Paediatric cardiac CT examinations: impact of the iterative reconstruction method ASIR on image quality--preliminary findings.

BACKGROUND: Radiation dose exposure is of particular concern in children due to the possible harmful effects of ionizing radiation. The adaptive statistical iterative reconstruction (ASIR) method is a promising new technique that reduces image noise and produces better overall image quality compared with routine-dose contrast-enhanced methods. OBJECTIVE: To assess the benefits of ASIR on the diagnostic image quality in paediatric cardiac CT examinations. MATERIALS AND METHODS: Four paediatric radiologists based at two major hospitals evaluated ten low-dose paediatric cardiac examinations (80 kVp, CTDI(vol) 4.8-7.9 mGy, DLP 37.1-178.9 mGy·cm). The average age of the cohort studied was 2.6 years (range 1 day to 7 years). Acquisitions were performed on a 64-MDCT scanner. All images were reconstructed at various ASIR percentages (0-100%). For each examination, radiologists scored 19 anatomical structures using the relative visual grading analysis method. To estimate the potential for dose reduction, acquisitions were also performed on a Catphan phantom and a paediatric phantom. RESULTS: The best image quality for all clinical images was obtained with 20% and 40% ASIR (p < 0.001) whereas with ASIR above 50%, image quality significantly decreased (p < 0.001). With 100% ASIR, a strong noise-free appearance of the structures reduced image conspicuity. A potential for dose reduction of about 36% is predicted for a 2- to 3-year-old child when using 40% ASIR rather than the standard filtered back-projection method. CONCLUSION: Reconstruction including 20% to 40% ASIR slightly improved the conspicuity of various paediatric cardiac structures in newborns and children with respect to conventional reconstruction (filtered back-projection) alone.

European French-speaking study from the GEMO group on bone metastases management: a special focus on external beam radiotherapy practice survey.

This study seeks to perform a survey of patterns of practice among the different physicians involved in the bone metastases management, with special focus on external beam radiotherapy (EBRT).A questionnaire about bone metastases based on clinical cases and supplemented with general questions, including medical therapies, EBRT and metabolic radiotherapy strategies, surgery, and supportive care approaches, was sent to 4,706 French-speaking physicians in Belgium, France, Luxemburg, and Switzerland.Overall, 644 questionnaires were analyzed. Twenty-eight percent concerned the radiotherapy approach and were judged adequate to respond to the part dedicated to EBRT. Sixty-nine percent of physicians used a total dose irradiation of 30 Gy delivered in ten fractions. A large majority (75%) used two opposed fields prescribed at mid-depth (30%), or with non-equally weighted fields (45%). Seventy percent irradiated also above and below the concerned vertebra. A dosimetry planning treatment was done in 85% and high-energy megavoltage photons were used in 42%. Moreover, 54% physicians used short course radiotherapy in routine.Radiotherapy remains the mainstay of treatment of bone metastases, but there is substantial heterogeneity in clinical practice. Guidelines and treatment protocols are required to improve the treatment quality.

Focal dependent pleural thickening at MDCT: pleural lesion or functional abnormality?

PURPOSE: To describe the characteristics of reversible focal pleural thickenings (PTs) mimicking real plaques, that firstly suggest asbestos exposure or pleural metastasis; to propose an imaging strategy and propose an explanation for their mechanism of formation. PATIENTS AND METHODS: Retrospective review of data from 19 patients with PTs fitting the description of pleural plaques at chest computed tomography (CT) and presenting modifications (clearance or appearance) of at least one PT at an additional chest examination in prone position. RESULTS: A total of 152 PTs were recorded on the first chest CT examinations with a range of two to 19 pleural opacities per patient. All PTs had a posterior distribution in the lower lobes. On the additional acquisitions, 144 PTs disappeared. Seventeen patients presented complete regression of PTs and two patients presented persistence of eight PTs. CONCLUSION: Additional low dose acquisition in prone position should be performed in all patients presenting with focal PT in a dependent and basal location. This may allow to exclude a pleural plaque in case of asbestos exposure but also a pleural metastasis in oncologic patients. These reversible dependent PTs could be related to physiological focal accumulation of lymphatic fluid in subpleural area.

Domestic radon exposure and risk of childhood cancer: a prospective census-based cohort study

BACKGROUND: In contrast with established evidence linking high doses of ionizing radiation with childhood cancer, research on low-dose ionizing radiation and childhood cancer has produced inconsistent results. OBJECTIVE: We investigated the association between domestic radon exposure and childhood cancers, particularly leukemia and central nervous system (CNS) tumors. METHODS: We conducted a nationwide census-based cohort study including all children < 16 years of age living in Switzerland on 5 December 2000, the date of the 2000 census. Follow-up lasted until the date of diagnosis, death, emigration, a child's 16th birthday, or 31 December 2008. Domestic radon levels were estimated for each individual home address using a model developed and validated based on approximately 45,000 measurements taken throughout Switzerland. Data were analyzed with Cox proportional hazard models adjusted for child age, child sex, birth order, parents' socioeconomic status, environmental gamma radiation, and period effects. RESULTS: In total, 997 childhood cancer cases were included in the study. Compared with children exposed to a radon concentration below the median (< 77.7 Bq/m3), adjusted hazard ratios for children with exposure ≥ the 90th percentile (≥ 139.9 Bq/m3) were 0.93 (95% CI: 0.74, 1.16) for all cancers, 0.95 (95% CI: 0.63, 1.43) for all leukemias, 0.90 (95% CI: 0.56, 1.43) for acute lymphoblastic leukemia, and 1.05 (95% CI: 0.68, 1.61) for CNS tumors. CONCLUSIONS: We did not find evidence that domestic radon exposure is associated with childhood cancer, despite relatively high radon levels in Switzerland.

Treatment of mediastinal fibrosis with mycophenolate mofetil.

We present the case of a 67-year-old male patient with mediastinal and retroperitoneal fibrosis. In Europe, this is a rare disease. Treatment was established to prevent complications due to strictures or compressions. Because of his diabetes, a therapy of low-dose prednisone combined with mycophenolate mofetil, known as steroid sparing agent, was applied. As a result, the radiological follow-up showed a marked decrease in the mediastinal and retroperitoneal masses.

How to Preserve Renal Function in Transcatheter Aortic Valve Therapies

Background: Transcatheter aortic valve implantations (TAVI) are indicated in high risk patients requiring aortic valve replacement (AVR). However, CT-scans, coronary angiograms and intraoperative aortographies can induce contrast-related nephro-toxicity with a concrete risk of acute postoperative renal failure, especially in severely diseased patients. To prevent this complication, we routinely perform transapical (TA) TAVI guided by transesophageal echocardiogram and fluoroscopy without angiography. Material and Methods: From November 2008 to December 2009, 31 high-risk patients suffering from severe symptomatic aortic stenosis underwent TA-TAVI in our institution. The preoperative imaging assessment (cardiac CT-scan and coronary angiogram) was performed no less than 10 days before the TA-TAVI in all patients (to recover the renal function) with a low-dose protocol for injected contrast medium (equivalent to the patient's weight for the CT-scan). During the TA-TAVI, the stent-valve positioning was performed without any contrast injection. Results: 32 consecutive stent-valve were successfully positioned in 31 patients (mean age 80.76 8 8.3 years; mean EuroSCORE: 32.2 8 12.9%) through a transapical access (1 patient required 2 valves for valve embolisation). The mean preoperative creatinine and urea blood levels were 102.6 8 67.7 _ g/dl (range 53-339 _ g/dl) and 8.45 8 4.9 mmol/l, respectively. A chronic renal insufficiency affected 12 patients (38.7%) with 1 patient in pre-dialysis. Postoperatively, no patient developed acute myocardial infarction, atrio-ventricular block or acute renal insufficiency (mean creatinine level: 89.7 8 64.55 _ g/dl; urea level: 7.11 8 3.47 mmol/l) and the 30-days mortality was 9.67% (3 patients). Conclusion: Specific preoperative and intraoperative protocols that require lowdoses or absence of contrast medium are useful to preserve the renal function in high risk patients operated for TAVI.

Variations of CYP3A activity induced by antiretroviral treatment in HIV-1 infected patients.

OBJECTIVE: To measure the in vivo variations of CYP3A activity induced by anti-HIV drugs in human immunodeficiency virus (HIV)1-positive patients. METHODS: A low oral dose of midazolam (MID) (0.075 mg) was given to the patients and the 30-min total 1-OH midazolam (1-OHMID)/MID ratio was determined. Patients were phenotyped either before the introduction of antiretroviral treatments (control group, 90 patients) or after a variable period of antiretroviral treatment (56 patients). Twenty-one subjects underwent multiple phenotyping tests (before and during the course of the treatment). RESULTS: The median MID ratio was 3.51 in the control group (range 0.20-14.6). It was 5-fold higher in the group with efavirenz (28 patients; median, range: 16.0, 3.81-367; P < 0.0001), 13-fold lower with nelfinavir (18 patients; 0.27, 0.06-36.3; P < 0.0001), 17-fold lower with efavirenz + ritonavir (three patients; 0.21, 0.05-0.47; P = 0.006), 50-fold lower with ritonavir (four patients; 0.07, 0.06-0.17; P = 0.0007), and 7-fold lower with nevirapine + (ritonavir or nelfinavir or grapefruit juice) (three patients; 0.48, 0.03-1.83; P = 0.03). CYP3A activity was lower in the efavirenz + ritonavir group (P = 0.01) and in the ritonavir group (P = 0.04) than in the nelfinavir group, although already strongly inhibited in the latter. CONCLUSION: The low-dose MID phenotyping test was successfully used to measure the in vivo variations of CYP3A activity induced by antiretroviral drugs. Efavirenz strongly induces CYP3A activity, while ritonavir almost completely inhibits it. Nelfinavir strongly decreases CYP3A activity, but to a lesser extent than ritonavir. The inhibition of CYP3A by ritonavir or nelfinavir offsets the inductive effects of efavirenz or nevirapine administered concomitantly. Finally, no induction of CYP3A activity was noticeable after long-term administration of ritonavir at low dosages (200 mg/day b.i.d.) or of nelfinavir at standard dosages (2,500 mg/day b.i.d.).

Long-term treatment of eosinophilic esophagitis esophagitis with budesonide

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic-inflammatory disease of the esophagus, characterized by esophagus-related symptoms and a dense tissue eosinophilia, both refractory to proton pump inhibitors. Topical corticosteroids have proven effective in inducing clinical and histologic remission. However, a long-term strategy for the management of this chronic disease is not yet defined. METHODS: In a randomized, double-blind, placebocontrolled, long-term trial, we evaluated the efficacy of twice-daily 0.25 mg swallowed budesonide in maintaining a remission in adult EoE with prior response to induction therapy. Pre- and post-treatment disease activity was assessed clinically, endoscopically, histologically, by immunofluorescence and by high-resolution endosonography. The primary end point was the ability to maintain histologic remission (<5 eos/hpf) of EoE in. Secondary end points were the efficacy on symptom control and on tissue remodeling as well as the determination of the safety of long-term esophageal administration of topical corticosteroids. RESULTS: During a 50-week therapy of quiescent EoE with low-dose budesonide the esophageal eosinophil load (ECP staining) increased from 1.1 to 29.9 eos/hpf, but under placebo the increase was significantly larger (0.5 to 51.1 eos/hpf; p=0.01). At the end of the studyperiod, 35.7% (5/14) of the budesonide patients were in complete and 14.3% (2/14) in partial histologic remission; with placebo no patient was in complete and 28.6% (4/14) were in partial remission (p=0.0647). The increase of the symptom score was markedly lower in budesonide- (0.79 to 2.29 points) than in placebo-patients (0.71 to 4.00 points; p=0.0875). The median time to relapse of symptoms was >125 days in the budesonide and 95 days in the placebo group (p = 0.14). Measured by high-resolution endosonography, all EoE patients had pre-treatment a highly thickened esophageal wall compared with healthy controls (3.05±1.08 mm vs. 2.18±0.35 mm; p<0.0001). Long-term topical budesonide reduced mainly the thickness of the superficial wall layers (mucosa, 0.75 mm to 0.45 mm; p=0.025) whereas the response of the deeper layers was less pronounced (submucosa 1.31 to 1.08 mm; p=0.19 and muscularis 0.82 to 0.76 mm; p=0.72). Budesonide did not evoke any mucosal atrophy. CONCLUSIONS: This study clearly demonstrates that 1) Untreated eosinophil inflammation results in an impressive remodeling of the esophagus; 2) A therapy is therefore needed; 3) The high relapse rate after short-term therapy requires a long-term management and 4) Maintenance treatment with budesonide is well tolerated and keeps half of the patients in remission.

Antiretroviral drug toxicity in relation to pharmacokinetics, metabolic profile and pharmacogenetics.

Introduction: Besides therapeutic effectiveness, drug tolerability is a key issue for treatments that must be taken indefinitely. Given the high prevalence of toxicity in HIV therapy, the factors implicated in drug-induced morbidities should be identified in order to improve the safety, tolerability and adherence to the treatments. Current approaches have focused almost exclusively on parent drug concentrations; whereas recent evidence suggests that drug metabolites resulting from complex genetic and environmental influences can also contribute to treatment outcome. Pharmacogenetic variations have shown to play a relevant role in the variability observed in antiretroviral drug exposure, clinical response and sometimes toxicity. The integration of pharmacokinetic, pharmacogenetic and metabolic determinants will more probably address current therapeutic needs in patients. Areas covered: This review offers a concise description of three classes of antiretroviral drugs. The review looks at the metabolic profile of these drugs and gives a comprehensive summary of the existing literature on the influence of pharmacogenetics on their pharmacokinetics and metabolic pathways, and the associated drug or metabolite toxicity. Expert opinion: Due to the high prevalence of toxicity and the related risk of low adherence to the treatments, association of kinetic, genetic and metabolic markers predictive of therapeutic or toxicity outcomes could represent a more complete approach for optimizing antiretroviral therapy.

Sedation and analgesia for colonoscopy: patient tolerance, pain, and cardiorespiratory parameters.

BACKGROUND: Colonoscopy is generally performed with the patient sedated and receiving analgesics. However, the benefit of the most often used combination of intravenous midazolam and pethidine on patient tolerance and pain and its cardiorespiratory risk have not been fully defined. METHODS: In this double-blind prospective study, 150 outpatients undergoing routine colonoscopy were randomly assigned to receive either (1) low-dose midazolam (35 micrograms/kg) and pethidine (700 micrograms/kg in 48 patients, 500 micrograms/kg in 102 patients), (2) midazolam and placebo pethidine, or (3) pethidine and placebo midazolam. RESULTS: Tolerance (visual analog scale, 0 to 100 points: 0 = excellent; 100 = unbearable) did not improve significantly more in group 1 compared with group 2 (7 points; 95% confidence interval [-2-17]) and group 3 (2 points; 95% confidence interval [-7-12]). Similarly, pain was not significantly improved in group 1 as compared with the other groups. Male gender (p < 0.001) and shorter duration of the procedure (p = 0.004), but not amnesia, were associated with better patient tolerance and less pain. Patient satisfaction was similar in all groups. Oxygen desaturation and hypotension occurred in 33% and 11%, respectively, with a similar frequency in all three groups. CONCLUSIONS: In this study, the combination of low-dose midazolam and pethidine does not improve patient tolerance and lessen pain during colonoscopy as compared with either drug given alone. When applying low-dose midazolam, oxygen desaturation and hypotension do not occur more often after combined use of both drugs. For the individual patient, sedation and analgesia should be based on the endoscopist's clinical judgement.

Markedly reduced blood pressure responsiveness in endotoxemic rats; reversal by neuropeptide Y.

This study in conscious normotensive rats was performed to assess the effect of the vasoconstrictor peptide, neuropeptide Y (NPY), on blood pressure responsiveness to exogenous norepinephrine in endotoxaemia. NPY and endotoxin were infused at doses which had no effect on blood pressure, whether given alone or in combination. Endotoxin markedly reduced the pressor responses to bolus injections of norepinephrine. However, blood pressure responsiveness could be enhanced by infusing NPY simultaneously with the endotoxin. It is suggested that low dose NPY infusions may be clinically useful in reversing the reduced vascular responsiveness to pressor amines in shock.

Intoxications létales à l'amisulpride en Suisse romande depuis 2005 : concentrations sanguines thérapeutiques, toxiques et létales. [Lethal amisulpride intoxications in Western Switzerland since 2005: Therapeutical, toxic and lethal concentrations]

Parmi les neuroleptiques disponibles, l'amisulpride est de plus en plus prescrit. De par son affinité sélective dose-dépendante aux récepteurs dopaminergiques, il est possible de moduler les effets de cette substance montrant des propriétés antidépressives à faible dose et agissant comme un puissant antipsychotique à forte dose. Toutefois, l'amisulpride induit une prolongation dose-dépendante de l'intervalle QT ce qui peut potentialiser la survenue d'arythmies ventriculaires, souvent fatales lorsque sa consommation est concomitante à celles d'autres médicaments ou stupéfiants allongeant l'intervalle QT. Cependant, la littérature scientifique demeure peu documentée en ce qui concerne la détermination de concentrations sanguines thérapeutiques, toxiques et létales. Après avoir présenté les propriétés pharmacodynamiques et pharmacocinétiques de l'amisulpride, nous nous proposons de définir plus précisément les seuils sanguins de concentrations thérapeutiques, toxiques et létales pour cette molécule illustrée par la revue des cas mortels impliquant l'amisulpride en Suisse romande depuis 2005. Among the available neuroleptic drugs, amisulpride is increasingly prescribed. Thanks to its dose-dependent selective affinity for dopamine receptors, it is possible to modulate the effects of this substance showing antidepressant properties at low dose and acting as a powerful antipsychotic at high dose. However, amisulpride induces a dose-dependent prolongation of the QT interval which may potentiate the occurrence of ventricular arrhythmias, often fatal when its consumption is concomitant with those of other drugs that prolong the QT interval. However, the scientific literature remains poorly documented with regard to the determination of therapeutic, toxic and lethal blood concentrations. After presenting the pharmacodynamic and pharmacokinetic properties of amisulpride, we propose to define more precisely the blood levels of therapeutic, toxic and lethal concentrations for this molecule illustrated by a review of the fatal cases involving amisulpride in Western Switzerland since 2005.

Increase of [(18)F]FLT Tumor Uptake In Vivo Mediated by FdUrd: Toward Improving Cell Proliferation Positron Emission Tomography.

PURPOSE: 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT), a cell proliferation positron emission tomography (PET) tracer, has been shown in numerous tumors to be more specific than 2-deoxy-2-[(18)F]fluoro-D: -glucose ([(18)F]FDG) but less sensitive. We studied the capacity of a nontoxic concentration of 5-fluoro-2'-deoxyuridine (FdUrd), a thymidine synthesis inhibitor, to increase uptake of [(18)F]FLT in tumor xenografts. METHODS: The duration of the FdUrd effect in vivo on tumor cell cycling and thymidine analogue uptake was studied by varying FdUrd pretreatment timing and holding constant the timing of subsequent flow cytometry and 5-[(125)I]iodo-2'-deoxyuridine biodistribution measurements. In [(18)F]FLT studies, FdUrd pretreatment was generally performed 1 h before radiotracer injection. [(18)F]FLT biodistributions were measured 1 to 3 h after radiotracer injection of mice grafted with five different human tumors and pretreated or not with FdUrd and compared with [(18)F]FDG tumor uptake. Using microPET, the dynamic distribution of [(18)F]FLT was followed for 1.5 h in FdUrd pretreated mice. High-field T2-weighted magnetic resonance imaging (MRI) and histology were used comparatively in assessing tumor viability and proliferation. RESULTS: FdUrd induced an immediate increase in tumor uptake of 5-[(125)I]iodo-2'-deoxyuridine, that vanished after 6 h, as also confirmed by flow cytometry. Biodistribution measurements showed that FdUrd pretreatment increased [(18)F]FLT uptake in all tumors by factors of 3.2 to 7.8 compared with controls, while [(18)F]FDG tumor uptake was about fourfold and sixfold lower in breast cancers and lymphoma. Dynamic PET in FdUrd pretreated mice showed that [(18)F]FLT uptake in all tumors increased steadily up to 1.5 h. MRI showed a well-vascularized homogenous lymphoma with high [(18)F]FLT uptake, while in breast cancer, a central necrosis shown by MRI was inactive in PET, consistent with the histomorphological analysis. CONCLUSION: We showed a reliable and significant uptake increase of [(18)F]FLT in different tumor xenografts after low-dose FdUrd pretreatment. These results show promise for a clinical application of FdUrd aimed at increasing the sensitivity of [(18)F]FLT PET.

Activation of c-Jun in the nuclei of neurons of the CA-1 in thrombin preconditioning occurs via PAR-1.

Recently it has been shown that the c-Jun N-terminal kinase (JNK) plays a role in thrombin preconditioning (TPC) in vivo and in vitro. To investigate further the pathways involved in TPC, we performed an immunohistochemical study in hippocampal slice cultures. Here we show that the major target of JNK, the AP-1 transcription factor c-Jun, is activated by phosphorylation in the nuclei of neurons of the CA1 region by using phospho-specific antibodies against the two JNK phosphorylation sites. The activation is early and transient, peaking at 90 min and not present by 3 hr after low-dose thrombin administration. Treatment of cultures with a synthetic thrombin receptor agonist results in the same c-Jun activation profile and protection against subsequent OGD, both of which are prevented by specific JNK inhibitors, showing that thrombin signals through PAR-1 to JNK. By using an antibody against the Ser 73 phosphorylation site of c-Jun, we identify possible additional TPC substrates.

Expression of the NH(2)-terminal fragment of RasGAP in pancreatic beta-cells increases their resistance to stresses and protects mice from diabetes.

OBJECTIVE: Our laboratory has previously established in vitro that a caspase-generated RasGAP NH(2)-terminal moiety, called fragment N, potently protects cells, including insulinomas, from apoptotic stress. We aimed to determine whether fragment N can increase the resistance of pancreatic beta-cells in a physiological setting. RESEARCH DESIGN AND METHODS: A mouse line, called rat insulin promoter (RIP)-N, was generated that bears a transgene containing the rat insulin promoter followed by the cDNA-encoding fragment N. The histology, functionality, and resistance to stress of RIP-N islets were then assessed. RESULTS: Pancreatic beta-cells of RIP-N mice express fragment N, activate Akt, and block nuclear factor kappaB activity without affecting islet cell proliferation or the morphology and cellular composition of islets. Intraperitoneal glucose tolerance tests revealed that RIP-N mice control their glycemia similarly as wild-type mice throughout their lifespan. Moreover, islets isolated from RIP-N mice showed normal glucose-induced insulin secretory capacities. They, however, displayed increased resistance to apoptosis induced by a series of stresses including inflammatory cytokines, fatty acids, and hyperglycemia. RIP-N mice were also protected from multiple low-dose streptozotocin-induced diabetes, and this was associated with reduced in vivo beta-cell apoptosis. CONCLUSIONS: Fragment N efficiently increases the overall resistance of beta-cells to noxious stimuli without interfering with the physiological functions of the cells. Fragment N and the pathway it regulates represent, therefore, a potential target for the development of antidiabetes tools.