Immune response, phenotyping and molecular graft surveillance in kidney transplant recipients following severe acute respiratory syndrome coronavirus 2 vaccination.

BACKGROUND: Understanding immunogenicity and alloimmune risk following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in kidney transplant recipients is imperative to understanding the correlates of protection and to inform clinical guidelines. METHODS: We studied 50 kidney transplant recipients following SARS-CoV-2 vaccination and quantified their anti-spike protein antibody, donor-derived cell-free DNA (dd-cfDNA), gene expression profiling (GEP), and alloantibody formation. RESULTS: Participants were stratified using nucleocapsid testing as either SARS-CoV-2-naïve or experienced prior to vaccination. One of 34 (3%) SARS-CoV-2 naïve participants developed anti-spike protein antibodies. In contrast, the odds ratio for the association of a prior history of SARS-CoV-2 infection with vaccine response was 18.3 (95% confidence interval 3.2, 105.0, p < 0.01). Pre- and post-vaccination levels did not change for median dd-cfDNA (0.23% vs. 0.21% respectively, p = 0.13), GEP scores (9.85 vs. 10.4 respectively, p = 0.45), calculated panel reactive antibody, de-novo donor specific antibody status, or estimated glomerular filtration rate. CONCLUSIONS: SARS-CoV-2 vaccines do not appear to trigger alloimmunity in kidney transplant recipients. The degree of vaccine immunogenicity was associated most strongly with a prior history of SARS-CoV-2 infection.

Excreted testosterone and male sexual proceptivity: A hormone validation and proof-of-concept experiment in túngara frogs.

Conventional methods for sampling hormones often preclude strong inference experimental designs, including repeated measures of both hormones and behavior and balanced or simultaneous designs for hormone-behavior sampling. In amphibians there is an opportunity to non-invasively and repeatedly sample excreted steroids in the water. We examined testosterone (T) in túngara frogs (Physalaemus (=Engystomops) pustulosus) using minimally invasive water-borne methods. First, we validated procedures for the collection, extraction and measurement of T in adult males and females using pharmacological challenges coupled with estimates of parallelism and recovery determination. Next, we extended the timeline of sampling over 9 days in order to evaluate the kinetics of excretion (baseline phase, challenge phase, recovery phase), including the estimation of individual differences during baseline sampling. We also estimated concentrations of creatinine (Cr) in each water sample and evaluated whether correcting for this proxy of urine concentration significantly decreased error variance in T estimates. Lastly, we incorporated a standardized and repeated measures assay of male sexual proceptivity (phonotaxis) during the predicted peak T and recovery T timepoints. We found strong evidence supporting the utility of these methods for precise, biologically informative estimates of T in both sexes. Males had higher T than females and responded to pharmacological challenges by elevating T substantially within 48 h of challenge (hCG, GnRH). Males exhibited repeatability in baseline T and phonotaxis frequencies were positively associated with higher T. Adjusting T levels for the simultaneous measure of Cr significantly improved model fit, which in conjunction with marked variation in urine concentration, suggests that urine likely serves as the major source of excreted T. In summary, this proof-of-concept and methods study demonstrates the utility and accuracy of measuring water-borne T and behavior in amphibians.

Hepatic lentiviral gene transfer prevents the long-term onset of hepatic tumours of glycogen storage disease type 1a in mice.

Glycogen storage disease type 1a (GSD1a) is a rare disease due to the deficiency in the glucose-6-phosphatase (G6Pase) catalytic subunit (encoded by G6pc), which is essential for endogenous glucose production. Despite strict diet control to maintain blood glucose, patients with GSD1a develop hepatomegaly, steatosis and then hepatocellular adenomas (HCA), which can undergo malignant transformation. Recently, gene therapy has attracted attention as a potential treatment for GSD1a. In order to maintain long-term transgene expression, we developed an HIV-based vector, which allowed us to specifically express the human G6PC cDNA in the liver. We analysed the efficiency of this lentiviral vector in the prevention of the development of the hepatic disease in an original GSD1a mouse model, which exhibits G6Pase deficiency exclusively in the liver (L-G6pc(-/-) mice). Recombinant lentivirus were injected in B6.G6pc(ex3lox/ex3lox). SA(creERT2/w) neonates and G6pc deletion was induced by tamoxifen treatment at weaning. Magnetic resonance imaging was then performed to follow up the development of hepatic tumours. Lentiviral gene therapy restored glucose-6 phosphatase activity sufficient to correct fasting hypoglycaemia during 9 months. Moreover, lentivirus-treated L-G6pc(-/-) mice presented normal hepatic triglyceride levels, whereas untreated mice developed steatosis. Glycogen stores were also decreased although liver weight remained high. Interestingly, lentivirus-treated L-G6pc(-/-) mice were protected against the development of hepatic tumours after 9 months of gene therapy while most of untreated L-G6pc(-/-) mice developed millimetric HCA. Thus the treatment of newborns by recombinant lentivirus appears as an attractive approach to protect the liver from the development of steatosis and hepatic tumours associated to GSD1a pathology.

In vivo MRS for the assessment of mouse colon using a dedicated endorectal coil: initial findings.

Inflammatory bowel disease is a common group of inflammation conditions that can affect the colon and the rectum. These pathologies require a careful follow-up of patients to prevent the development of colorectal cancer. Currently, conventional endoscopy is used to depict alterations of the intestinal walls, and biopsies are performed on suspicious lesions for further analysis (histology). MRS enables the in vivo analysis of biochemical content of tissues (i.e. without removing any samples). Combined with dedicated endorectal coils (ERCs), MRS provides new ways of characterizing alterations of tissues. An MRS in vivo protocol was specifically set up on healthy mice and on mice chemically treated to induce colitis. Acquisitions were performed on a 4.7 T system using a linear volume birdcage coil for the transmission of the B1 magnetic field, and a dedicated ERC was used for signal reception. Colon-wall complex, lumen and visceral fat were assessed on healthy and treated mice with voxel sizes ranging from 0.125 µL to 2 µL while keeping acquisition times below 3 min. The acquired spectra show various biochemical contents such as α- and ß-methylene but also glycerol backbone and diacyl. Choline was detected in tumoral regions. Visceral fat regions display a high lipid content with no water, whereas colon-wall complex exhibits both high lipid and high water contents. To the best of our knowledge, this is the first time that in vivo MRS using an ERC has been performed in the assessment of colon walls and surrounding structures. It provides keys for the in vivo characterization of small local suspicious lesions and offers complementary solutions to biopsies.

Endoluminal high-resolution MR imaging protocol for colon walls analysis in a mouse model of colitis.

OBJECTIVE: An endoluminal magnetic resonance (MR) imaging protocol including the design of an endoluminal coil (EC) was defined for high-spatial-resolution MR imaging of mice gastrointestinal walls at 4.7 T. MATERIALS AND METHODS: A receive-only radiofrequency single-loop coil was developed for mice colon wall imaging. Combined with a specific protocol, the prototype was first characterized in vitro on phantoms and on vegetables. Signal-to-noise ratio (SNR) profiles were compared with a quadrature volume birdcage coil (QVBC). Endoluminal MR imaging protocol combined with the EC was assessed in vivo on mice. RESULTS: The SNR measured close to the coil is significantly higher (10 times and up to 3 mm of the EC center) than the SNR measured with the QVBC. The gain in SNR can be used to reduce the in-plane pixel size up to 39 × 39 µm(2) (234 µm slice thickness) without time penalty. The different colon wall layers can only be distinguished on images acquired with the EC. CONCLUSION: Dedicated EC provides suitable images for the assessment of mice colon wall layers. This proof of concept provides gains in spatial resolution and leads to adequate protocols for the assessment of human colorectal cancer, and can now be used as a new imaging tool for a better understanding of the pathology.

Anaemia in Hospitalized Cancer Patients: A Retrospective Study of Two Cohorts before and after the Guideline Update.

INTRODUCTION: The incidence of anaemia and its consequences are often underestimated during cancer management. We propose to evaluate the situation before and after the recommendations were updated in order to assess their impact on the day-to-day practice. METHODS: In this single-centre retrospective study, eligible patients were treated for cancer and warranted overnight hospitalization over two periods (n = 206 in 2011, n = 143 in 2018). The diagnosis of anaemia was defined by a haemoglobin level below 12 and 13 g/dL for women and men, respectively. RESULTS: The prevalence of anaemia was 26% in 2011 and 16% in 2018 (p < 0.001). Biological assessment had changed between the two periods, with more tests of iron metabolism and measurements of inflammatory parameters. Patients hospitalized in 2018 had more advanced cancer and more severe anaemia (8.2 g/dL [±1.07] in 2011 vs. 7.9 g/dL [±1.18] in 2018). Rate of transfusion therapy did not change, but patients with mild and moderate anaemia were transfused less in 2018 (57% in 2011 vs. 44% in 2018). Intravenous iron and erythropoiesis-stimulating agent were used more frequently in 2018 (1 and 5 and 13 and 23% in 2011 and 2018, respectively), mainly for mild anaemia and life-threatening anaemia, respectively. Overall survival was poor in both cohorts at 24 months (15.4% in 2011 and 6.5% in 2018, p = 0.048). CONCLUSION: Practices have changed in the diagnosis of anaemia and prescriptions for erythropoiesis-stimulating agents and intravenous iron have increased. Efforts must continue to explore the causes of anaemia, optimize patients' quality of life, and reduce transfusions.

SARS-CoV-2 inflammation durably imprints memory CD4 T cells.

Memory CD4 T cells are critical to human immunity, yet it is unclear whether viral inflammation during memory formation has long-term consequences. Here, we compared transcriptional and epigenetic landscapes of Spike (S)-specific memory CD4 T cells in 24 individuals whose first exposure to S was via SARS-CoV-2 infection or mRNA vaccination. Nearly 2 years after memory formation, S-specific CD4 T cells established by infection remained enriched for transcripts related to cytotoxicity and for interferon-stimulated genes, likely because of a chromatin accessibility landscape altered by inflammation. Moreover, S-specific CD4 T cells primed by infection had reduced proliferative capacity in vitro relative to vaccine-primed cells. Furthermore, the transcriptional state of S-specific memory CD4 T cells was minimally altered by booster immunization and/or breakthrough infection. Thus, infection-associated inflammation durably imprints CD4 T cell memory, which affects the function of these cells and may have consequences for long-term immunity.

Inflammation durably imprints memory CD4+ T cells.

Adaptive immune responses are induced by vaccination and infection, yet little is known about how CD4+ T cell memory differs when primed in these two contexts. Notably, viral infection is generally associated with higher levels of systemic inflammation than is vaccination. To assess whether the inflammatory milieu at the time of CD4+ T cell priming has long-term effects on memory, we compared Spike-specific memory CD4+ T cells in 22 individuals around the time of the participants' third SARS-CoV-2 mRNA vaccination, with stratification by whether the participants' first exposure to Spike was via virus or mRNA vaccine. Multimodal single-cell profiling of Spike-specific CD4+ T cells revealed 755 differentially expressed genes that distinguished infection- and vaccine-primed memory CD4+ T cells. Spike-specific CD4+ T cells from infection-primed individuals had strong enrichment for cytotoxicity and interferon signaling genes, whereas Spike-specific CD4+ T cells from vaccine-primed individuals were enriched for proliferative pathways by gene set enrichment analysis. Moreover, Spike-specific memory CD4+ T cells established by infection had distinct epigenetic landscapes driven by enrichment of IRF-family transcription factors, relative to T cells established by mRNA vaccination. This transcriptional imprint was minimally altered following subsequent mRNA vaccination or breakthrough infection, reflecting the strong bias induced by the inflammatory environment during initial memory differentiation. Together, these data suggest that the inflammatory context during CD4+ T cell priming is durably imprinted in the memory state at transcriptional and epigenetic levels, which has implications for personalization of vaccination based on prior infection history.

mRNA COVID-19 vaccine elicits potent adaptive immune response without the persistent inflammation seen in SARS-CoV-2 infection.

SARS-CoV-2 infection and vaccination elicit potent immune responses. Our study presents a comprehensive multimodal single-cell dataset of peripheral blood of patients with acute COVID-19 and of healthy volunteers before and after receiving the SARS-CoV-2 mRNA vaccine and booster. We compared host immune responses to the virus and vaccine using transcriptional profiling, coupled with B/T cell receptor repertoire reconstruction. COVID-19 patients displayed an enhanced interferon signature and cytotoxic gene upregulation, absent in vaccine recipients. These findings were validated in an independent dataset. Analysis of B and T cell repertoires revealed that, while the majority of clonal lymphocytes in COVID-19 patients were effector cells, clonal expansion was more evident among circulating memory cells in vaccine recipients. Furthermore, while clonal αß T cell responses were observed in both COVID-19 patients and vaccine recipients, dramatic expansion of clonal γδT cells was found only in infected individuals. Our dataset enables comparative analyses of immune responses to infection versus vaccination, including clonal B and T cell responses. Integrating our data with publicly available datasets allowed us to validate our findings in larger cohorts. To our knowledge, this is the first dataset to include comprehensive profiling of longitudinal samples from healthy volunteers pre/post SARS-CoV-2 vaccine and booster.

mRNA COVID-19 vaccine elicits potent adaptive immune response without the acute inflammation of SARS-CoV-2 infection.

SARS-CoV-2 infection and vaccination elicit potent immune responses. Our study presents a comprehensive multimodal single-cell analysis of blood from COVID-19 patients and healthy volunteers receiving the SARS-CoV-2 vaccine and booster. We profiled immune responses via transcriptional analysis and lymphocyte repertoire reconstruction. COVID-19 patients displayed an enhanced interferon signature and cytotoxic gene upregulation, absent in vaccine recipients. B and T cell repertoire analysis revealed clonal expansion among effector cells in COVID-19 patients and memory cells in vaccine recipients. Furthermore, while clonal αß T cell responses were observed in both COVID-19 patients and vaccine recipients, expansion of clonal γδ T cells was found only in infected individuals. Our dataset enables side-by-side comparison of immune responses to infection versus vaccination, including clonal B and T cell responses. Our comparative analysis shows that vaccination induces a robust, durable clonal B and T cell responses, without the severe inflammation associated with infection.

Robust immune responses are observed after one dose of BNT162b2 mRNA vaccine dose in SARS-CoV-2-experienced individuals.

The use of coronavirus disease 2019 (COVID-19) vaccines will play the major role in helping to end the pandemic that has killed millions worldwide. COVID-19 vaccines have resulted in robust humoral responses and protective efficacy in human trials, but efficacy trials excluded individuals with a prior diagnosis of COVID-19. As a result, little is known about how immune responses induced by mRNA vaccines differ in individuals who recovered from COVID-19. Here, we evaluated longitudinal immune responses to two-dose BNT162b2 mRNA vaccination in 15 adults who had experienced COVID-19, compared to 21 adults who did not have prior COVID-19. Consistent with prior studies of mRNA vaccines, we observed robust cytotoxic CD8+ T cell responses in both cohorts after the second dose. Furthermore, SARS-CoV-2­naive individuals had progressive increases in humoral and antigen-specific antibody-secreting cell (ASC) responses after each dose of vaccine, whereas SARS-CoV-2­experienced individuals demonstrated strong humoral and antigen-specific ASC responses to the first dose but these responses were not further enhanced after the second dose of the vaccine at the time points studied. Together, these data highlight the relevance of immunological history for understanding vaccine immune responses and may have implications for personalizing mRNA vaccination regimens used to prevent COVID-19, including for the deployment of booster shots.

Vaccine-Acquired SARS-CoV-2 Immunity versus Infection-Acquired Immunity: A Comparison of Three COVID-19 Vaccines.

Around the world, rollout of COVID-19 vaccines has been used as a strategy to end COVID-19-related restrictions and the pandemic. Several COVID-19 vaccine platforms have successfully protected against severe SARS-CoV-2 infection and subsequent deaths. Here, we compared humoral and cellular immunity in response to either infection or vaccination. We examined SARS-CoV-2 spike-specific immune responses from Pfizer/BioNTech BNT162b2, Moderna mRNA-1273, Janssen Ad26.COV2.S, and SARS-CoV-2 infection approximately 4 months post-exposure or vaccination. We found that these three vaccines all generate relatively similar immune responses and elicit a stronger response than natural infection. However, antibody responses to recent viral variants are diminished across all groups. The similarity of immune responses from the three vaccines studied here is an important finding in maximizing global protection as vaccination campaigns continue.

Robust immune responses after one dose of BNT162b2 mRNA vaccine dose in SARS-CoV-2 experienced individuals.

The use of COVID-19 vaccines will play the major role in helping to end the pandemic that has killed millions worldwide. COVID-19 vaccines have resulted in robust humoral responses and protective efficacy in human trials, but efficacy trials excluded individuals with a prior diagnosis of COVID-19. As a result, little is known about how immune responses induced by mRNA vaccines differ in individuals who recovered from COVID-19. Here, we evaluated longitudinal immune responses to two-dose BNT162b2 mRNA vaccination in 15 adults who recovered from COVID-19, compared to 21 adults who did not have prior COVID-19 diagnosis. Consistent with prior studies of mRNA vaccines, we observed robust cytotoxic CD8+ T cell responses in both cohorts following the second dose. Furthermore, SARS-CoV-2-naive individuals had progressive increases in humoral and antigen-specific antibody-secreting cell (ASC) responses following each dose of vaccine, whereas SARS-CoV-2-experienced individuals demonstrated strong humoral and antigen-specific ASC responses to the first dose but muted responses to the second dose of the vaccine at the time points studied. Together, these data highlight the relevance of immunological history for understanding vaccine immune responses and may have significant implications for personalizing mRNA vaccination regimens used to prevent COVID-19, including booster shots.

Hyperpolarized 3He MR for sensitive imaging of ventilation function and treatment efficiency in young cystic fibrosis patients with normal lung function.

PURPOSE: To assess the sensitivity of hyperpolarized helium 3 ((3)He) magnetic resonance (MR) imaging for the detection of peripheral airway obstruction in younger cystic fibrosis (CF) patients showing normal spirometric results (mean forced expiratory volume in 1 second [FEV(1)], 112% +/- 14.5 [standard deviation]) and to observe the immediate effects of a single chest physical therapy (CPT) session, thereby comparing two image quantification techniques. MATERIALS AND METHODS: Ten pediatric CF patients (age range, 8-16 years) with normal spirometric results were included in this study after approval from the local research ethics committee. Spirometry followed by proton and hyperpolarized (3)He three-dimensional lung imaging were performed with a 1.5-T MR unit before and after 20 minutes of CPT. The number of ventilation defects per image (VDI) and the ventilated lung fraction (VF), defined as the ratio of ventilated lung volume divided by total lung volume, were quantified. RESULTS: Ventilation defects were found in all patients (mean VDI, 5.1 +/- 1.9; mean global VF, 78.5% +/- 12.3; and mean peripheral VF, 75.5% +/- 17.1) despite normal spirometric results. After CPT, disparate changes in the distribution of ventilation defects were observed but the average VDI and VF did not change significantly (mean VDI, 5.1 +/- 1.1; mean global VF, 83.5% +/- 12.2; and mean peripheral VF, 80.3% +/- 12.2). There was no correlation between FEV(1) and VDI (rho = -0.041, P = .863) or global VF (rho = -0.196, P = .408) values but peripheral VF and VDI were correlated (rho = -0.563, P = .011). CONCLUSION: Although spirometric results indicate normal lung function, the mean VDI in patients (5.1) found in this study is well above the VDI in healthy subjects (1.6) reported in the literature. A single CPT session induces disparate changes in the distribution and extent of ventilation defects.

Cardiovascular safety of gadoterate meglumine (Gd-DOTA).

OBJECTIVES: Gadolinium complexes are not considered to be a drug class at high risk for prolonging cardiac repolarization, which can lead to potentially life-threatening arrhythmias such as torsade de pointes. However, only limited robust data are available on these compounds despite their extensive use as contrast enhancers in magnetic resonance imaging. We present an overview of recent cardiovascular safety data obtained on gadoterate meglumine (Gd-DOTA). MATERIALS AND METHODS: Cardiovascular safety was evaluated by "state-of-the-art" nonclinical ex vitro (dog Purkinje fibers) and in vivo studies in both normal (dogs) and sensitized animal models (rabbits) and in patients with various diseases in a specific clinical trial. RESULTS: In all of these studies, Gd-DOTA did not show any direct deleterious effect on cardiac electrophysiology and especially on ventricular repolarization. CONCLUSION: These results confirmed the good safety profile of Gd-DOTA derived from postmarketing evaluations. Nonspecific gadolinium complexes used for magnetic resonance contrast enhancement do not constitute a class-at-risk for drug-related arrhythmias.

Highly constrained backprojection for improving dynamic 3He MR ventilation imaging in rats.

The highly constrained backprojection algorithm (HYPR) has recently been shown to allow accelerated acquisition in various fields of MRI, including angiography, perfusion and diffusion imaging as well as hyperpolarized gas imaging. Increase in temporal resolution is of particular interest in the case of small animal ventilation imaging due to the high respiration rate. In the present study, the two-dimensional HYPR technique and its iterative version (I-HYPR) were applied to (3)He ventilation imaging in rats. Two imaging protocols were used for two separate groups of animals. A single inspiration protocol consisted of (3)He imaging of the lungs during gas inflow and a following apnea. A multiple inspiration protocol involved spontaneous breathing of (3)He contained in a gas reservoir. Series of HYPR frames with four-fold increase in the temporal resolution were obtained in the case of the single inspiration experiment. For the multiple inspiration protocol, series of HYPR images corresponding to four different echo times were obtained and were used to reconstruct T(2)(*) maps at the inspiration and the expiration phases of the breathing cycle. The feasibility of using the two-dimensional HYPR technique for different (3)He ventilation protocols in small animals is demonstrated. Image quality and signal kinetics representations are compared for two variants of the HYPR algorithm.

Safety and tolerability of ultrasmall superparamagnetic iron oxide contrast agent: comprehensive analysis of a clinical development program.

BACKGROUND: Because of its cellular uptake pattern, ferumoxtran-10 may be potentially useful for the imaging of a variety of diseases (eg, atheroma, multiple sclerosis, stroke, renal graft rejection, glomerulonephritis and brain tumors, in addition to differentiation of metastatic and nonmetastatic lymph nodes). The aim of this article is to present a comprehensive review of the safety and tolerability of ferumoxtran-10 as reported during clinical development of the compound as an ultrasmall superparamagnetic iron oxide contrast agent for use in magnetic resonance imaging. MATERIALS AND METHODS: The safety profile of ferumoxtran-10 was assessed using pooled data from 37 phase I to III clinical studies in 1777 adults (1663 received the contrast agent [1527 patients and 136 healthy volunteers], 75 received placebo, and 39 patients were enrolled but did not receive study medication). RESULTS: At least one adverse event was reported in 23.2% of patients who received ferumoxtran-10. Adverse events were of mild-to-moderate severity in 86.3% of patients in the ferumoxtran-10 group. At least 1 event considered by the investigator to be related to study treatment was reported in 18.2% of patients in the ferumoxtran-10 group. The most commonly reported treatment-related adverse events were back pain, pruritus, headache, and urticaria. A total of 44 patients (2.6%) in the ferumoxtran-10 group reported 76 serious adverse event (SAE). Only 7 SAEs (0.42%) were considered to be treatment-related (anaphylactic shock, chest pain, dyspnea, skin rash, oxygen saturation decreased, and 2 cases of hypotension). There were 12 deaths, only one of which (anaphylactic shock) was considered to be related to ferumoxtran-10 which was administered by bolus injection of undiluted product, a mode of administration that is no longer recommended. Results in high-risk groups of patients including the elderly and those with hepatic, renal or cardiovascular disease seemed to show no cause for special clinical concern in these groups. CONCLUSIONS: Clinical experience to date therefore shows ferumoxtran-10 to be a well tolerated contrast agent.

In vivo imaging of carbon nanotube biodistribution using magnetic resonance imaging.

As novel engineered nanoparticles such as carbon nanotubes (CNTs) are extensively used in nanotechnology due to their superior properties, it becomes critical to fully understand their biodistribution and effect when accidently inhaled. A noninvasive follow-up study would be beneficial to evaluate the biodistribution and effect of nanotube deposition after exposure directly in vivo. Combined helium-3 and proton magnetic resonance resonance (MRI) were used in a rat model to evaluate the biodistribution and biological impact of raw single-wall CNTs (raw-SWCNTs) and superpurified SWCNTs (SP-SWCNTs). The susceptibility effects induced by metal impurity in the intrapulmonary instilled raw-SWCNT samples were large enough to induce a significant drop in magnetic field homogeneity detected in 3He MR image acquired under spontaneous breathing conditions using a multiecho radial sequence. No MRI susceptibility variation was observed with SP-SWCNT exposition even though histological analysis confirmed their presence in instilled lungs. Proton MRI allowed detection of intravenously injected raw-SWCNTs in spleen and kidneys using gradient echo sequence sensitive to changes of relaxation time values. No signal modifications were observed in the SP-SWCNT injected group. In instilled groups, the contrast-to-noise ratio in liver, spleen, and kidneys stayed unchanged and were comparable to values obtained in the control group. Histological analysis confirms the absence of SWCNTs in systemic organs when SWCNTs were intrapulmonary instilled. In conclusion, the presence of SWCNTs with associated metal impurities can be detected in vivo by noninvasive MR techniques. Hyperpolarized 3He can be used for the investigation of CNT pulmonary biodistribution while standard proton MR can be performed for systemic investigation following injection of CNT solution.

Free breathing hyperpolarized 3He lung ventilation spiral MR imaging.

OBJECTIVES: Current clinical hyperpolarized He lung ventilation MR imaging protocols rely on the patient's ability to control inhalation and exhalation and hold their breath on demand. This is impractical for intensive care unit patients under ventilation or for pediatric populations under the age of 3 to 4 years. To address this problem, we propose a free-breathing protocol for hyperpolarized He lung ventilation spiral imaging. This approach was evaluated in vitro and on rabbits. MATERIALS AND METHODS: The protocol was implemented on a clinical 1.5-T magnetic resonance imaging scanner. Ventilation images were acquired using a spiral sequence, in vitro on a lung phantom and in vivo on rabbits, the animal breathing freely from a gas reservoir. Dynamic spiral ventilation images were reconstructed using retrospective Cine synchronization. Magnetic resonance (MR) signal dynamics was modeled taking account of gas inflow and outflow, radiofrequency depolarization and oxygen-induced relaxation. RESULTS: Cine ventilation images acquired in spontaneously breathing rabbits were reconstructed with a temporal resolution of 50 milliseconds. Gas volume variations and time-to-maximum maps were obtained. The numerical model was validated in vitro and in vivo with various gas mixtures. Ventilation parameters (functional residual capacity, tidal volume, and alveolar pO2) were extracted from the MR signal dynamics. CONCLUSIONS: Ventilation imaging can be performed at tidal volume using a simple experimental protocol, without any ventilation device or breath-hold period. Acquisition time, SNR and pO2 decay can be optimized using the developed numerical model. Free-breathing ventilation images can be obtained without artifacts related to motion or gas flow. Lastly, parametric maps can be derived from the time-resolved ventilation images and physiological parameters extracted from the global signal dynamics.

Longitudinal 3He and proton imaging of magnetite biodistribution in a rat model of instilled nanoparticles.

Epidemiological and toxicological studies have provided evidence that accidentally inhaled nanosize ultrafine particles can induce chronic or acute health damage. MRI, being noninvasive, is able to assess the biodistribution and clearance of magnetically labeled nanoparticles induced by instillation or inhalation. We report 3He and proton MRI follow-up of lung, liver, spleen, and kidney distribution of USPIO (ultrasmall superparamagnetic iron oxide) in a rat model. The sensitivity of the imaging technique to various concentrations of instilled magnetite suspension was first assessed in vivo (n=12). A 2-week longitudinal imaging study was then performed on animals (n=7) instilled with a 0.5 mg magnetite solution. Hypointense and void signal regions associated with intrapulmonary USPIO were observed in the 3He ventilation images throughout the study, whereas no USPIO-related proton signal intensity changes were found. Intrapulmonary magnetite nanoparticle confinement was confirmed by ex vivo iron assay and histological analysis. This study demonstrates that combined 3He and proton MRI enables noninvasive assessment of the distribution and clearance of magnetically labeled instilled nanoparticles.