MDP, and diagnostic bone scan images were assessed at 3.5 h. Additional whole-body scans (10 min, 1, 2, 3 and 4 h) were analysed for 99m Tc-MDP skeletal plasma clearance (Kbone). Regional Kbone differences were obtained for the whole skeleton and six regions (calvarium, mandible, spine, pelvis, upper and lower extremities). Bone turnover markers (BTM) were also measured. Results Most subjects showed visual changes on 3- and 18month bone scan images that disappeared after 6 months off therapy. Enhanced uptake was seen predominantly in the calvarium and lower extremities. Whole skeleton Kbone displayed a median increase of 22 % (3 months, p=0.004) and 34 % (18 months, p=0.002) decreasing to 0.7% (6 months off therapy). Calvarium Kbone changes were three times larger than other sites. After 6 months off therapy, all Kbone and BTM values returned towards baseline

G protein-coupled receptor-mediated calcium signaling in astrocytes

Astrocytes express a large variety of G~protein-coupled receptors (GPCRs) which mediate the transduction of extracellular signals into intracellular calcium responses. This transduction is provided by a complex network of biochemical reactions which mobilizes a wealth of possible calcium-mobilizing second messenger molecules. Inositol 1,4,5-trisphosphate is probably the best known of these molecules whose enzymes for its production and degradation are nonetheless calcium-dependent. We present a biophysical modeling approach based on the assumption of Michaelis-Menten enzyme kinetics, to effectively describe GPCR-mediated astrocytic calcium signals. Our model is then used to study different mechanisms at play in stimulus encoding by shape and frequency of calcium oscillations in astrocytes.Comment: 35 pages, 6 figures, 1 table, 3 appendices (book chapter

HLA Class II–Triggered Signaling Cascades Cause Endothelial Cell Proliferation and Migration: Relevance to Antibody-Mediated Transplant Rejection

Transplant recipients developing donor-specific HLA class II (HLA-II) Abs are at higher risk for Ab-mediated rejection (AMR) and transplant vasculopathy. To understand how HLA-II Abs cause AMR and transplant vasculopathy, we determined the signaling events triggered in vascular endothelial cells (EC) following Ab ligation of HLA-II molecules. HLA-II expression in EC was induced by adenoviral vector expression of CIITA or by pretreatment with TNF-α/IFN-γ. Ab ligation of class II stimulated EC proliferation and migration. Class II Ab also induced activation of key signaling nodes Src, focal adhesion kinase, PI3K, and ERK that regulated downstream targets of the mammalian target of rapamycin (mTOR) pathway Akt, p70 ribosomal S6 kinase, and S6 ribosomal protein. Pharmacological inhibitors and small interfering RNA showed the protein kinases Src, focal adhesion kinase, PI3K/Akt, and MEK/ERK regulate class II Ab-stimulated cell proliferation and migration. Treatment with rapalogs for 2 h did not affect HLA-II Ab-induced phosphorylation of ERK; instead, mTOR complex (mTORC)1 targets were dependent on activation of ERK. Importantly, suppression of mTORC2 for 24 h with rapamycin or everolimus or treatment with mTOR active-site inhibitors enhanced HLA-II Ab-stimulated phosphorylation of ERK. Furthermore, knockdown of Rictor with small interfering RNA caused overactivation of ERK while abolishing phosphorylation of Akt Ser473 induced by class II Ab. These data are different from HLA class I Ab-induced activation of ERK, which is mTORC2-dependent. Our results identify a complex signaling network triggered by HLA-II Ab in EC and indicate that combined ERK and mTORC2 inhibitors may be required to achieve optimal efficacy in controlling HLA-II Ab-mediated AMR

Filamin C is Essential for mammalian myocardial integrity

FLNC, encoding filamin C, is one of the most mutated genes in dilated and hypertrophic cardiomyopathy. However, the precise role of filamin C in mammalian heart remains unclear. In this study, we demonstrated Flnc global (FlncgKO) and cardiomyocyte-specific knockout (FlnccKO) mice died in utero from severely ruptured ventricular myocardium, indicating filamin C is required to maintain the structural integrity of myocardium in the mammalian heart. Contrary to the common belief that filamin C acts as an integrin inactivator, we observed attenuated activation of β1 integrin specifically in the myocardium of FlncgKO mice. Although deleting β1 integrin from cardiomyocytes did not recapitulate the heart rupture phenotype in Flnc knockout mice, deleting both β1 integrin and filamin C from cardiomyocytes resulted in much more severe heart ruptures than deleting filamin C alone. Our results demonstrated that filamin C works in concert with β1 integrin to maintain the structural integrity of myocardium during mammalian heart development

Femoral strength in osteoporotic women treated with teriparatide or alendronate

To gain insight into the clinical effect of teriparatide and alendronate on the hip, we performed non-linear finite element analysis of quantitative computed tomography (QCT) scans from 48 women who had participated in a randomized, double-blind clinical trial comparing the effects of 18-month treatment of teriparatide 20 μg/d or alendronate 10 mg/d. The QCT scans, obtained at baseline, 6, and 18 months, were analyzed for volumetric bone mineral density (BMD) of trabecular bone, the peripheral bone (defined as all the cortical bone plus any endosteal trabecular bone within 3 mm of the periosteal surface), and the integral bone (both trabecular and peripheral), and for overall femoral strength in response to a simulated sideways fall. At 18 months, we found in the women treated with teriparatide that trabecular volumetric BMD increased versus baseline (+ 4.6%, p < 0.001), peripheral volumetric BMD decreased (− 1.1%, p < 0.05), integral volumetric BMD (+ 1.0%, p = 0.38) and femoral strength (+ 5.4%, p = 0.06) did not change significantly, but the ratio of strength to integral volumetric BMD ratio increased (+ 4.0%, p = 0.04). An increase in the ratio of strength to integral volumetric BMD indicates that overall femoral strength, compared to baseline, increased more than did integral density. For the women treated with alendronate, there were small ( < 1.0%) but non-significant changes compared to baseline in all these parameters. The only significant between-treatment difference was in the change in trabecular volumetric BMD (p < 0.005); related, we also found that, for a given change in peripheral volumetric BMD, femoral strength increased more for teriparatide than for alendronate (p = 0.02). We conclude that, despite different compartmental volumetric BMD responses for these two treatments, we could not detect any overall difference in change in femoral strength between the two treatments, although femoral strength increased more than integral volumetric BMD after treatment with teriparatide

Cytochrome P450-Mediated Bioactivation of the Epidermal Growth Factor Receptor Inhibitor Erlotinib to a Reactive Electrophile

The epidermal growth factor receptor tyrosine kinase inhibitor erlotinib (ERL) is approved for treatment of non–small-cell lung cancer. Numerous reports of ERL-associated toxicities are consistent with immune-mediated toxicity, including drug-induced hepatitis, interstitial lung disease, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Although the mechanism of toxicity has not been established, we present evidence that reactive intermediates are formed during the metabolism of ERL, which can covalently conjugate to the cysteine group of the peptide-mimetic GSH. Seven ERL-GSH conjugates were identified in incubations with hepatic microsomes. Cytochrome P450 (P450)-dependent adducts are proposed to be formed via reactive epoxide and electrophilic quinone-imine intermediates. In incubations of human liver microsomes, intestinal microsomes, pulmonary microsomes, and recombinant P450s, CYP3A4 was the primary enzyme responsible for the bioactivation of ERL; however, CYP1A1, CYP1A2, CYP3A5, and CYP2D6 were capable of catalyzing the bioactivation as well. During the metabolism of ERL, CYP3A4 and CYP3A5 are irreversibly inactivated by ERL in a time- and concentration-dependent manner. Inactivation was not dependent on oxidation of the ERL alkyne group to form a reactive oxirene or ketene, as shown by synthesizing analogs where the alkyne was replaced with a cyano group. CYP1A1, CYP1A2, and CYP2D6 were not inactivated despite catalyzing the formation of ERL-GSH adducts