Comparison of MCNPX and MIRDcell in assessing self-dose and cross-dose delivered to cell nuclei and the development of a realistic geometric model.

Purpose: This study aims to provide a comparison between MCNPX and MIRDcell calculations for self-dose and cross-dose for three therapeutic isotopes used in internal radiotherapy (Lu-177, I-131 and Y-90) and to develop a multi-cellular geometric model to simulate an in vitro scenario.Materials and Methods: The self- and cross-dose to individual cell nuclei were assessed by Monte Carlo N-Particle eXtended (MCNPX). A close-packed cubic cell arrangement was assumed with the same amount of radioactivity per cell. Various cell sizes and subcellular distributions of radioactivity (nucleus, cytoplasm and cell membrane) were simulated. S values were obtained by MIRDcell for comparison. A Python 3.4 program was used to generate random cell coordinates in order to build a complex model that takes certain real conditions (cell size and cluster size) into account.Results: The relative differences of MCNPX versus MIRD S values (Sself) ranged from 2.88 to 10.10% for Lu-177; from 0 to 8.41% for I-131 and from 2.80 to 9.58% for Y-90. The relative differences of MCNPX versus MIRDcell cross-dose S values were 3.6%-15.7% for a sphere. The ratio of Scross max to Sself decreased for Lu-177 and I-131 with increasing cell size. The source localization within the cells had no significant impact on the cross-dosing. For single cells, the subcellular location of the source had an effect on Sself.Conclusions: MCNPX and MIRD cell-calculated S values showed good agreement. The model provided could be used to predict the biological effect caused by emitted radiation from therapeutic radionuclides at the cellular level.

Does the road go up the mountain? Fictive motion between linguistic conventions and cognitive motivations.

Fictive motion (FM) characterizes the use of dynamic expressions to describe static scenes. This phenomenon is crucial in terms of cognitive motivations for language use; several explanations have been proposed to account for it, among which mental simulation (Talmy in Toward a cognitive semantics, vol 1. MIT Press, Cambridge, 2000) and visual scanning (Matlock in Studies in linguistic motivation. Mouton de Gruyter, Berlin and New York, pp 221-248, 2004a). The aims of this paper were to test these competing explanations and identify language-specific constraints. To do this, we compared the linguistic strategies for expressing several types of static configurations in four languages, French, Italian, German and Serbian, with an experimental set-up (59 participants). The experiment yielded significant differences for motion-affordance versus no motion-affordance, for all four languages. Significant differences between languages included mean frequency of FM expressions. In order to refine the picture, and more specifically to disentangle the respective roles of language-specific conventions and language-independent (i.e. possibly cognitive) motivations, we completed our study with a corpus approach (besides the four initial languages, we added English and Polish). The corpus study showed low frequency of FM across languages, but a higher frequency and translation ratio for some FM types--among which those best accounted for by enactive perception. The importance of enactive perception could thus explain both the universality of FM and the fact that language-specific conventions appear mainly in very specific contexts--the ones furthest from enaction.

Effect on comprehension of preposed versus postposed adverbial phrases.

A challenge for psycholinguistics is to describe how linguistic cues influence the construction of the mental representation resulting from the comprehension of a text. In this paper, we will focus on one of these linguistic devices: the sentence-initial positioning of spatial adverbials such as In the park.... Three self-paced reading experiments were conducted to test the 'Discourse Framing Hypothesis' according to which preposed adverbials can be seen as frame builders announcing that incoming contents satisfy the same informational criterion specified by the adverbial. Our results indicate that spatial adverbials do not play the same role when they are in sentence-initial and in sentence-final position. These results are discussed in the framework of Zwaan's Event Indexing Model.

Dysregulation of 4q35- and muscle-specific genes in fetuses with a short D4Z4 array linked to facio-scapulo-humeral dystrophy.

Facio-scapulo-humeral dystrophy (FSHD) results from deletions in the subtelomeric macrosatellite D4Z4 array on the 4q35 region. Upregulation of the DUX4 retrogene from the last D4Z4 repeated unit is thought to underlie FSHD pathophysiology. However, no one knows what triggers muscle defect and when alteration arises. To gain further insights into the molecular mechanisms of the disease, we evaluated at the molecular level, the perturbation linked to the FSHD genotype with no a priori on disease onset, severity or penetrance and prior to any infiltration by fibrotic or adipose tissue in biopsies from fetuses carrying a short pathogenic D4Z4 array (n = 6) compared with fetuses with a non-pathogenic D4Z4 array (n = 21). By measuring expression of several muscle-specific markers and 4q35 genes including the DUX4 retrogene by an RT-PCR and western blotting, we observed a global dysregulation of genes involved in myogenesis including MYOD1 in samples with <11 D4Z4. The DUX4-fl pathogenic transcript was detected in FSHD biopsies but also in controls. Importantly, in FSHD fetuses, we mainly detected the non-spliced DUX4-fl isoform. In addition, several other genes clustered at the 4q35 locus are upregulated in FSHD fetuses. Our study is the first to examine fetuses carrying an FSHD-linked genotype and reveals an extensive dysregulation of several muscle-specific and 4q35 genes at early development stage at a distance from any muscle defect. Overall, our work suggests that even if FSHD is an adult-onset muscular dystrophy, the disease might also involve early molecular defects arising during myogenesis or early differentiation.

Novel neurotensin analogues for radioisotope targeting to neurotensin receptor-positive tumors.

The increased expression of the neurotensin (NT) receptor NTS1 by different cancer cells, such as pancreatic adenocarcinoma and ductal breast cancer cells, as compared to normal epithelium, offers the opportunity to target these tumors with radiolabeled neurotensin analogues for diagnostic or therapeutic purposes. The aim of the present study was to design and synthesize new neurotensin radioligands and to select a lead molecule with high in vivo tumor selectivity for further development. Two series of neurotensin analogues bearing DTPA were tested: a series of NT(8-13) analogues, with DTPA coupled to the α-NH(2), sharing the same peptide sequence with analogues previously developed for radiolabeling with technetium or rhenium, as well as an NT(6-13) series in which DTPA was coupled to the ε-NH(2) of Lys(6). Changes were introduced to stabilize the bonds between Arg(8)-Arg(9), Pro(10)-Tyr(11), and Tyr(11)-Ile(12) to provide metabolic stability. Structure-activity studies of NT analogues have shown that the attachment of DTPA induces an important loss of affinity unless the distance between the chelator and the NT(8-13) sequence, which binds to the NTS1 receptor, is increased. The doubly stabilized DTPA-NT-20.3 exhibits a high affinity and an elevated stability to enzymatic degradation. It shows specific tumor uptake and high tumor to blood, to liver, and to intestine activity uptake ratios and affords high-contrast planar and SPECT images in an animal model. The DTPA-NT-20.3 peptide is a promising candidate for imaging neurotensin receptor-positive tumors, such as pancreatic adenocarcinoma and invasive ductal breast cancer. Analogues carrying DOTA are being developed for yttrium-90 or lutetium-177 labeling.

Impact of liver transplantation on cardiac autonomic denervation in familial amyloid polyneuropathy.

Familial amyloid polyneuropathy (FAP) is a rare and severe hereditary form of amyloidosis, due to the deposition of a genetic variant transthyretin essentially produced by the liver, and characterized by both sensorimotor and autonomic neuropathy. Liver transplantation (LT) is the most effective treatment to stop the progression of the disease. Cardiac amyloid infiltration is usually associated with cardiac denervation, restrictive cardiomyopathy, conduction disturbances, and sometimes sudden death. Whether the cardiac involvement related to amyloid deposition may be altered after LT remains unclear. We conducted the present study to define the outcome of cardiac involvement after LT in 31 patients with FAP (age, 39 +/- 12 yr). Patients were evaluated before and after LT (24 +/- 15 mo). Cardiac sympathetic denervation was assessed by both iodine-123 metaiodobenzylguanidine (MIBG) scintigraphy and heart rate variability (HRV) analysis. The scintigraphic importance of sympathetic denervation was evaluated globally on planar imaging using heart-to-mediastinum activity ratio (H/M) measured 4 hours after injection, and regionally using single-photon emission tomography (SPET) imaging. Amyloid myocardial infiltration was assessed by echocardiography. Diffuse sympathetic denervation was found when using cardiac MIBG planar imaging in patients evaluated before LT and compared with 12 control subjects (H/M: 1.45 +/- 0.29 vs. 1.98 +/- 0.35, p < 0.001). On SPET images, defects were diffuse in 12 patients and focal in 19 patients, with predominance at the inferior and apical segments. No change in sympathetic innervation was found in patients after LT as assessed either with planar imaging (H/M after LT: 1.46 +/- 0.28, p = not significant vs. H/M before LT) or with SPET imaging. HRV nonspectral indexes showed that the standard deviation of all cycles was significantly lower in patients compared with control subjects, and remained unchanged after LT. Conduction disturbances and ventricular arrhythmias were associated with low cardiac MIBG uptake, and progressed after LT. The left ventricular wall was slightly thickened in patients, and a further increase was observed after LT (posterior wall from 9.2 +/- 1.8 to 10.1 +/- 2.3 mm, p = 0.02; septal wall from 10.6 +/- 2.7 to 12.1 +/- 4, p = 0.046). Neurologic status stabilized in 26 patients, but worsened in the 5 patients who had the most severe cardiac sympathetic denervation before LT as measured by MIBG imaging. The magnitude of the cardiac sympathetic denervation remained stable 2 years after LT in patients with FAP, whereas the cardiac amyloid infiltration progressed. The importance of cardiac sympathetic denervation found in FAP patients before LT was associated with a neurologic worsening after LT.

Inability of 99mTc-ciprofloxacin scintigraphy to discriminate between septic and sterile osteoarticular diseases.

UNLABELLED: Ciprofloxacin labeled with (99m)Tc specifically binds to various bacteria. Thus, it potentially constitutes a specific marker allowing discrimination between septic arthritis/osteomyelitis and aseptic osteoarticular diseases. The aim of this prospective study was to evaluate such properties in patients with skeletal diseases. METHODS: We prospectively investigated 2 groups of patients: patients with suspected osteoarticular infections (G1, n = 16) and a control group of patients with a presentation of osteoarticular diseases and no sign suggestive of infection (G2, n = 11). All had clinical, biologic, and radiologic evaluations and had 1-, 4-, and 24-h images from (99m)Tc-ciprofloxacin scintigraphy (370 MBq) before planned biopsy or surgery. For 23 patients, the scintigraphic results were compared with histologic and bacteriologic analyses of biopsy tissue samples; for 4 patients, the scintigraphic results were compared with the findings from 23 +/- 5 mo of follow-up. RESULTS: In G1, (99m)Tc-ciprofloxacin findings were true-positive in all 11 infected sites, true-negative in 2 cases, and false-positive in 3. In G2, (99m)Tc-ciprofloxacin was true-negative in 4 cases and false-positive in 7. Neither the location of (99m)Tc-ciprofloxacin activity nor its intensity or kinetics between 1, 4, and 24 h allowed discrimination between infection and aseptic diseases (sterile loosened joint replacement, pseudoarthrosis, or arthrosis). Sensitivity, specificity, and accuracy were 100%, 37.5%, and 63%. CONCLUSION: (99m)Tc-Ciprofloxacin scintigraphy showed good sensitivity and a high negative predictive value for the detection of bone and joint infection, but it did not discriminate between infected and aseptic osteoarticular diseases in symptomatic patients referred for surgery.

Evaluation of (99m)Tc-ciprofloxacin scintigraphy in a rabbit model of Staphylococcus aureus prosthetic joint infection.

UNLABELLED: Ciprofloxacin, a quinolone antibiotic drug, binds to DNA topoisomerase IV and DNA gyrase of various bacteria. Thus ciprofloxacin labeled with (99m)Tc could potentially act as a specific marker allowing discrimination between infection and sterile inflammation. We evaluated these properties on a rabbit model of prosthetic joint infection previously validated. We compared the images obtained in 2 groups of animals: rabbits with infected (G1; n = 6) and uninfected (G2; n = 7) prosthesis. METHODS: Partial right-knee arthroplasty was performed on 13 New Zealand White female rabbits, with a tibial silicone-elastomer implant fitting into the intramedullary canal of the tibia. After the surgical wound was closed, 10(7) cfu of a clinical strain of methicillin-susceptible Staphylococcus aureus were injected into the joint in G1 rabbits. G2 rabbits were injected with sterile saline. No antibiotic therapy was given to the animals. (99m)Tc-ciprofloxacin planar imaging was performed on days 5, 12, and 19 after surgery, and after 3 mo in 1 uninfected rabbit. Images were obtained 1, 4, and 24 h after injection (147 +/- 13 MBq). RESULTS: In G1, increased right knee (99m)Tc-ciprofloxacin uptake was observed in 3 of 5 rabbits on day 5, and in all cases on days 12 and 19. Killing of the animals revealed purulent arthritis, osteitis, and tibial myelitis. In G2, significant right-knee uptake was found on days 12 and 19 in 5 of 6 rabbits, and after 3 mo in 1; all sets of images were negative in 1 animal. Bacteriologic studies after the animals were killed were negative in G2. Mean right/left knee uptake ratios on day 19 (4-h images) were 1.8 +/- 0.4 in G1 versus 1.4 +/- 0.3 in G2 (not significant). Late images did not discriminate between infected and uninfected arthroplasty. CONCLUSION: Results of (99m)Tc-ciprofloxacin imaging in rabbits with infected/uninfected knee prosthesis suggest good sensitivity but lack of specificity for the detection of S. aureus infection.