Macrocyclic chelator-coupled gastrin-based radiopharmaceuticals for targeting of gastrin receptor-expressing tumours

PURPOSE: Diethylenetriamine-pentaacetic acid (DTPA)-coupled minigastrins are unsuitable for therapeutic application with the available beta-emitting radiometals due to low complex stability. Low tumour-to-kidney ratio of the known radiopharmaceuticals is further limiting their potency. We used macrocyclic chelators for coupling to increase complex stability, modified the peptide sequence to enhance radiolytic stability and studied tumour-to-kidney ratio and metabolic stability using (111)In-labelled derivatives. METHODS: Gastrin derivatives with decreasing numbers of glutamic acids were synthesised using (111)In as surrogate for therapeutic radiometals for in vitro and in vivo studies. Gastrin receptor affinities of the (nat)In-metallated compounds were determined by receptor autoradiography using (125)I-CCK as radioligand. Internalisation was evaluated in AR4-2J cells. Enzymatic stability was determined by incubating the (111)In-labelled peptides in human serum. Biodistribution was performed in AR4-2J-bearing Lewis rats. RESULTS: IC(50) values of the (nat)In-metallated gastrin derivatives vary between 1.2 and 4.8 nmol/L for all methionine-containing derivatives. Replacement of methionine by norleucine, isoleucine, methionine-sulfoxide and methionine-sulfone resulted in significant decrease of receptor affinity (IC(50) between 9.9 and 1,195 nmol/L). All cholecystokinin receptor affinities were >100 nmol/L. All (111)In-labelled radiopeptides showed receptor-specific internalisation. Serum mean-life times varied between 2.0 and 72.6 h, positively correlating with the number of Glu residues. All (111)In-labelled macrocyclic chelator conjugates showed higher tumour-to-kidney ratios after 24 h (0.37-0.99) compared to (111)In-DTPA-minigastrin 0 (0.05). Tumour wash out between 4 and 24 h was low. Imaging studies confirmed receptor-specific blocking of the tumour uptake. CONCLUSIONS: Reducing the number of glutamates increased tumour-to-kidney ratio but resulted in lower metabolic stability. The properties of the macrocyclic chelator-bearing derivatives make them potentially suitable for clinical purposes.

Elevated levels of placental growth factor represent an adaptive host response in sepsis

Recently, we demonstrated that circulating levels of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) are increased in sepsis (Yano, K., P.C. Liaw, J.M. Mullington, S.C. Shih, H. Okada, N. Bodyak, P.M. Kang, L. Toltl, B. Belikoff, J. Buras, et al. 2006. J. Exp. Med. 203:1447-1458). Moreover, enhanced VEGF/Flk-1 signaling was shown to contribute to sepsis morbidity and mortality. We tested the hypothesis that PlGF also contributes to sepsis outcome. In mouse models of endotoxemia and cecal ligation puncture, the genetic absence of PlGF or the systemic administration of neutralizing anti-PlGF antibodies resulted in higher mortality compared with wild-type or immunoglobulin G-injected controls, respectively. The increased mortality associated with genetic deficiency of PlGF was reversed by adenovirus (Ad)-mediated overexpression of PlGF. In the endotoxemia model, PlGF deficiency was associated with elevated circulating levels of VEGF, induction of VEGF expression in the liver, impaired cardiac function, and organ-specific accentuation of barrier dysfunction and inflammation. Mortality of endotoxemic PlGF-deficient mice was increased by Ad-mediated overexpression of VEGF and was blocked by expression of soluble Flt-1. Collectively, these data suggest that up-regulation of PlGF in sepsis is an adaptive host response that exerts its benefit, at least in part, by attenuating VEGF signaling.

[Lung volume reduction in severe emphysema]

BACKGROUND: Lung volume reduction (LVR) surgery is an effective and organ-preserving treatment option for patients suffering from severe dyspnea due to endstage emphysema. METHOD: Resection of functionally inactive lung parenchyma reduces over-inflation and restores the elastic recoil of the lungs. Thus it results in improvement of dyspnea, mobility and pulmonary function. Patient selection is crucial. Of simliar importance is pulmonary rehabilitation, as well as sufficient expertise in the treatment of endstage chronic respiratory failure. RESULTS AND CONCLUSION: The in-hospital morbidity and mortality after LVR are acceptable (0 to 5%) and the good results seem to last at least 18 to 24 months. LVR can be offered to selected patients either as an alternative or as bridge to lung transplantation.

Rapid estimation of cartilage T2 based on double echo at steady state (DESS) with 3 Tesla

The double-echo-steady-state (DESS) sequence generates two signal echoes that are characterized by a different contrast behavior. Based on these two contrasts, the underlying T2 can be calculated. For a flip-angle of 90 degrees , the calculated T2 becomes independent of T1, but with very low signal-to-noise ratio. In the present study, the estimation of cartilage T2, based on DESS with a reduced flip-angle, was investigated, with the goal of optimizing SNR, and simultaneously minimizing the error in T2. This approach was validated in phantoms and on volunteers. T2 estimations based on DESS at different flip-angles were compared with standard multiecho, spin-echo T2. Furthermore, DESS-T2 estimations were used in a volunteer and in an initial study on patients after cartilage repair of the knee. A flip-angle of 33 degrees was the best compromise for the combination of DESS-T2 mapping and morphological imaging. For this flip angle, the Pearson correlation was 0.993 in the phantom study (approximately 20% relative difference between SE-T2 and DESS-T2); and varied between 0.429 and 0.514 in the volunteer study. Measurements in patients showed comparable results for both techniques with regard to zonal assessment. This DESS-T2 approach represents an opportunity to combine morphological and quantitative cartilage MRI in a rapid one-step examination.

Coronary artery disease is common in asymptomatic patients with signs of myocardial ischemia

BACKGROUND: The incidence of coronary artery disease (CAD) in totally asymptomatic patients with myocardial ischemia during stress testing is unknown. METHODS: 54 patients with asymptomatic myocardial ischemia participated in the Swiss Interventional Study on Silent Ischemia type I (SWISSI I). Asymptomatic myocardial ischemia was verified by bicycle ergometry and stress imaging (echocardiography or scintigraphy). Findings from coronary angiographies in the course of the study constituted the main outcome. RESULTS: Of the 54 study participants, 29 patients (53.7%) underwent coronary angiography. CAD was found in 27 of 29 patients (93.1%). In those 27 patients with CAD, 9 patients (33.3%) suffered from single vessel disease, 9 patients (33.3%) from two vessel disease, and 9 patients (33.3%) from triple vessel disease. Two patients showed left main coronary artery stenosis. CONCLUSION: This study shows a high incidence of relevant CAD among totally asymptomatic patients with myocardial ischemia during stress testing. Previously healthy subjects with exercise-induced ST-segment depression at check-up examinations, even if asymptomatic, should have further diagnostic evaluation.

Bilateral malformation of maxillary third molars

A case of bilateral compound odontomas in the region of the third molars in the maxilla is reported. The differential diagnosis for this case is discussed.

Whole-body vibration dosage alters leg blood flow

The effect of whole-body vibration dosage on leg blood flow was investigated. Nine healthy young adult males completed a set of 14 random vibration and non-vibration exercise bouts whilst squatting on a Galileo 900 plate. Six vibration frequencies ranging from 5 to 30 Hz (5 Hz increments) were used in combination with a 2.5 mm and 4.5 mm amplitude to produce twelve 1-min vibration bouts. Subjects also completed two 1-min bouts where no vibration was applied. Systolic and diastolic diameters of the common femoral artery and blood cell velocity were measured by an echo Doppler ultrasound in a standing or rest condition prior to the bouts and during and after each bout. Repeated measures MANOVAs were used in the statistical analysis. Compared with the standing condition, the exercise bouts produced a four-fold increase in mean blood cell velocity (P<0.001) and a two-fold increase in peak blood cell velocity (P<0.001). Compared to the non-vibration bouts, frequencies of 10-30 Hz increased mean blood cell velocity by approximately 33% (P<0.01) whereas 20-30 Hz increased peak blood cell velocity by approximately 27% (P<0.01). Amplitude was additive to frequency but only achieved significance at 30 Hz (P<0.05). Compared with the standing condition, squatting alone produced significant increases in mean and peak blood cell velocity (P<0.001). The results show leg blood flow increased during the squat or non-vibration bouts and systematically increased with frequency in the vibration bouts.

Characterization of microfluidic systems with Doppler optical coherence tomography

Doppler Optical Coherence Tomography (DOCT) is a biomedical imaging technique that allows simultaneous structural imaging and flow monitoring inside biological tissues and materials with spatial resolution in the micrometer scale. It has recently been applied to the characterization of microfluidic systems. Structural and flow imaging of novel microfluidics platforms for cytotoxicologic applications were obtained with a real-time, Near Infrared Spectral Domain DOCT system. Characteristics such as flow homogeneity in the chamber, which is one of the most important parameters for cell culture, are investigated. OCT and DOCT images were used to monitor flow inside a specific platform that is based on microchannel division for a better flow homogeneity. In particular, the evolution of flow profile at the transition between the microchannel structure and the chamber is studied.

Dose optimization approach to fast X-ray microtomography of the lung alveoli

A basic prerequisite for in vivo X-ray imaging of the lung is the exact determination of radiation dose. Achieving resolutions of the order of micrometres may become particularly challenging owing to increased dose, which in the worst case can be lethal for the imaged animal model. A framework for linking image quality to radiation dose in order to optimize experimental parameters with respect to dose reduction is presented. The approach may find application for current and future in vivo studies to facilitate proper experiment planning and radiation risk assessment on the one hand and exploit imaging capabilities on the other.

Microcirculation in hypertensive patients

Regardless of the mechanisms that initiate the increase in blood pressure, functional and structural changes in the systemic vasculature are the final result of long-standing hypertension. These changes can occur in the macro- but also in the microvasculature. The supply of the tissues with oxygen, nutrients, and metabolites occurs almost exclusively in the microcirculation (which comprises resistance arterioles, capillaries and venules), and an adequate perfusion via the microcirculatory network is essential for the integrity of tissue and organ function. This review focuses on results from clinical studies in hypertensive patients, which have been performed in close cooperation with different clinical groups over the last three decades. Intravital microscopy was used to study skin microcirculation, microcatheters for the analysis of skeletal muscle microcirculation, the slit lamp for conjunctival microcirculation and the laser scanning ophthalmoscope for the measurement of the retinal capillary network. The first changes of the normal microcirculation can be found in about 93% of patients with essential hypertension, long before organ dysfunctions become clinically manifest. The earliest disorders were found in skin capillaries and thereafter in the retina and the skeletal muscle. In general, the disorders in the different areas were clearly correlated. While capillary rarefaction occurred mainly in the retina and the conjunctiva bulbi, in skin capillaries morphological changes were rare. A significant decrease of capillary erythrocyte velocities under resting conditions together with a marked damping of the postischemic hyperemia was found, both correlating with the duration of hypertension or WHO stage or the fundus hypertonicus stage. Also the mean oxygen tension in the skeletal muscle was correlated with the state of the disease. These data show that the microcirculatory disorders in hypertension are systemic and are hallmarks of the long-term complications of hypertension. There is now a large body of evidence that microvascular changes occur very early and may be important in their pathogenesis and progression.

Approximate decoding approaches for network coded correlated data

This paper considers a framework where data from correlated sources are transmitted with the help of network coding in ad hoc network topologies. The correlated data are encoded independently at sensors and network coding is employed in the intermediate nodes in order to improve the data delivery performance. In such settings, we focus on the problem of reconstructing the sources at decoder when perfect decoding is not possible due to losses or bandwidth variations. We show that the source data similarity can be used at decoder to permit decoding based on a novel and simple approximate decoding scheme. We analyze the influence of the network coding parameters and in particular the size of finite coding fields on the decoding performance. We further determine the optimal field size that maximizes the expected decoding performance as a trade-off between information loss incurred by limiting the resolution of the source data and the error probability in the reconstructed data. Moreover, we show that the performance of the approximate decoding improves when the accuracy of the source model increases even with simple approximate decoding techniques. We provide illustrative examples showing how the proposed algorithm can be deployed in sensor networks and distributed imaging applications.

Successful surgical resection in non-lesional operculo-insular epilepsy without intracranial monitoring

Pre-operative assessment and surgical management of patients with non-lesional extratemporal epilepsy remain challenging due to a lack of precise localisation of the epileptic zone. In most cases, invasive recording with depth or subdural electrodes is required. Here, we describe the case of 6.5-year-old girl who underwent comprehensive non-invasive phase I video-EEG investigation for drug-resistant epilepsy, including electric source and nuclear imaging. Left operculo-insular epilepsy was diagnosed. Post-operatively, she developed aphasia which resolved within one year, corroborating the notion of enhanced language plasticity in children. The patient remained seizure-free for more than three years.

Multiple osteosclerotic lesions in an Iron Age skull from Switzerland (320 - 250 BC) - An unusual case

The single Hochdorf burial was found in 1887 during construction work in the Canton of Lucerne, Switzerland. It dates from between 320 and 250 BC. The calvarium, the left half of the pelvis and the left femur were preserved. The finding shows an unusual bony alteration of the skull. The aim of this study was to obtain a differential diagnosis and to examine the skull using various methods. Sex and age were determined anthropologically. Radiological examinations were performed with plain X-ray imaging and a multislice computed tomography (CT) scanner. For histological analysis, samples of the lesion were taken. The pathological processing included staining after fixation, decalcification, and paraffin embedding. Hard-cut sections were also prepared. The individual was female. The age at death was between 30 and 50 years. There is an intensely calcified bone proliferation at the right side of the os frontalis. Plain X-ray and CT imaging showed a large sclerotic lesion in the area of the right temple with a partly bulging appearance. The inner boundary of the lesion shows multi-edged irregularities. There is a diffuse thickening of the right side. In the left skull vault, there is a mix of sclerotic areas and areas which appear to be normal with a clear differentiation between tabula interna, diploë and tabula externa. Histology showed mature organised bone tissue. Radiological and histological findings favour a benign condition. Differential diagnoses comprise osteomas which may occur, for example, in the setting of hereditary adenomatous polyposis coli related to Gardner syndrome.