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Objective. In proton therapy, range uncertainties prevent to optimally benefit from the superior depth-dose characteristics of proton beams over conventional photon-based radiotherapy. To reduce these uncertainties we recently proposed the use of phase-change ultrasound contrast agents as an affordable and effective range verification tool. In particular, superheated nanodroplets can convert into echogenic microbubbles upon proton irradiation, whereby the resulting ultrasound contrast relates to the proton range with high reproducibility. Here, we provide a first in vivo proof-of-concept of this technology.&#xD;&#xD; Approach. First, the in vitro biocompatibility of radiation-sensitive poly(vinyl) alcohol perfluorobutane nanodroplets was investigated using several colorimetric assays. Then, in vivo ultrasound contrast was characterized using acoustic droplet vaporization and later using proton beam irradiations at varying energies (49.7 MeV and 62 MeV) in healthy Sprague Dawley rats. A preliminary evaluation of the in vivo biocompatibility was performed using acoustic droplet vaporization and a combination of physiology monitoring and histology.&#xD;&#xD; Main results. Nanodroplets were non-toxic over a wide concentration range (< 1 mM). In healthy rats, intravenously injected nanodroplets primarily accumulated in the organs of the reticuloendothelial system, where the lifetime of the generated ultrasound contrast (< 30 min) was compatible with a typical radiotherapy fraction (< 5 min). Spontaneous droplet vaporization did not result in significant background signals. Online ultrasound imaging of the liver of droplet-injected rats demonstrated an energy-dependent proton response, which can be tuned by varying the nanodroplet concentration. However, caution is warranted when deciding on the exact nanodroplet dose regimen as a mild physiological response (drop in cardiac rate, granuloma formation) was observed after acoustic droplet vaporization.&#xD; &#xD; Significance. These findings underline the potential of phase-change ultrasound contrast agents for in vivo proton range verification and provide the next step towards eventual clinical applications.&#xD., (© 2024 Institute of Physics and Engineering in Medicine. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Aims: Aortic valve calcification (AVC) of surgical valve bioprostheses (BPs) has been poorly explored. We aimed to evaluate in vivo and ex vivo BP AVCs and its prognosis value., Methods and Results: Between 2011 and 2019, AVC was assessed using in vivo computed tomography (CT) in 361 patients who had undergone surgical valve replacement 6.4 ± 4.3 years earlier. Ex vivo CT scans were performed for 37 explanted BPs. The in vivo CT scans were interpretable for 342 patients (19 patients [5.2%] were excluded). These patients were 77.2 ± 9.1 years old, and 64.3% were male. Mean in vivo AVC was 307 ± 500 Agatston units (AU). The AVC was 562 ± 570 AU for the 183 (53.5%) patients with structural valve degeneration (SVD) and 13 ± 43 AU for those without SVD (P < 0.0001). In vivo and ex vivo AVCs were strongly correlated (r = 0.88, P < 0.0001). An in vivo AVC > 100 AU (n = 147, 43%) had a specificity of 96% for diagnosing Stage 2-3 SVD (area under the curve = 0.92). Patients with AVC > 100 AU had a worse outcome compared with those with AVC ≤ 100 AU (n = 195). In multivariable analysis, AVC was a predictor of overall mortality (hazard ratio [HR] and 95% confidence interval = 1.16 [1.04-1.29]; P = 0.006), cardiovascular mortality (HR = 1.22 [1.04-1.43]; P = 0.013), cardiovascular events (HR = 1.28 [1.16-1.41]; P < 0.0001), and re-intervention (HR = 1.15 [1.06-1.25]; P < 0.0001). After adjustment for Stage 2-3 SVD diagnosis, AVC remained a predictor of overall mortality (HR = 1.20 [1.04-1.39]; P = 0.015) and cardiovascular events (HR = 1.25 [1.09-1.43]; P = 0.001)., Conclusion: CT scan is a reliable tool to assess BP leaflet calcification. An AVC > 100 AU is tightly associated with SVD and it is a strong predictor of overall mortality and cardiovascular events., Competing Interests: Conflict of interest: T.L.T. and J.-Christ R. received a basic research grant from Abbott-St Jude company dedicated to a mitral valve prolapse project. The other authors have no disclosure., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Radiotherapy treatment plans have become highly conformal, posing additional constraints on the accuracy of treatment delivery. Here, we explore the use of radiation-sensitive ultrasound contrast agents (superheated phase-change nanodroplets) as dosimetric radiation sensors. In a series of experiments, we irradiated perfluorobutane nanodroplets dispersed in gel phantoms at various temperatures and assessed the radiation-induced nanodroplet vaporization events using offline or online ultrasound imaging. At 25 °C and 37 °C, the nanodroplet response was only present at higher photon energies (≥10 MV) and limited to <2 vaporization events per cm 2 per Gy. A strong response (~2000 vaporizations per cm 2 per Gy) was observed at 65 °C, suggesting radiation-induced nucleation of the droplet core at a sufficiently high degree of superheat. These results emphasize the need for alternative nanodroplet formulations, with a more volatile perfluorocarbon core, to enable in vivo photon dosimetry. The current nanodroplet formulation carries potential as an innovative gel dosimeter if an appropriate gel matrix can be found to ensure reproducibility. Eventually, the proposed technology might unlock unprecedented temporal and spatial resolution in image-based dosimetry, thanks to the combination of high-frame-rate ultrasound imaging and the detection of individual vaporization events, thereby addressing some of the burning challenges of new radiotherapy innovations.

Purpose: The purpose of this study was to evaluate the percentage of coronary angiography that can be securely avoided by the interpretation of coronary arteries on pre transcatheter aortic valve implantation CT (TAVI-CT), using CT images obtained with deep-learning reconstruction and motion correction algorithms., Material and Method: All consecutive patients who underwent TAVI-CT and coronary angiography, from December 2021 to July 2022 were screened for inclusion in the study. Patients who had previous coronary artery revascularization or who did not undergo TAVI were excluded. All TAVI-CT examinations were obtained using deep-learning reconstruction and motion correction algorithms. On TAVI-CT examinations, quality and stenosis of coronary artery were analyzed retrospectively. When insufficient image quality and/or when diagnosis or doubt of one significant coronary artery stenosis, patients were considered as having possible coronary artery stenosis. The results of coronary angiography were used as the standard of reference for significant CAS., Results: A total of 206 patients (92 men; mean age, 80.6 years) were included; of these 27/206 (13%) had significant coronary artery stenosis on coronary angiography and were referred for potential revascularization. Sensitivity, specificity, negative predictive value, positive predictive value, and accuracy of TAVI-CT to identify patients requiring coronary artery revascularization was 100% (95% confidence interval [CI]: 87.2-100%), 100% (95% CI: 96.3-100%), 54% (95% CI: 46.6-61.6), 25% (95% CI: 17.0-34.0%) and 60% (95% CI: 53.1-66.9%) respectively. Intra- and inter observer variability was substantial agreement for quality and decision to recommend coronary angiography. Mean reading time was 2 ± 1.2 (standard deviation) min (range: 1-5 min). Overall, TAVI-CT could potentially rule out indication for revascularization for 97 patients (47%)., Conclusion: Analysis of coronary artery on TAVI-CT using deep-learning reconstruction and motion correction algorithms can potentially safely avoid coronary angiography in 47% of patients., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest related to this work to declare., (Copyright © 2023 Société française de radiologie. Published by Elsevier Masson SAS. All rights reserved.)

Objective. External beam radiotherapy is aimed to precisely deliver a high radiation dose to malignancies, while optimally sparing surrounding healthy tissues. With the advent of increasingly complex treatment plans, the delivery should preferably be verified by quality assurance methods. Recently, online ultrasound imaging of vaporized radiosensitive nanodroplets was proposed as a promising tool for in vivo dosimetry in radiotherapy. Previously, the detection of sparse vaporization events was achieved by applying differential ultrasound (US) imaging followed by intensity thresholding using subjective parameter tuning, which is sensitive to image artifacts. Approach . A generalized deep learning solution (i.e. BubbleNet) is proposed to localize vaporized nanodroplets on differential US frames, while overcoming the aforementioned limitation. A 5-fold cross-validation was performed on a diversely composed 5747-frame training/validation dataset by manual segmentation. BubbleNet was then applied on a test dataset of 1536 differential US frames to evaluate dosimetric features. The intra-observer variability was determined by scoring the Dice similarity coefficient (DSC) on 150 frames segmented twice. Additionally, the BubbleNet generalization capability was tested on an external test dataset of 432 frames acquired by a phased array transducer at a much lower ultrasound frequency and reconstructed with unconventional pixel dimensions with respect to the training dataset. Main results. The median DSC in the 5-fold cross validation was equal to ∼0.88, which was in line with the intra-observer variability (=0.86). Next, BubbleNet was employed to detect vaporizations in differential US frames obtained during the irradiation of phantoms with a 154 MeV proton beam or a 6 MV photon beam. BubbleNet improved the bubble-count statistics by ∼30% compared to the earlier established intensity-weighted thresholding. The proton range was verified with a -0.8 mm accuracy. Significance. BubbleNet is a flexible tool to localize individual vaporized nanodroplets on experimentally acquired US images, which improves the sensitivity compared to former thresholding-weighted methods., (© 2022 Institute of Physics and Engineering in Medicine.)

Methods allowing for in situ dosimetry and range verification are essential in radiotherapy to reduce the safety margins required to account for uncertainties introduced in the entire treatment workflow. This study suggests a non-invasive dosimetry concept for carbon ion radiotherapy based on phase-change ultrasound contrast agents. Injectable nanodroplets made of a metastable perfluorobutane (PFB) liquid core, stabilized with a crosslinked poly(vinylalcohol) shell, are vaporized at physiological temperature when exposed to carbon ion radiation (C-ions), converting them into echogenic microbubbles. Nanodroplets, embedded in tissue-mimicking phantoms, are exposed at 37 °C to a 312 MeV/u clinical C-ions beam at different doses between 0.1 and 4 Gy. The evaluation of the contrast enhancement from ultrasound imaging of the phantoms, pre- and post-irradiation, reveals a significant radiation-triggered nanodroplets vaporization occurring at the C-ions Bragg peak with sub-millimeter shift reproducibility and dose dependency. The specific response of the nanodroplets to C-ions is further confirmed by varying the phantom position, the beam range, and by performing spread-out Bragg peak irradiation. The nanodroplets' response to C-ions is influenced by their concentration and is dose rate independent. These early findings show the ground-breaking potential of polymer-shelled PFB nanodroplets to enable in vivo carbon ion dosimetry and range verification., (© 2022. The Author(s).)

The potential of proton therapy to improve the conformity of the delivered dose to the tumor volume is currently limited by range uncertainties. Injectable superheated nanodroplets have recently been proposed for ultrasound-based in vivo range verification, as these vaporize into echogenic microbubbles on proton irradiation. In previous studies, offline ultrasound images of phantoms with dispersed nanodroplets were acquired after irradiation, relating the induced vaporization profiles to the proton range. However, the aforementioned method did not enable the counting of individual vaporization events, and offline imaging cannot provide real-time feedback. In this study, we overcame these limitations using high-frame-rate ultrasound imaging with a linear array during proton irradiation of phantoms with dispersed perfluorobutane nanodroplets at 37°C and 50°C. Differential image analysis of subsequent frames allowed us to count individual vaporization events and to localize them with a resolution beyond the ultrasound diffraction limit, enabling spatial and temporal quantification of the interaction between ionizing radiation and nanodroplets. Vaporization maps were found to accurately correlate with the stopping distribution of protons (at 50°C) or secondary particles (at both temperatures). Furthermore, a linear relationship between the vaporization count and the number of incoming protons was observed. These results indicate the potential of real-time high-frame-rate contrast-enhanced ultrasound imaging for proton range verification and dosimetry., Competing Interests: Conflict of interest disclosure The authors declare no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The inherent fluorescence properties of iron oxide nanoparticles (IONPs) were characterized, and their applicability for multiphoton imaging in cells was tested in combination with their magnetic resonance imaging (MRI) capabilities., Methods: Superparamagnetic iron oxide nanoparticles were synthesized and subsequently coated with polyethylene glycol to make them water-dispersible. Further characterization of the particles was performed using Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), dynamic light scattering (DLS), superconducting quantum interference device (SQUID) and magnetic resonance relaxivity measurements. MRI and fluorescence properties of bare IONPs were first studied in solution and subsequently in A549-labeled cells., Results: The particles, with a core size of 11.3 ± 4.5 nm, showed a good negative MRI contrast in tissue-mimicking phantoms. In vitro studies in mammalian A549 cells demonstrate that these IONPs are biocompatible and can also produce significant T2/T2* contrast enhancement in IONPs-labeled cells. Furthermore, excitation-wavelength dependent photoluminescence was observed under one- and two-photon excitation., Discussion: The obtained results indicated that IONPs could be used for fluorescence label-free bioimaging at multiple wavelengths, which was proven by multiphoton imaging of IONPs internalization in A549 cancer cells., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Reynders et al.)

Purpose: We investigate the vaporization of phase-change ultrasound contrast agents using photon radiation for dosimetry perspectives in radiotherapy., Methods: We studied superheated perfluorobutane nanodroplets with a crosslinked poly(vinylalcohol) shell. The nanodroplets' physico-chemical properties, and their acoustic transition have been assessed firstly. Then, poly(vinylalcohol)-perfluorobutane nanodroplets were dispersed in poly(acrylamide) hydrogel phantoms and exposed to a photon beam. We addressed the effect of several parameters influencing the nanodroplets radiation sensitivity (energy/delivered dose/dose rate/temperature). The nanodroplets-vaporization post-photon exposure was evaluated using ultrasound imaging at a low mechanical index., Results: Poly(vinylalcohol)-perfluorobutane nanodroplets show a good colloidal stability over four weeks and remain highly stable at temperatures up to 78 °C. Nanodroplets acoustically-triggered phase transition leads to microbubbles with diameters <10 μm and an activation threshold of mechanical index = 0.4, at 7.5 MHz. A small number of vaporization events occur post-photon exposure (6MV/15MV), at doses between 2 and 10 Gy, leading to ultrasound contrast increase up to 60% at RT. The nanodroplets become efficiently sensitive to photons when heated to a temperature of 65 °C (while remaining below the superheat limit temperature) during irradiation., Conclusions: Nanodroplets' core is linked to the degree of superheat in the metastable state and plays a critical role in determining nanodroplet' stability and sensitivity to ionizing radiation, requiring higher or lower linear energy transfer vaporization thresholds. While poly(vinylalcohol)-perfluorobutane nanodroplets could be slightly activated by photons at ambient conditions, a good balance between the degree of superheat and stability will aim at optimizing the design of nanodroplets to reach high sensitivity to photons at physiological conditions., (Copyright © 2021 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Purpose: Despite the physical benefits of protons over conventional photon radiation in cancer treatment, range uncertainties impede the ability to harness the full potential of proton therapy. While monitoring the proton range in vivo could reduce the currently adopted safety margins, a routinely applicable range verification technique is still lacking. Recently, phase-change nanodroplets were proposed for proton range verification, demonstrating a reproducible relationship between the proton range and generated ultrasound contrast after radiation-induced vaporization at 25°C. In this study, previous findings are extended with proton irradiations at different temperatures, including the physiological temperature of 37°C, for a novel nanodroplet formulation. Moreover, the potential to modulate the linear energy transfer (LET) threshold for vaporization by varying the degree of superheat is investigated, where the aim is to demonstrate vaporization of nanodroplets directly by primary protons., Methods: Perfluorobutane nanodroplets with a shell made of polyvinyl alcohol (PVA-PFB) or 10,12-pentacosadyinoic acid (PCDA-PFB) were dispersed in polyacrylamide hydrogels and irradiated with 62 MeV passively scattered protons at temperatures of 37°C and 50°C. Nanodroplet transition into echogenic microbubbles was assessed using ultrasound imaging (gray value and attenuation analysis) and optical images. The proton range was measured independently and compared to the generated contrast., Results: Nanodroplet design proved crucial to ensure thermal stability, as PVA-shelled nanodroplets dramatically outperformed their PCDA-shelled counterpart. At body temperature, a uniform radiation response proximal to the Bragg peak is attributed to nuclear reaction products interacting with PVA-PFB nanodroplets, with the 50% drop in ultrasound contrast being 0.17 mm ± 0.20 mm (mean ± standard deviation) in front of the proton range. Also at 50°C, highly reproducible ultrasound contrast profiles were obtained with shifts of -0.74 mm ± 0.09 mm (gray value analysis), -0.86 mm ± 0.04 mm (attenuation analysis) and -0.64 mm ± 0.29 mm (optical analysis). Moreover, a strong contrast enhancement was observed near the Bragg peak, suggesting that nanodroplets were sensitive to primary protons., Conclusions: By varying the degree of superheat of the nanodroplets' core, one can modulate the intensity of the generated ultrasound contrast. Moreover, a submillimeter reproducible relationship between the ultrasound contrast and the proton range was obtained, either indirectly via the visualization of secondary reaction products or directly through the detection of primary protons, depending on the degree of superheat. The potential of PVA-PFB nanodroplets for in vivo proton range verification was confirmed by observing a reproducible radiation response at physiological temperature, and further studies aim to assess the nanodroplets' performance in a physiological environment. Ultimately, cost-effective online or offline ultrasound imaging of radiation-induced nanodroplet vaporization could facilitate the reduction of safety margins in treatment planning and enable adaptive proton therapy., (© 2021 American Association of Physicists in Medicine.)

Technologies enabling in vivo range verification during proton therapy are actively sought as a means to reduce the clinical safety margins currently adopted to avoid tumor underdosage. In this contribution, we applied the semi-empirical theory of radiation-induced vaporization of superheated liquids to coated nanodroplets. Nanodroplets are injectable phase-change contrast agents that can vaporize into highly echogenic microbubbles to provide contrast in ultrasound images. We exposed nanodroplet dispersions in aqueous phantoms to monoenergetic proton beams of varying energies and doses. Ultrasound imaging of the phantoms revealed that radiation-induced droplet vaporization occurred in regions proximal to the proton Bragg peak. A statistically significant increase in contrast was observed in irradiated regions for doses as low as 2 Gy and found to be proportional to the proton fluence. The absence of enhanced response in the vicinity of the Bragg peak, combined with theoretical considerations, suggest that droplet vaporization is induced by high linear energy transfer (LET) recoil ions produced by nuclear reactions with incoming protons. Vaporization profiles were compared to non-elastic cross sections and LET characteristics of oxygen recoils. Shifts between the ultrasound image contrast drop and the expected proton range showed a sub-millimeter reproducibility. These early findings confirm the potential of superheated nanodroplets as a novel tool for proton range verification.

Background: Social exclusion (SE), or the inability to participate fully in society, is considered one of the driving forces of health inequalities. Systematic evidence on this subject is pertinent but scarce. This review aims to systematically summarise peer reviewed studies examining the association between the multidimensional concepts of SE and social inclusion (SI) and health among adults in EU and OECD countries., Methods: The protocol was registered on Prospero (CRD42017052718). Three major medical databases were searched to identify studies published before January 2018, supplemented by reference and citation tracking. Articles were included if they investigated SE or SI as a multidimensional concept with at least two out of the four dimensions of SE/SI, i.e. economic, social, political and cultural. A qualitative synthesis was conducted., Results: Twenty-two observational studies were included. In the general population, high SE/low SI was associated with adverse mental and general health. For physical health, the evidence was inconclusive. In groups at high risk of SE, support was found for the association between high SE/low SI and adverse mental health but no conclusions could be drawn for physical and general health., Conclusions: This review found evidence for the association between high SE/low SI and adverse health outcomes, particularly mental health outcomes. The evidence is mainly based on cross-sectional studies using simple and often ad hoc indicators of SE/SI. The development and use of validated measures of SE/SI and more longitudinal research is needed to further substantiate the evidence base and gain better understanding of the causal pathways., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Public Health Association.)

Purpose: To investigate the influence of poor health on job-search behavior and re-employment, and the mediating role of job-search cognitions and coping resources., Methods: A prospective study was conducted among unemployed persons receiving social security benefits in the Netherlands (n = 510). Self-rated health, self-esteem, mastery, job-search cognitions, and the intention to search for a job were measured at baseline. Logistic regression analysis was used to investigate determinants of job-search behavior during a follow-up period of 6 months. Cox proportional hazards analysis was used to investigate the influence of health, job-search cognitions and coping resources on re-employment during a mean follow-up period of 23 months., Results: Persons with poor health were less likely to search for paid employment (OR 0.58, 95 % CI 0.39-0.85) and were also less likely to find paid employment (HR 0.58, 95 % CI 0.39-0.89). Persons with a positive attitude toward job-search, high perceived social pressure to look for a job, high job-search self-efficacy and high job-search intention were more likely to search actively and also to actually find paid employment. Adjustment for job-search cognitions and coping reduced the influence of health on active search behavior by 50 % and on re-employment by 33 %., Conclusions: Health-related differences in job-search behavior and re-employment can be partly explained by differences in coping, job-search attitude, self-efficacy, and subjective norms towards job-search behavior. Measures to reduce the negative impact of poor health on re-employment should address the interplay of health with job-search cognitions and coping resources.

Backgrounds: Few studies have addressed the specific contribution of health in relation to socio-demographic and motivational aspects to re-entering paid employment. The purpose of this study among beneficiaries of unemployment benefits is to evaluate the detrimental effects of poor health and a lack of motivation on the likelihood of getting a job and to develop a decision support model that predicts remaining unemployment after 12 months., Methods: A longitudinal cohort study was conducted among people on unemployment benefit (UB) or social insurance benefit (SIB). The time-window of the study was 18 months. Written questionnaires were filled out 3 months post-benefit assessment, 6, 12 and 18 months. Multivariate logistic regression analysis was used to identify the barriers of re-entering paid employment. Subsequently, a predictive model was constructed to estimate the probability for every combination of determinants for a person to remain unemployed in the next 12 months., Results: Older age (≥55 years), a poor perceived health, and a lack of willingness to accept a job were the most prominent predictive factors for remaining unemployed after 12 months in both UB and SIB groups. Lower education in the UB group and being married or living together and poor self-reliance in the SIB group were additional risk factors for long-term unemployment., Conclusion: Vocational rehabilitation of people on long-term social benefit should address perceived health, socio-demographic, and motivational aspects as key factors that determine prolonged unemployment. A predictive flow chart can be used to detect most vulnerable persons at risk for remaining long-term unemployment.

We characterized the histamine H(1) receptor agonism of various histaprodifen derivatives in guinea pig isolated ileum and trachea in comparison with histamine. Based on their affinity (calculated pK(A) values for ileum and trachea, respectively), the compounds were ranked as follows: suprahistaprodifen (8.31/8.08) > N(alpha)-(4-phenylbutyl)histaprodifen (7.22/5.93) >or= histamine (5.79/5.19) approximately methylhistaprodifen (5.57/6.07). Based on their efficacy (calculated tau values for ileum and trachea, respectively), the compounds were ranked as follows: methylhistaprodifen (37.67/2.50) > histamine (5.64/1.80) > suprahistaprodifen (1.63/1.42) >or= N(alpha)-(4-phenylbutyl)histaprodifen (0.083/1.54). In the ileum, histamine and methylhistaprodifen showed a high histamine H(1) receptor reserve while suprahistaprodifen and N(alpha)-(4-phenylbutyl)histaprodifen are devoid of any histamine H(1 )receptor reserve. On the trachea, no histamine H(1 )receptor reserve was demonstrable with the four tested agonists. The kinetic of contraction/relaxation of the ileum was faster with histamine and methylhistaprodifen than with suprahistaprodifen and N(alpha)-(4-phenylbutyl)histaprodifen. Histamine contracted the trachea faster than histaprodifen derivatives. Levocetirizine antagonized contractions induced by histamine and histaprodifen derivatives in both tissues. The differences observed in the calculated pA(2) (7.60-8.29) and/or pD'(2) values (6.28-7.90) depending on the tissue and/or the agonist are discussed.

We characterised histamine H(1) receptor antagonism by cetirizine and its enantiomers on isolated guinea pig ileum and trachea. Competitive or mixed (competitive and apparent noncompetitive) antagonism profiles were observed. The order of potency was: chlorpheniramine> or =mepyramine>levocetirizine>cetirizine> or =terfenadine>loratadine>dextrocetirizine. The inhibitory effects of cetirizine, levocetirizine, terfenadine and loratadine were slowly reversible compared to those of dextrocetirizine or mepyramine. Cetirizine and its enantiomers were inactive on L-type Ca(2+) channels. Reduction of the histamine H(1) receptor reserve by dibenamine in the ileum (100-fold higher than in the trachea) showed a gradual change from the competitive profile of dextrocetirizine and mepyramine to a mixed profile. The present results show that cetirizine and levocetirizine are selective competitive but slowly reversible histamine H(1) receptor antagonists. Their mixed antagonism profile observed in the trachea can be explained by the small receptor reserve present in this tissue compared to the ileum and their very slow dissociation rate from the histamine H(1) receptor.

We report on four patients, from three different families, with Senior-Loken syndrome (SLS). They were unusual in that they reached end-stage renal failure (ESRF) only during the fifth or sixth decade. SLS is an autosomal-recessive disorder defined by the association of nephronophthisis and retinal dystrophy. Affected individuals invariably progress to ESRF, usually before the age of 20 years. The diagnosis was based on typical clinical presentation and characteristic renal histology, that is, a picture of chronic interstitial nephritis with pronounced thickening and multilayering of tubular basement membranes. Deterioration of renal function was slow, leading to ESRF between the ages of 42 and 56 years. Retinal dystrophy, already symptomatic during childhood in two patients, led to severe visual impairment in all. In contrast with four cases of SLS recently reported in very young patients, the NPH1 gene (the main gene responsible for nephronophthisis) was not deleted in our two tested patients. We conclude that SLS should be considered in adults who suffer from both chronic interstitial nephropathy and retinal degeneration. Whether the SLS is a variant of nephronophthisis and whether early- and late-onset renal failure in SLS is accounted for by genetic or allelic heterogeneity remain to be determined.

The authors report an observation of Wegener's granulomatosis with pulmonary, bronchial, renal, cutaneous and sinusal involvement. Five years ago, the patient was referred to us because of bilateral diffuse pulmonary infiltrates of unknown origin. A corticotherapy was introduced at that time and a complete clearance of the pulmonary infiltrates was noted. Nineteen months after the treatment's withdrawal, the disease recurs with the reappearance of pulmonary infiltrates. Beyond these unusual clinical aspects, histological examination of the bronchial biopsies were of diagnostic value.

We describe the case of a 63-year-old woman with an IgD-type multiple myeloma and hyperamylasaemia. The evolution of the amylase concentration, the immunohistochemical data and the intracellular amylase contents of the plasma cell were consistent with secretion of amylase by the malignant clone. Moreover, cytogenetic analysis of the bone marrow revealed two structural rearrangements involving chromosome 1 near the amylase locus. Multiple myeloma should be added to the amylase-secreting tumours. This rare entity is not confined to Japan, where it was first recognized.

Urinary N-acetyl-beta-glucosaminidase (NAG) excretion was measured in 14 healthy, preterm, male neonates with gestational ages between 32 and 35 weeks. Daily NAG excretion increased significantly during the first four weeks of life. No correlation was observed between urinary NAG:creatinine ratio and postnatal age regardless of whether measurements were taken from the whole 24 hour urine collection or from an isolated urine spot sample at the same time on each day. When the preterm infants were compared with a group of 20 healthy, full term, male infants at a postnatal age of 7 days the NAG:creatinine ratio was significantly higher in the preterm group, the measurements having been taken from single urine spot samples. We suggest that this variable be used in the evaluation of renal tubular integrity during the neonatal period.

The effect of cimetidine on abnormally elevated serum levels of parathyroid hormone was studied in 21 patients with secondary hyperparathyroidism due to chronic renal failure, receiving regular dialysis treatment. The concentrations of carboxyl (-COOH) and aminoterminal (-NH2) fragments of circulating immunoreactive parathyroid hormone (iPTH) were determined before and after 2 months af treatment with cimetidine 400 mg/day. All patients had, on admission, raised levels of either hormonal fragment. The mean pre-treatment value was 17.2 mU/ml for -COOH terminus (upper normal limit 6.5 mU/ml) and 5.7 mU/ml for -NH2 terminus (upper normal limit 1.9 mU/ml). At the end of cimetidine treatment the mean values were 19.9 and 5.7 mU/ml respectively for the two forms of circulating iPTH. No changes in total serum calcium, phosphate or alkaline phosphatase activity were recorded during the study. These results do not indicate any lowering effect of cimetidine on serum iPTH in chronic uraemic patients with secondary hyperparathyroidism.