Management of patient dose and image noise in routine pediatric CT abdominal examinations.

The aim was to propose a strategy for finding reasonable compromises between image noise and dose as a function of patient weight. Weighted CT dose index (CTDI(w)) was measured on a multidetector-row CT unit using CTDI test objects of 16, 24 and 32 cm in diameter at 80, 100, 120 and 140 kV. These test objects were then scanned in helical mode using a wide range of tube currents and voltages with a reconstructed slice thickness of 5 mm. For each set of acquisition parameter image noise was measured and the Rose model observer was used to test two strategies for proposing a reasonable compromise between dose and low-contrast detection performance: (1) the use of a unique noise level for all test object diameters, and (2) the use of a unique dose efficacy level defined as the noise reduction per unit dose. Published data were used to define four weight classes and an acquisition protocol was proposed for each class. The protocols have been applied in clinical routine for more than one year. CTDI(vol) values of 6.7, 9.4, 15.9 and 24.5 mGy were proposed for the following weight classes: 2.5-5, 5-15, 15-30 and 30-50 kg with image noise levels in the range of 10-15 HU. The proposed method allows patient dose and image noise to be controlled in such a way that dose reduction does not impair the detection of low-contrast lesions. The proposed values correspond to high- quality images and can be reduced if only high-contrast organs are assessed.

A quantitative analysis of antagonism and inverse agonism at wild-type and constitutively active hamster alpha1B-adrenoceptors.

In order to characterize inverse agonism at alpha1B-adrenoceptors, we have compared the concentration-response relationships of several quinazoline and non-quinazoline alpha1-adrenoceptor antagonists at cloned hamster wild-type (WT) alpha1B-adrenoceptors and a constitutively active mutant (CAM) thereof upon stable expression in Rat-1 fibroblasts. Receptor activation or inhibition thereof was assessed as [3H]inositol phosphate (IP) accumulation. Quinazoline (alfuzosin, doxazosin, prazosin, terazosin) and non-quinazoline alpha1-adrenoceptor antagonists (BE 2254, SB 216,469, tamsulosin) concentration-dependently inhibited phenylephrine-stimulated IP formation at both WT and CAM with Ki values similar to those previously found in radioligand binding studies. At CAM in the absence of phenylephrine, the quinazolines produced concentration-dependent inhibition of basal IP formation; the maximum inhibition was approximately 55%, and the corresponding EC50 values were slightly smaller than the Ki values. In contrast, BE 2254 produced much less inhibition of basal IP formation, SB 216,469 was close to being a neutral antagonist, and tamsulosin even weakly stimulated IP formation. The inhibitory effects of the quinazolines and BE 2254 as well as the stimulatory effect of tamsulosin were equally blocked by SB 216,469 at CAM. At WT in the absence of phenylephrine, tamsulosin did not cause significant stimulation and none of the other compounds caused significant inhibition of basal IP formation. We conclude that alpha1-adrenoceptor antagonsits with a quinazoline structure exhibit greater efficacy as inverse agonists than those without.

Dose-dependent acute and sustained renal effects of the endothelin receptor antagonist avosentan in healthy subjects

Enjeu : L'incidence d'insuffisance rénale terminale augmente d'environ 5-6% par année dans nos régions. L'une des causes majeures d'insuffisance rénale est la néphropathie diabétique qui représente selon les pays entre 25 et 40% des néphropathies terminales. La progression de la néphropathie diabétique peut être ralentie de manière efficace par un bon contrôle du diabète et de l'hypertension artérielle et par le blocage du système rénine-angiotensine. Néanmoins, malgré l'application stricte de ces thérapies préventives, la néphropathie de bons nombres de patients diabétiques continue de progresser. Il est donc important de développer de nouvelles stratégies permettant de préserver la fonction rénale des patients diabétiques soit en améliorant le contrôle de la pression artérielle soit en diminuant la protéinurie. Contexte : Il existe un certain nombre d'évidences expérimentales que le blocage des récepteurs de l'endothéline pourrait avoir un effet positif sur le devenir de la néphropathie diabétique en diminuant de manière efficace la protéinurie même chez des animaux déjà traités efficacement avec un bloqueur du système rénine-angiotensine. Dans des études de phase 2 impliquant l'avosentan, un antagoniste des récepteurs de l'endothéline actuellement en cours de développement pour le traitement de la néphropathie diabétique, on a pu démontrer que cet antagoniste, prescrit à des doses oscillant entre 5 et 50 mg par jour per os, diminue la protéinurie d'environ 20-40% chez des patients déjà traités avec un IEC ou un antagoniste de l'angiotensine. Toutefois, une grande étude de phase III conduite avec ce médicament chez des patients diabétiques a du être interrompue précocement en raison de l'apparition d'oedèmes et d'une surcharge hydrosodée conduisant dans certains cas à une décompensation cardiaque aiguë. La rétention hydrosodée est un effet secondaire connu des antagonistes de l'endothéline déjà sur le marché. Toutefois, pour l'avosentan, on ne savait pas si des doses plus faibles du médicament avaient aussi un effet négative sur la balance hydrosodée. En outre, les mécanismes rénaux responsables de la rétention hydrosodée sont encore mal connus chez l'homme. C'est pourquoi, nous avons organisé et réalisé cette étude de pharmacologie clinique chez le volontaire sain posant 2 questions : 1) des doses faibles d'avosentan produisent-elles aussi une rétention hydrosodée chez l'homme ? et 2) quels sont les mécanismes rénaux pouvant expliquer la rétention hydrosodée ? Cette thèse est donc une étude clinique de phase I testant chez 23 volontaires sains les effets rénaux de différentes doses d'avosentan ou d'un placebo pour établir la courbe dose-réponse des effets rénaux de ce médicament. L'idée était également de définir quelle dose est sure et bien tolérée pour être utilisée dans une nouvelle étude de phase II. L'avosentan a été administré par voie orale une fois par jour pendant 8 jours à des doses de 0.5, 1.5, 5 et 50 mg. Les effets rénaux hémodynamiques et tubulaires ont été étudiés chez chaque sujet lors de la première administration (jour 1) et après une semaine de traitement (jour 8). Le médicament a induit une prise de poids dose-dépendante déjà présente à 5 mg et maximale à 50 mg (+ 0.8 kg au jour 8). Nous n'avons pas mesuré d'impact de l'avosentan sur l'hémodynamique rénale ni sur les électrolytes plasmatiques. En revanche, nous avons constaté une diminution dose-dépendante de la fraction d'excrétion de sodium (jusqu'à -8.7% avec avosentan 50 mg). Cette diminution était en rapport avec une augmentation dose-dépendante de la réabsorption proximale de sodium. Nous avons également constaté une baisse de la pression artérielle aux doses élevées et une hémodilution marquée par une baisse de l'hématocrite suggérant une rétention hydrique à la plus haute dose. Nos résultats suggèrent donc que l'avosentan induit une rétention sodée rénale dose-dépendante expliquée avant tout par une rétention du sodium au niveau du tubule proximal. Cet effet n'est pas observé à des doses plus basses que 5 mg chez le volontaire sain, suggérant que ce médicament devrait être évalué pour son activité réno-protectrice à des doses inférieures ou égales à 5 mg par jour. La raison pour laquelle les hautes doses produisent plus de rétention sodée est peut être liée à une perte de sélectivité pour les sous-types (A et B) de récepteurs à l'endothéline lorsque l'on administre des doses plus élevées que 5 mg. Perspectives : Les résultats de ce travail de thèse ont donc permis de caractériser les propriétés rénales d'un nouvel antagoniste des récepteurs de l'endothéline chez l'homme. Ces résultats ont aussi permis de guider le développement futur de ce médicament vers des doses plus faibles avec l'espoir de garder les effets bénéfiques sur la protéinurie tout en améliorant le profil de tolérance du médicament par l'utilisation de doses plus faibles. ANGLAIS The endothelin receptor antagonist avosentan may cause fluid overload at doses of 25 and 50 mg, but the actual mechanisms of this effect are unclear. We conducted a placebo-controlled study in 23 healthy subjects to assess the renal effects of avosentan and the dose dependency of these effects. Oral avosentan was administered once daily for 8 days at doses of 0.5, 1.5, 5, and 50 mg. The drug induced a dose-dependent median increase in body weight, most pronounced at 50 mg (0.8 kg on day 8). Avosentan did not affect renal hemodynamics or plasma electrolytes. A dose-dependent median reduction in the fractional renal excretion of sodium was found (up to 8.7% at avosentan 50 mg); this reduction was paralleled by a dose-related increase in proximal sodium reabsorption. It is suggested that avosentan dose-dependently induces sodium retention by the kidney, mainly through proximal tubular effects. The potential clinical benefits of avosentan should therefore be investigated at doses of ≤ 5 mg.

Incomplete markets, labor supply and capital accumulation

In this paper we explore the accumulation of capital in the presence oflimited insurance against idiosyncratic shocks, borrowing constraintsand endogenous labor supply. As in the exogenous labor supply case(e.g. Aiyagari 1994, Huggett 1997), we find that steady states arecharacterized with an interest rate smaller than the rate of timepreference. However,wealsofind that when labor supply is endogenous thepresence of uncertainty and a borrowing limit are not enough to giverise to aggregate precautionary savings .

Efeito dos Parâmetros Técnicos na Dose e Qualidade de Imagem num Sistema de Radiografia Computorizada

Em radiologia, a qualidade diagnóstica está intimamente ligada à qualidade de imagens radiográficas. Sendo a qualidade de imagem (QI) o reflexo da exposição do paciente, a sua a maximização não pode ser conseguida a qualquer custo. É fulcral ter sempre em mente que uma boa QI pode significar maior exposição do paciente. Deste modo, a otimização é fundamental e deve-se guiar pela maximização da fração benefícios/riscos, sendo para isso necessário compreender os parâmetros técnicos que influenciam a dose e a QI. Neste trabalho foi feito um estudo dos efeitos dos parâmetros técnicos (tensão de ampola (kVp) e o produto da intensidade do feixe (mA) pelo tempo de exposição (s) (mA*s)) e da filtração adicional tanto na dose como na QI. A medição da dose, para diferentes valores de kVp, mA*s e espessura de cobre (Cu) usada na filtração adicional, foi feita utilizando uma câmara de ionização e um medidor do produto dose-área (DAP). Utilisando o fantoma CDRAD, a QI foi analisada através de Image Quality Figure (IQF) e parâmetros como contraste, ruído, razão sinal-ruído (SNR) e razão contraste-ruído (CNR). Verificou-se que, no modo manual de exposição, a dose varia de forma direta com kVp e mA*s e, no modo semiautomático, a variação é inversa entre o kVp e a dose. Mantendo fixo o kVp e mA*s, a redução da dose pode ser conseguida com recurso à filtração adicional. A QI é degradada quando o kVp aumenta e na presença da filtração adicional. Melhor QI está associada a maiores valores de dose. CNR é pouca efetada pela variação da dose. Com o aumento do DAP, o ruído diminui e a SNR aumenta, com elevada correlação.

Financial integration, productivity and capital accumulation

Understanding the mechanism through which financial globalization affect economic performance is crucial for evaluating the costs and benefits of opening financial markets. This paper is a first attempt at disentangling the effects of financial integration on the two main determinants of economic performance: productivity (TFP)and investments. I provide empirical evidence from a sample of 93 countries observed between 1975 and 1999. The results suggest that financial integration has a positive direct effect on productivity, while it spurs capital accumulation only with some delay and indirectly, since capital follows the rise in productivity. I control for indirect effects of financial globalization through banking crises. Such episodes depress both investments and TFP, though they are triggered by financial integration only to a minor extent. The paper also provides a discussion of a simple model on the effects of financial integration, and shows additional empirical evidence supporting it.

KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours.

A recent randomized EORTC phase III trial, comparing two doses of imatinib in patients with advanced gastrointestinal stromal tumours (GISTs), reported dose dependency for progression-free survival. The current analysis of that study aimed to assess if tumour mutational status correlates with clinical response to imatinib. Pre-treatment samples of GISTs from 377 patients enrolled in phase III study were analyzed for mutations of KIT or PDGFRA by combination of D-HPLC and direct sequencing of tumour genomic DNA. Mutation types were correlated with patients' survival data. The presence of exon 9-activating mutations in KIT was the strongest adverse prognostic factor for response to imatinib, increasing the relative risk of progression by 171% (P<0.0001) and the relative risk of death by 190% (P<0.0001) when compared with KIT exon 11 mutants. Similarly, the relative risk of progression was increased by 108% (P<0.0001) and the relative risk of death by 76% (P=0.028) in patients without detectable KIT or PDGFRA mutations. In patients whose tumours expressed an exon 9 KIT oncoprotein, treatment with the high-dose regimen resulted in a significantly superior progression-free survival (P=0.0013), with a reduction of the relative risk of 61%. We conclude that tumour genotype is of major prognostic significance for progression-free survival and overall survival in patients treated with imatinib for advanced GISTs. Our findings suggest the need for differential treatment of patients with GISTs, with KIT exon 9 mutant patients benefiting the most from the 800 mg daily dose of the drug.

A single high dose of oral Vitamin D3 is not enough to correct insufficiency and deficiency in a rheumatologic population

Introduction: Vitamin D plays a major role in bone metabolism and neuromuscular function. Supplementation with vitamin D is effective to reduce the risk of fall and of fracture. However adherence to oral daily vitamin D supplementation is low. Screening and correcting vitamin D insufficiency in a general rheumatologic population could improve both morbidity and quality of life in these patients with chronic painful disorders and at high risk of osteoporosis. After determining the prevalence of vitamin D deficiency in this population, we evaluated if supplementation with a single high dose of oral 25-OH vitamin D3 was sufficient to correct this abnormality. Methods: During one month (November 2009), levels of 25-OH vitamin D were systematically determined in our rheumatology outpatient clinic and classified into three groups: vitamin D deficiency (<10 µg/l), vitamin D insufficiency (10 to 30µg/l) or normal vitamin D (>30 µg/l). Patients with insufficiency or deficiency received respectively a single high dose of 300'000 IU or 600'000 IU oral vitamin D3. In addition, all patients with osteoporosis were prescribed daily supplement of calcium (1g) and vitamin D (800 IU). 25-OH vitamin D levels were reevaluated after 3 months. Results: Vitamin D levels were initially determined in 292 patients (mean age 53, 211 women, 87% Caucasian). 77% had inflammatory rheumatologic disease (IRD), 20% osteoporosis (OP) and 12% degenerative disease (DD). Vitamin D deficiency was present in 20 (6.8%), while 225 (77.1%) had insufficiency. Of the 245 patients with levels <30µg/l, a new determination of vitamin D level was available in 173 (71%) at 3 months (table 1). Conclusion: Vitamin D insufficiency is highly prevalent in our rheumatologic population (84%), and is not adequately corrected by a single high dose of oral vitamin D3 in more than half of the patients with IRD and DD. In patients with OP, despite association of a single high dose with daily oral vitamin D supplementation, 40% of patients are still deficient when reevaluated at 3 months.

High-dose daptomycin plus fosfomycin is safe and effective in treating methicillin-susceptible and methicillin-resistant Staphylococcus aureus endocarditis.

We describe 3 patients with left-sided staphylococcal endocarditis (1 with methicillin-susceptible Staphylococcus aureus [MSSA] prosthetic aortic valve endocarditis and 2 with methicillin-resistant S. aureus [MRSA] native-valve endocarditis) who were successfully treated with high-dose intravenous daptomycin (10 mg/kg/day) plus fosfomycin (2 g every 6 h) for 6 weeks. This combination was tested in vitro against 7 MSSA, 5 MRSA, and 2 intermediately glycopeptide-resistant S. aureus isolates and proved to be synergistic against 11 (79%) strains and bactericidal against 8 (57%) strains. This combination deserves further clinical study.

Effects of uncertain lifetime and annuity insurance on capital accumulation and growth

This paper studies the effects of uncertain lifetime on capitalaccumulation and growth and also the sensitivity of thoseeffects to the existence of a perfect annuities market. Themodel is an overlapping generations model with uncertainlifetimes. The technology is convex and such that the marginalproduct of capital is bounded away from zero. A contribution ofthis paper is to show that the existence of accidental bequestsmay lead the economy to an equilibrium that exhibits asymptoticgrowth, which is impossible in an economy with a perfect annuitiesmarket or with certain lifetimes. This paper also shows that ifindividuals face a positive probability of surviving in everyperiod, they may be willing to save at any age. This effect ofuncertain lifetime on savings may also lead the economy to anequilibrium exhibiting asymptotic growth even if there exists aperfect annuities market.

Growth accounting in items of turbulence and death: efficiency, technology, capital accumulation and human capital 1929-1950

We employ a non-parametrical approach to growth accounting (Data Envelopment Analysis,DEA) to disentangle the proximate sources of labour productivity growth in 41 nationsbetween 1929 and 1950 by decomposing productivity growth into four components:technological change; efficiency catch-up (movements towards the production frontier),capital accumulation and human capital accumulation. We show that efficiency catch-upgenerally explains productivity growth, whereas technological change and factoraccumulation were limited and distorted by the effects of war. War clearly hamperedefficiency. Moreover, an unbalanced ratio of human capital to physical capital (a gap to thetechnological leader) was crucial for efficiency catching-up.

Overexpressed or intraperitoneally injected human transferrin prevents photoreceptor degeneration in rd10 mice.

PURPOSE: Retinal degeneration has been associated with iron accumulation in age-related macular degeneration (AMD), and in several rodent models that had one or several iron regulating protein impairments. We investigated the iron concentration and the protective role of human transferrin (hTf) in rd10 mice, a model of retinal degeneration. METHODS: The proton-induced X-ray emission (PIXE) method was used to quantify iron in rd10 mice 2, 3, and 4 weeks after birth. We generated mice with the β-phosphodiesterase mutation and hTf expression by crossbreeding rd10 mice with TghTf mice (rd10/hTf mice). The photoreceptor loss and apoptosis were evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling in 3-week-old rd10/hTf mice and compared with 3-week-old rd10 mice. The neuroprotective effect of hTf was analyzed in 5-day-old rd10 mice treated by intraperitoneal administration with hTf for up to 25 days. The retinal hTf concentrations and the thickness of the outer nuclear layer were quantified in all treated mice at 25 days postnatally. RESULTS: PIXE analysis demonstrated an age-dependent iron accumulation in the photoreceptors of rd10 mice. The rd10/hTf mice had the rd10 mutation, expressed high levels of hTf, and showed a significant decrease in photoreceptor death. In addition, rd10 mice intraperitoneally treated with hTf resulted in the retinal presence of hTf and a dose-dependent reduction in photoreceptor degeneration. CONCLUSIONS: Our results suggest that iron accumulation in the retinas of rd10 mutant mice is associated with photoreceptor degeneration. For the first time, the enhanced survival of cones and rods in the retina of this model has been demonstrated through overexpression or systemic administration of hTf. This study highlights the therapeutic potential of Tf to inhibit iron-induced photoreceptor cell death observed in degenerative diseases such as retinitis pigmentosa and age-related macular degeneration.

Setting standards: Information accumulation in development

We propose a model in which economic relations and institutions in advancedand less developed economies differ as these societies have access to different amounts of information. This lack of information makes it hard to give the right incentives to managers and entrepreneurs. We argue that differences in the amount of information arise because of the differences in the scale of activities in rich and poor economies; namely, there is too little repetition of similar activities in pooreconomies, thus insufficient information to set the appropriate standards for firm performance. Our model predicts a number of institutional and structural transformations as the economy accumulates capital and information.

Fetal dose reduction in head and neck radiotherapy of a pregnant woman.

BACKGROUND AND PURPOSE: A pregnant woman was referred for post-operative radiotherapy of a malignant schwannoma in the head and neck region. A best-treatment plan was devised in order to minimize the fetal dose. MATERIAL AND METHODS: The fetal dose resulting from radiological examinations was determined according to international protocols, that resulting from radiotherapy was calculated according to Recommendation 36 of the American Association of Physicists in Medicine (AAPM) Task Group. Pre-treatment dosimetry was performed with an anthropomorphic phantom. Several alternative treatment plans were evaluated. The use of a multileaf collimator (MLC) and a virtual wedge (VW) was compared to cerrobend blocks (CB) and physical wedge (PW). In-vivo dosimetry was performed using a vaginal probe containing thermoluminescent dosimeters (TLD). RESULTS: The total fetal dose resulting from diagnostic and radiotherapy procedures was estimated to be 36 mGy. The technique based on MLC and VW was elected for patient treatment. Measurements for this configuration resulted in afetal dose reduction of 82%. The shielding of the patient's abdomen further reduced the fetal dose by 42%. CONCLUSION: The use of VW and MLC for the treatment of a pregnant woman is highly recommended. Each case should be individually studied with pre-treatment and in-vivo dosimetry.