Philippe Chaumet-Riffaud

Carbon dioxide inhalation causes pulmonary inflammation

The aim of this study was to assess whether one of the most common poisons of cellular respiration, i.e., carbon dioxide, is proinflammatory. CO(2) is naturally present in the atmosphere at the level of 0.038% and involved in numerous cellular biochemical reactions. We analyzed in vitro the inflammation response induced by exposure to CO(2) for 48 h (0-20% with a constant O(2) concentration of 21%). In vivo mice were submitted to increasing concentrations of CO(2) (0, 5, 10, and 15% with a constant O(2) concentration of 21%) for 1 h. The exposure to concentrations above 5% of CO(2) resulted in the increased transcription (RNase protection assay) and secretion (ELISA) of proinflammatory cytokines [macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, MIP-2, IL-8, IL-6, monocyte chemoattractant protein-1, and regulated upon activation, normal T cell expressed, and, presumably, secreted (RANTES)] by epithelial cell lines HT-29 or A549 and primary pulmonary cells retrieved from the exposed mice. Lung inflammation was also demonstrated in vivo by mucin 5AC-enhanced production and airway hyperreactivity induction. This response was mostly mediated by the nuclear translocation of p65 NF-kappaB, itself a consequence of protein phosphatase 2A (PP2A) activation. Short inhibiting RNAs (siRNAs) targeted toward PP2Ac reversed the effect of carbon dioxide, i.e., disrupted the NF-kappaB activation and the proinflammatory cytokine secretion. In conclusion, this study strongly suggests that exposure to carbon dioxide may be more toxic than previously thought. This may be relevant for carcinogenic effects of combustion products.

Hyperosmotic stress contributes to mouse colonic inflammation through the methylation of protein phosphatase 2A

There are several reports suggesting hyperosmotic contents in the feces of patients suffering from inflammatory bowel disease (IBD). Previous works have documented that hyperosmolarity can cause inflammation attributable to methylation of the catalytic subunit of protein phosphatase 2A (PP2A) and subsequent NF-kappaB activation resulting in cytokine secretion. In this study, we demonstrate that dextran sulfate sodium (DSS) induces colitis due to hyperosmolarity and subsequent PP2A activation. Mice were randomized and fed with increased concentrations of DSS (0 mOsm, 175 mOsm, 300 mOsm, and 627 mOsm) for a duration of 3 wk or with hyperosmotic concentrations of DSS (627 mOsm) or mannitol (450 mOsm) for a duration of 12 wk. Long-term oral administration of hyposmotic DSS or mannitol had no demonstrable effect. Hyperosmotic DSS or mannitol produced a significant increase in colonic inflammation, as well as an increase in the weight of sacral lymph nodes and in serum amyloid A protein levels. Similar results were obtained through the ingestion of comparable osmolarities of mannitol. Hyperosmolarity induces the methylation of PP2A, nuclear p65 NF-kappaB activation. and cytokine secretion. The rectal instillation of okadaic acid, a well-known PP2A inhibitor, reverses the IBD. Short inhibiting RNAs (siRNAs) targeted toward PP2Ac reverse the effect of hyperosmotic DSS. The present study strongly suggests that DSS-induced chronic colitis is a consequence of the methylation of PP2Ac induced by hyperosmolarity.

Optimizing statistical parametric mapping analysis of 18F-FDG PET in children

BackgroundStatistical parametric mapping (SPM) procedure is an objective tool to analyze 18F-fluoro-2-deoxy-d-glucose-positron-emission tomography (FDG-PET) images and a useful complement to visual analysis. However, SPM requires a comparison to control data set that cannot be obtained in healthy children for ethical reasons. Using adults as controls showed some limitations. The purpose of the present study was to generate and validate a group of pseudo-normal children as a control group for FDG-PET studies in pediatrics.MethodsFDG-PET images of 47 children (mean ± SD age 10.2 ± 3.1 years) with refractory symptomatic (MRI-positive, n = 20) and cryptogenic (MRI-negative, n = 27) focal epilepsy planned for surgery were analyzed using visual and SPM analysis. Performances of SPM analysis were compared using two different control groups: (1) an adult control group consisting of healthy young adults (n = 25, 30.5 ± 5.8 years, adult PET template) and (2) a pediatric pseudo-control group consisting of patients (n = 24, 10.6 ± 3.1 years, children PET template) with refractory focal epilepsy but with negative MRI and with PET considered normal not only on visual analysis but also on SPM.ResultsAmong the 47 children, visual analysis succeeded detecting at least one hypometabolic area in 87% of the cases (interobserver kappa = 0.81). Regarding SPM analysis, the best compromise between sensitivity and specificity was obtained with a threshold of p less than 0.001 as an extent of more than 40 voxels. There was a significant concordance to detect hypometabolic areas between both SPM analyses [kappa (K) = 0.59; p < 0.005] and between both SPM and visual analyses (K = 0.45; p < 0.005), in symptomatic (K = 0.74; p < 0.005) as in cryptogenic patients (K = 0.26; p < 0.01). The pediatric pseudo-control group dramatically improved specificity (97% vs. 89%; p < 0.0001) by increasing the positive predictive value (86% vs. 65%). Sensitivity remained acceptable although it was not better (79% vs. 87%, p = 0.039). The main impact was to reduce by 41% the number of hypometabolic cortical artifacts detected by SPM, especially in the younger epileptic patients, which is a key point in clinical practice.ConclusionsThis age-matched pseudo-control group is a way to optimize SPM analysis of FDG-PET in children with epilepsy. It might also be considered for other brain pathologies in pediatrics in the future.

Synthesis and application of lactosylated, 99mTc chelating albumin for measurement of liver function.

Neogalactosylated and neolactosylated albumins are currently used as radiopharmaceutical agents for imaging the liver asialoglycoprotein receptors, which allows the quantification of hepatic liver function in various diseases and also in healthy liver transplant donors. We developed an original process for synthesizing a chelating neolactosylated human albumin using maleimidopropyl-lactose and maleimidopropyl-diethylene triamine pentaacetic acid (DTPA) derivatives. The lactosylated protein (LACTAL) conjugate showed excellent liver uptake compared to nonlactosylated protein and a very high signal-to-noise ratio, based on functional assessment of biodistribution in mice using (99m)Tc-scintigraphy.

Functional Renal Imaging: New Trends in Radiology and Nuclear Medicine

The objective of this work is to compare the characteristics of various techniques for functional renal imaging, with a focus on nuclear medicine and magnetic resonance imaging. Even with low spatial resolution and rather poor signal-to-noise ratio, classical nuclear medicine has the advantage of linearity and good sensitivity. It remains the gold standard technique for renal relative functional assessment. Technetium-99m ((99m)Tc)-labeled diethylenetriamine penta-acetate remains the reference glomerular tracer. Tubular tracers have been improved: (123)I- or (131)I-hippuran, (99m)Tc-MAG3 and, recently, (99m)Tc-nitrilotriacetic acid. However, advancement in molecular imaging has not produced a groundbreaking tracer. Renal magnetic resonance imaging with classical gadolinated tracers probably has potential in this domain but has a lack of linearity and, therefore, its value still needs evaluation. Moreover, the advent of nephrogenic systemic fibrosis has delayed its expansion. Other developments, such as diffusion or blood oxygen level-dependent imaging, may have a role in the future. The other modalities have a limited role in clinical practice for functional renal imaging.

Chronic Urinary Obstruction: Evaluation of Dynamic Contrast-enhanced MR Urography for Measurement of Split Renal Function

PURPOSE To evaluate if measurement of split renal function ( SRF split renal function ) with dynamic contrast material-enhanced ( DCE dynamic contrast enhanced ) magnetic resonance (MR) urography is equivalent to that with renal scintigraphy ( RS renal scintigraphy ) in patients suspected of having chronic urinary obstruction. MATERIALS AND METHODS The study protocol was approved by the institutional ethics committee of the coordinating center on behalf of all participating centers. Informed consent was obtained from all adult patients or both parents of children. This prospective, comparative study included 369 pediatric and adult patients from 14 university hospitals who were suspected of having chronic or intermittent urinary obstruction, and data from 295 patients with complete data were used for analysis. SRF split renal function was measured by using the area under the curve and the Patlak-Rutland methods, including successive review by a senior and an expert reviewer and measurement of intra- and interobserver agreement for each technique. An equivalence test for mean SRF split renal function was conducted with an α of 5%. RESULTS Reproducibility was substantial to almost perfect for both methods. Equivalence of DCE dynamic contrast enhanced MR urography and RS renal scintigraphy for measurement of SRF split renal function was shown in patients with moderately dilated kidneys (P < .001 with the Patlak-Rutland method). However, in severely dilated kidneys, the mean SRF split renal function measurement was underestimated by 4% when DCE dynamic contrast enhanced MR urography was used compared with that when RS renal scintigraphy was used. Age and type of MR imaging device had no significant effect. CONCLUSION For moderately dilated kidneys, equivalence of DCE dynamic contrast enhanced MR urography to RS renal scintigraphy was shown, with a standard deviation of approximately 12% between the techniques, making substitution of DCE dynamic contrast enhanced MR urography for RS renal scintigraphy acceptable. For severely dilated kidneys, a mean underestimation of SRF split renal function of 4% should be expected with DCE dynamic contrast enhanced MR urography, making substitution questionable.

Carbon dioxide is largely responsible for the acute inflammatory effects of tobacco smoke

Tobacco smoking is responsible for a vast array of diseases, particularly chronic bronchitis and lung cancer. It is still unclear which constituent(s) of the smoke is responsible for its toxicity. The authors decided to focus on carbon dioxide, since its level of concentration in mainstream cigarette smoke is about 200 times higher than in the atmosphere. The authors previously demonstrated that inhalation of carbon dioxide concentrations above 5% has a deleterious effect on lungs. In this study, the authors assessed the inflammatory potential of carbon dioxide contained in cigarette smoke. Mice were exposed to cigarette smoke containing a high or reduced CO2 level by filtration through a potassium hydroxyde solution. The inflammatory response was evaluated by histological analysis, protein phosphatase 2 A (PP2A) and nuclear factor (NF)-κB activation, and proinflammatory cytokine secretion measurements. The data show that the toxicity of cigarette smoke may be largely due to its high level of CO2. Pulmonary injuries consequent to tobacco smoke inhalation observed by histology were greatly diminished when CO2 was removed. Cigarette smoke exposure causes an inflammatory response characterized by PP2A and NF-κB activation followed by proinflammatory cytokine secretion. This inflammatory response was reduced when the cigarette smoke was filtered through a potassium hydroxide column, and reestablished when CO2 was injected downstream from the filtration column.Given that there is an extensive literature linking a chronic inflammatory response to the major smoking-related diseases, these data suggest that carbon dioxide may play a key role in the causation of these diseases by tobacco smoking.

Amphiphilic perfluoroalkyl carbohydrates as new tools for liver imaging

The synthesis of three molecules containing a fluorocarbon chain (either C(6)F(13), C(8)F(17) or C(10)F(21)), a sugar moiety (derived from lactobionic acid) and a chelate (derived from DTPA) is reported. These molecules (C(6)F(13)-Gal-DTPA, C(8)F(17)-Gal-DTPA or C(10)F(21)-Gal-DTPA) have been dispersed in water and their critical micellar concentration (CMC) as well as their size were determined. Their interaction with serum was weak as evaluated by time resolved fluorimetry of europium complexes. The presence of sugar on the surface of the nanoparticles was confirmed by the agglutination test using ricin. Conditions of pH and concentrations were optimised for in vivo studies. Finally, the nanoparticles formed with C(10)F(21)-Gal-DTPA have been complexed with (99m)Tc and injected to rats in order to follow their biodistribution by scintigraphy while following their stability by transmission electronic microscopy. A majority of the compound was found in the liver post-bolus injection.

Intrapancreatic accessory spleen diagnosed on radionuclide imaging.

Intrapancreatic accessory spleen (IPAS) is ectopic splenic tissue distinct from the main spleen. A 46-year-old man with chronic hepatitis C, presented in 2006 with low right chest pain which led to a diagnosis of tuberculosis pleurisy. CT scan and MRI showed a round, homogenous, well limited mass of 3cm in the pancreas tail. Tc-99m heat-damaged red blood cell scintigraphy with SPECT-CT was performed to confirm the diagnosis of IPAS. Most cases of IPAS described in the literature were diagnosed by pathologists after distal pancreatectomy and splenectomy performed for a suspicion of pancreatic tumor. However, heat-damaged red blood cell scintigraphy remains the most commonly used diagnostic procedure for IPAS, even if superparamagnetic iron oxide MRI contrast agent may be used in the future.

Is it possible to predict renal function in small animals using a multi-pinhole SPECT system?

1. In the data analysis, only the correlation was mentioned, without even the standard error of the estimate. Taking into account the fact that the same parameter, namely the uptake as a percentage of injected activity, was measured with two different techniques, correlation is not enough; rather, one needs to know whether the two methods agree sufficiently closely [2]. 2. The title of the paper, as well as the introduction, suggest that this technique could be used to assess renal function. We object to this suggestion because absolute DMSA uptake is not a valid parameter for renal function [3]. 3. The introduction states that DMSA is taken up by tubules after glomerular filtration, which is somewhat misleading. It is true that DMSA is filtered. It is also true that DMSA is taken up by tubules. However, these two phenomena are parallel and the uptake of DMSA is peritubular, i.e. the filtered DMSA is not taken up by the tubules [4]. 4. The introduction states that DMSA is a marker of tubular function, which is somewhat questionable. While the behaviour of MAG3, as an organic ion, is well known [5], this is not the case for DMSA. Indeed, even if DMSA is taken up by tubules, its uptake reflects renal functional mass [6] more than true tubular function, with possible discrepancies between DMSA and other radiotracers (DMSA may show higher [7] or lower [8] uptake in given cases).