Mechanisms of progression and regression of coronary artery disease by PET related to treatment intensity and clinical events at long-term follow-up.

Changes in regional myocardial perfusion throughout the entire coronary vascular tree, as opposed to changes in the worst regional perfusion defect, have not been described during long-term regression or progression of coronary artery disease (CAD) or related to clinical outcomes. METHODS: Four-hundred nine patients with CAD undergoing dipyridamole PET at baseline and after 2.6 +/- 1.4 y were followed over 5 more years for coronary events. PET images were objectively quantified by automated software for changes in severity of the (i) baseline worst quadrant, indicating the worst flow-limiting stenosis at baseline PET; (ii) follow-up worst quadrant, indicating the worst stenosis on follow-up PET; and (iii) maximal change quadrant, indicating the largest change of any same quadrant pair from baseline-to-follow-up images. RESULTS: At follow-up PET, new regional perfusion defects were seen in 40% of patients. In 77% of patients, the greatest change was in a quadrant different from the worst baseline defect. The maximal change quadrant improved in 70% of patients on intense lifestyle and pharmacologic lipid treatment, in 48% on moderate treatment, and in 39% on poor treatment (P < 0.0001). Combined quadrant changes integrated throughout the heart independently predicted cardiovascular events at long-term follow-up. In contrast, changes of any single baseline-to-follow-up quadrant pair did not. CONCLUSION: By PET, 77% of patients with CAD had the greatest perfusion changes in areas different from the baseline worst perfusion defect and 40% had new perfusion defects. Changes in perfusion defects throughout the entire coronary vascular tree predicted coronary events, whereas changes in the worst flow-limiting stenosis at baseline or in any one segment of myocardium did not. To our knowledge, these data provide the first direct evidence on mechanisms for disproportionately greater reduction in cardiac events than changes in single stenosis severity with lipid treatment.     

Frequent diagnostic errors in cardiac PET/CT due to misregistration of CT attenuation and emission PET images: a definitive analysis of causes, consequences, and corrections.

Cardiac PET combined with CT is rapidly expanding despite artifactual defects and false-positive results due to misregistration of PET and CT attenuation correction data-the frequency, cause, and correction of which remain undetermined. METHODS: Two hundred fifty-nine consecutive patients underwent diagnostic rest-dipyridamole myocardial perfusion PET/CT using (82)Rb, a 16-slice PET/CT scanner, helical CT attenuation correction with breathing and also at end-expiratory breath-hold, and averaged cine CT data during breathing. Misregistration on superimposed PET/CT fusion images was objectively measured in millimeters and correlated with associated quantitative size and severity of PET defects. Misregistration artifacts were defined as PET defects with corresponding misregistration on helical CT-PET fusion images that resolved after correct coregistration using a repeat CT scan, cine CT averaged attenuation during normal breathing, or shifted cine CT data that coregistered with PET data. RESULTS: Misregistration of standard helical CT PET images caused artifactual PET defects in 103 of 259 (40%) patients that were moderate to severe in 59 (23%) (P = 0.0000) and quantitatively normalized on cine or shifted cine CT PET (P = 0.0000). Quantitative misregistration was a powerful predictor of artifact size and severity (P = 0.0000), particularly for transaxial misregistration >6 mm occurring in anterior or lateral areas in 76%, in inferior areas in 16%, and at the apex in 8% of 103 artifactual defects. CONCLUSION: Misregistration of helical CT attenuation and PET emission images causes artifactual defects with false-positive results in 40% of patients that normalize on cine CT PET using averaged CT attenuation data during normal breathing comparable to normal breathing during PET emission scanning and shifting cine CT images to coregister visually with PET.     

The nitric oxide pathway in pre-eclampsia: pathophysiological implications

Pre-eclampsia, one of the most significant health problems inhuman pregnancy, complicates 6-7% of all gestations and is theleading cause of fetal growth retardation, infant morbidityand mortality, premature birth and maternal death. Recent researchimplicates free radicals in the pathophysiology of pre-eclampsia.This review covers the biochemistry of nitric oxide (NO) andpossible interactions with other free radicals. Studies in therat show that pregnancy is associated with enhanced productionand responsiveness to NO in both reproductive tissues and bloodvessels. Rats infused with N^G-nitro-L-arginine methyl ester(L-NAME, a NO synthase inhibitor) have been used as an animalmodel of pre-eclampsia, and the effects of steroid hormoneson blood pressure in this model have been tested. Results suggestthat pre-eclampsia may be a state of NO deficiency. However,in humans there seem to be contradictions regarding the involvementof NO in maternal adaptation to pregnancy. It is suggested thatNO may be one of several systems that act in concert to maintaina symbiotic relationship between mother and fetus. However,the input of each system may be genetically determined.     

Pharmacokinetics of high-dose methotrexate in adult osteogenic sarcoma

The pharmacokinetics of 222 infusions of high-dose methotrexate (MTX) with leucovorin rescue were studied in 22 adults with osteosarcoma. To reduce the variability of plasma concentration, we individualized dose regimens using a Bayesian method to reach a concentration of 10^–3 M MTX at the end of an 8-h infusion. The mean concentration observed at the end of the infusion was 1016±143 mol/l. The mean dose delivered was 13.2±2 g/m². The clearance was 49.1±11.7 ml min^–1 m^–2. The decay of the plasma concentration of MTX after completion of the infusion followed a two-compartment model with at _1/2 of 2.66±0.82 h and at _1/2 of 15.69±8.63 h. The volume of distribution was 0.32±0.08 l/kg. As compared with previously published data, the interindividual and intraindividual variations in the concentration at the end of the infusion were reduced, with values of 14% and 5.9%–21%, respectively, being obtained. Severe toxicities were avoided, and there were only 3 hematologic and 8 digestive grade 3 side effects and no grade 4 complication. Thet _1/2 and the MTX plasma concentrations at 23 and 47 h were correlated with renal toxicity (P<0.001). However, no correlation was found between the pharmacokinetic parameters and other signs of toxicity. There was no significant difference in pharmacokinetics between the toxic and nontoxic groups. In the same manner, the parameters of the group of patients sensitive to MTX were not statistically significantly different from those of the group of nonsensitive patients.     

A Bayesian dosing method for carboplatin given by continuous infusion for 120 h

Carboplatin (CBDCA), an analogue of cisplatin, exhibits reduced toxicity but wide interpatient variability of its pharmacokinetic parameters. Individualization of the CBDCA dose is therefore necessary. Although various formulas have been developed for this purpose, major side effects have been reported on CBDCA administration by short-term infusion (0.5 or 1h). We therefore propose a new schedule of CBDCA administration. Instead of a dosing method based on the estimation of renal function when a classic administration schedule is used, we propose a pharmacokinetic dosing method (Bayesian method), whereby CBDCA is given by continuous infusion for 120 h. First, CBDCA was given to 21 patients to determine the population pharmacokinetic parameters of carboplatin. Then, on the basis of total platinum plasma concentration measurements and Bayesian estimation of pharmacokinetic parameters, it was possible to individualize the CBDCA dose within the first 24 h of the infusion. This new protocol for CBDCA administration was evaluated in 36 new patients (60 courses). Three theoretical end points at the end of the infusion were considered. For a given theoretical end point, 20 courses were taken into account. The theoretical end points (i.e., 1, 1.5, and 1.8 mg/l) were compared with the concentrations measured at the end of the infusion, which were 0.99 ± 0.10, 1.41 ± 0.13, and 1.72 ± 0.20 mg/l, respectively. This Bayesian dosing method can easily be used in clinical practice, and the determination of predictive performances has shown that the method is precise and unbiased. With no more toxicity or practical difficulties than those produced by other methods, and with acceptable tolerance, it was possible to reach a median dose that was 20% higher than the usual dose (484 ± 190 mg/m² as compared with 400 mg/m²). In conclusion, this new schedule of CBDCA administration appears to be interesting in terms of tolerance. However, new studies are required to confirm that this new scheme leads to equal or better efficacy than the classic protocol. Received: 10 December 1995 / Accepted: 15 December 1996     

Activation profile of dorsal root ganglia Iba-1 (+) macrophages varies with the type of lesion in rats

The interactions between neurons, immune and immune-like glial cells can initiate the abnormal processes that underlie neuropathic pain. In the peripheral nervous system the resident macrophages may play an important role. In this study we investigated in experimental adult Sprague-Dawley rats how Iba-1 (ionized calcium binding adaptor molecule 1) (+) resident macrophages in the dorsal root ganglion (DRG) are activated after a spinal nerve ligation (SNL) or streptozotocin (STZ)-induced diabetes. The activation profile was defined by comparing the responses of resident macrophages against microglia in the spinal cord as they share a common origin. After SNL, the Iba-1 (+) macrophages in L5 DRG reached their activation peak 5 days later, clustered as satellite cells around large A-neurons, expressed the MHC-II marker, but did not show p-p38 and p-ERK1/2 activation and did not secrete IL-18. After STZ-induced diabetes, the Iba-1 (+) macrophages reached their activation peak 1 week later in L4 and L5 DRG, remained scattered between neurons, expressed the MHC-II marker only in L5 DRG, did not show p-p38 and p-ERK1/2 activation and did not secrete any of the investigated cytokines/chemokines. These responses suggest that depending on the type of lesion DRG Iba-1 (+) resident macrophages have different activation mechanisms, which are dissimilar to those in microglia.     

Characterization of the anti‐HBV activity of HLP1–23, a human lactoferrin‐derived peptide

Lactoferrin (Lf) was shown to exhibit its antiviral activity at an early phase of viral infection and a mechanism whereby the protein interacts with host cell surface molecules has been suggested. In this study, human Lf (HLf) and seven HLf‐derived synthetic peptides (HLP) corresponding to the N‐terminal domain of the native protein (1–47 amino acids sequence) were assayed for their capacity to prevent hepatitis B virus (HBV) infection and replication using the HepaRG and HepG2.2.2.15 cell lines. Of the series tested, four peptides showed 40–75% inhibition of HBV infection in HepaRG cells, HLP_1–23, containing the GRRRR cationic cluster, being the most potent. Interestingly, this cluster is one of the two glycosaminoglycan binding sites of the native HLf involved in its antiviral activity; however, the mechanism of the HLP_1–23 action was different from that of the full‐length protein, the peptide inhibiting HBV infection when pre‐incubated with the virus, while no effect was observed on the target cells. It is suggested that the cationic cluster is sufficient for the peptide to interact stably with negatively charged residues on the virion envelope, while the absence of the second glycosaminoglycan binding site prevents its efficient attachment to the cells. In conclusion, this peptide may constitute a non‐toxic approach for potential clinical applications in inhibiting HBV entry by neutralizing the viral particles. J. Med. Virol. 85:780–788, 2013. © 2013 Wiley Periodicals, Inc.     

Decreased Mechanical Strength and Collagen Content in SPARC‐Null Periodontal Ligament Is Reversed by Inhibition of Transglutaminase Activity

The periodontal ligament (PDL) is a critical tissue that provides a physical link between the mineralized outer layer of the tooth and the alveolar bone. The PDL is composed primarily of nonmineralized fibrillar collagens. Expression of secreted protein acidic and rich in cysteine (SPARC/osteonectin), a collagen‐binding matricellular protein, has been shown to be essential for collagen homeostasis in PDL. In the absence of SPARC, PDL collagen fibers are smaller and less dense than fibers that constitute WT PDL. The aim of this study was to identify cellular mechanisms by which SPARC affected collagen fiber assembly and morphology in PDL. Cross‐linking of fibrillar collagens is one parameter that is known to affect insoluble collagen incorporation and fiber morphology. Herein, the reduction in collagen fiber size and quantity in the absence of SPARC expression was shown to result in a PDL with reduced molar extraction force in comparison to that of WT mice (C57Bl/6J). Furthermore, an increase in transglutaminase activity was found in SPARC‐null PDL by biochemical analyses that was supported by immunohistochemical results. Specifically, collagen I was identified as a substrate for transglutaminase in PDL and transglutaminase activity on collagen I was found to be greater in SPARC‐null tissues in comparison to WT. Strikingly, inhibition of transglutaminase activity in SPARC‐null PDL resulted in increases in both collagen fiber thickness and in collagen content, whereas transglutaminase inhibitors injected into WT mice resulted in increases in collagen fiber thickness only. Furthermore, PDL treated with transglutaminase inhibitors exhibited increases in molar extraction force in WT and in SPARC‐null mice. Thus, SPARC is proposed to act as a critical regulator of transglutaminase activity on collagen I with implications for mechanical strength of tissues. © 2015 American Society for Bone and Mineral Research     

Numerical Modeling and Analysis of Ti6Al4V Alloy Chip for Biomedical Applications

The influence of cutting forces during the machining of titanium alloys has attained prime attention in selecting the optimal cutting conditions to improve the surface integrity of medical implants and biomedical devices. So far, it has not been easy to explain the chip morphology of Ti6Al4V and the thermo-mechanical interactions involved during the cutting process. This paper investigates the chip configuration of the Ti6Al4V alloy under dry milling conditions at a macro and micro scale by employing the Johnson-Cook material damage model. 2D modeling, numerical milling simulations, and post-processing were conducted using the Abaqus/Explicit commercial software. The uncut chip geometry was modeled with variable thicknesses to accomplish the macro to micro-scale cutting by adapting a trochoidal path. Numerical results, predicted for the cutting reaction forces and shearing zone temperatures, were found in close approximation to experimental ones with minor deviations. Further analyses evaluated the influence of cutting speeds and contact friction coefficients over the chip flow stress, equivalent plastic strain, and chip morphology. The methodology developed can be implemented in resolving the industrial problems in the biomedical sector for predicting the chip morphology of the Ti6Al4V alloy, fracture mechanisms of hard-to-cut materials, and the effects of different cutting parameters on workpiece integrity.