Determining heart muscle perfusion by magnetic resonance tomography progressing to clinical application

Magnetic resonance imaging detects the flow of contrast-enhanced blood and even allows the quantitative assessment of myocardial perfusion. The clinical application of this method is being held back by the difficulties in image evaluation and the limitation of standard techniques to the acquisition of a single slice per heart beat cycle. Recent developments in scanner hardware as well as in image acquisition techniques open up the possibility of assessing myocardial perfusion over the entire heart with a spatial resolution in the range of 2 mm. As an example of such a new scanning strategy, a segmented gradient-echo recalled echo planar imaging sequence with preceding saturation is discussed and results in a patient with an infarction are presented. The clinical use of perfusion assessment covering the entire heart for the diagnosis of coronary artery disease is enhanced by the flexibility of magnetic resonance imaging for the assessment of functional cardiac parameters.     

Anticoagulants for venous thrombosis

The anticoagulant agents heparin and warfarin were introduced before the era of randomised clinical trials. As a result, the indications, dosages and monitoring techniques of these drugs have undergone re-evaluation in multiple clinical trials in the past years. Low molecular weight heparin has been developed, which has led to new approaches in anticoagulant management. Current levels of laboratory, pharmacology and clinical knowledge in the treatment of venous thromboembolism are discussed.     

Identification of common and distinct residues involved in the interaction of alphai2 and alphas with adenylyl cyclase

The G protein alpha subunits, alphas and alphai2, have stimulatory and inhibitory effects, respectively, on a common effector protein, adenylyl cyclase. These effects require a GTP-dependent conformational change that involves three alpha subunit regions (Switches I-III). alphas residues in three adjacent loops, including Switch II, specify activation of adenylyl cyclase. The adenylyl cyclase-specifying region of alphai2 is located within a 78-residue segment that includes two of these loops but none of the conformational switch regions. We have used an alanine-scanning mutagenesis approach within Switches I-III and the 78-residue segment of alphai2 to identify residues required for inhibition of adenylyl cyclase. We found a cluster of conserved residues in Switch II in which substitutions cause major losses in the abilities of both alphai2 and alphas to modulate adenylyl cyclase activity but do not affect alpha subunit expression or the GTP-induced conformational change. We also found two regions within the 78-residue segment of alphai2 in which substitutions reduce the ability of alphai2 to inhibit adenylyl cyclase, one of which corresponds to an effector-activating region of alphas. Thus, both alphai2 and alphas interact with adenylyl cyclase using: 1) conserved Switch II residues that communicate the conformational state of the alpha subunit and 2) divergent residues that specify particular effectors and the nature of their modulation.     

Biodistribution of 125I-labeled des(1-3) insulin-like growth factor I in tumor-bearing nude mice and its in vitro catabolism

Insulin-like growth factor I (IGF-I) is a potent mitogen for many tumor cell lines, and IGF-I receptors are overexpressed in many tumors. Specific IGF-binding proteins (IGFBPs) modulate the interaction of IGF and its receptors. Consequently, radiolabeled IGF-I has been considered for tumor imaging. In the present study, we investigated the biodistribution of 125I-labeled des(1-3)IGF-I, a truncated analogue of IGF-I, in tumor-bearing nude mice. Additional studies included its catabolism by tumor cells in vitro and its binding to serum IGFBPs in vivo in nude mice. We also compared groups that were and were not injected with unlabeled peptide analogue. Our data showed that 125I-labeled des(1-3)IGF-I catabolized very fast, with a rapid appearance of nonprecipitable iodine, when incubated at 37 degrees C, but it was not catabolized at 4 degrees C incubation. 125I-labeled des(1-3)IGF-I was bound to serum-binding proteins, mainly in a complex with a molecular weight of M(r) 150,000. The uptake of radioactivity in normal tissues decreased quickly with time, particularly in the kidneys. In mice receiving higher doses of des(1-3)IGF-I, the radioactivity in all normal tissues was lower than in the mice with no carrier-added des(1-3)IGF-I, except in the stomach and spleen. These data suggest that 125I-labeled des(1-3)IGF-I is rapidly internalized after binding to the IGF receptor and is rapidly catabolized with release of breakdown products. Lower specific activity of 125I-labeled des(1-3)IGF-I resulted in altered biodistribution, including faster blood clearance and higher tumor uptake, by decreasing the formation of complexes with IGFBPs.     

Ozone-induced inflammation is attenuated with multiday exposure

It is well known that ozone (O3) causes acute lung inflammation. What is not known is whether there is progression of the inflammatory response in humans with repeated short-term exposures. Our study was designed to test the hypothesis that repeated exposures to a high-ambient concentration of O3 (0.2 ppm) over several days would cause more inflammation than a single exposure. Fifteen healthy volunteers were exposed in random fashion to 0.2 ppm ozone for 4 h on a single day and to 0.2 ppm O3 for 4 h on 4 consecutive days while exercising moderately for 30 min of each hour. Pulmonary function tests were obtained immediately before and after each 4-h exposure. Bronchoscopy was performed 20 h after the completion of each exposure arm to obtain bronchoalveolar lavage (BAL) for measurement of markers of inflammation. Our results show initial progression followed by attenuation of the acute physiologic response to O3 with repeated daily exposures. We found a significant difference in percent change in FEV1, FVC, and specific airway resistance (SRaw) across the single-day exposure when compared with the change across Day 4 of the 4-d exposure. Bronchial fraction (the first 15 ml of BAL return) and BAL were analyzed for the following end points: total and differential cell counts, total protein, lactate dehydrogenase (LDH), fibronectin, interleukin-6 (IL-6), interleukin-8 (IL-8), and granulocyte-macrophage colony-stimulating factor (GM-CSF). In the bronchial fraction the number of polymorphonuclear cells (PMN)s and fibronectin concentration were significantly decreased after 4-d exposure compared with single-day exposure. In BAL, significant decreases in the number of PMNs, fibronectin, and IL-6 were found after 4-d exposure versus single-day exposure. These results suggest that there is attenuation of the O3-induced inflammatory response in both proximal airways and distal lung with repeated daily exposures.     

The role of vasopressin in modulating circadian rhythm responses to phase shifts

Telemetered body temperature (BT), heart rate (HR), and motor activity (AC) data were collected in vasopressin-containing, Long-Evans (LE) and vasopressin-deficient, Brattleboro (DI) rats. In Experiment 1, the rats were initially exposed to a 12 h/12 h light/dark cycle under ad-libitum feeding and were then subjected to either a phase-advance or phase-delay shift of 6 h. After the phase-advance shift, neither strain adapted; however, after the phase-delay shift, both strains adapted rapidly. In Experiment 2, the animals were subjected to either a nocturnal or a diurnal restricted-feeding paradigm and were then exposed to either a phase-advance or phase-delay shift with synchronized feeding. In the nocturnal restricted-feeding paradigms, both strains rapidly adapted to both shifts. Concerning diurnal restricted-feeding, DI animals readily entrained to the presentation of food in both shifts; whereas, LE animals exhibited a confused rhythmicity. In Experiment 3, animals were subjected to a phase-advance shift, while the time of feeding was held constant. Following the shift, LE animals responded to the onset of the dark at the new time; yet, were still influenced by the presentation of food. The DI animals maintained the preshift circadian pattern and continued to be dominated by the presentation of food. These experiments indicate that circadian rhythms of LE animals are dominated by the light entrainable oscillator (LEO) in ad-libitum feeding and by both the LEO and food entrainable oscillator (FEO) in restricted-feeding. On the other hand, the circadian rhythms of DI animals are dominated by the FEO unless food is provided ad-libitum. The demonstrated role of vasopressin in synchronizing circadian rhythms to the LEO may be of significance in understanding human circadian rhythm disturbances, such as jet lag.     

Detecting inconsistency in biological molecular databases using ontologies

The rapid growth of life science databases demands the fusion of knowledge from heterogeneous databases to answer complex biological questions. The discrepancies in nomenclature, various schemas and incompatible formats of biological databases, however, result in a significant lack of interoperability among databases. Therefore, data preparation is a key prerequisite for biological database mining. Integrating diverse biological molecular databases is an essential action to cope with the heterogeneity of biological databases and guarantee efficient data mining. However, the inconsistency in biological databases is a key issue for data integration. This paper proposes a framework to detect the inconsistency in biological databases using ontologies. A numeric estimate is provided to measure the inconsistency and identify those biological databases that are appropriate for further mining applications. This aids in enhancing the quality of databases and guaranteeing accurate and efficient mining of biological databases.     

Gold nanosphere-antibody conjugates for hyperthermal therapeutic applications

Gold nanoparticles can be conjugated with antibodies or other proteins, and the resulting composite particles will selectively attach to various kinds of biological material. Although exploitation of this for staining microscopy specimens is well known, there has recently been interest in attaching gold nanoparticles tolive cells for therapeutic reasons. One motivation is that gold nanoparticles display a strong plasmon resonance with light, which can be exploited in principle for an ‘in vivo’ photothermal therapy. The treatment of cancer by this technique has recently received attention by others, but here we show how gold nanoparticlebased therapies can be developed to target live macrophage cells. We have employed ‘active targeting’, a scheme in which gold nanoparticles are functionalised with an antibody specific to the target macrophage cell. We describe how to prepare the conjugated particles, demonstrate that they will selectively attach ‘in vitro’ to their target macrophage cell but not to a non-target cell type and show that their presence renders the target cell susceptible to destruction by a low power laser.     

Effect of granulocyte macrophage-colony stimulating factor on Langerhans cells in normal and healthy atopic subjects

We conducted a reproducibility study of the alternating breath test (ABT) for assessing peripheral chemoreceptor function in infants. The ABT delivers a rapid hypoxic stimulus to the peripheral chemoreceptors with breath-by-breath alternations of the inspired O2 fraction. The reproducibility of the ABT performed on a single occasion has not been extensively studied in infants. Eight unsedated infants (postnatal age, 22+/-19 d; weight, 3.2+/-0.4 kg) were studied in standardized conditions: morning naps, supine position, room temperature 22-24 degrees C, quiet sleep, and face mask attached to a pneumotachograph connected to a two-way electric valve. Respiratory gases were analyzed by mass spectrometer. Two ABTs were performed. Each included a 2-min control run (CR) alternating between air and air, and a 2-min test run (TR) alternating between air and 0.15 O2. After data preprocessing, on average 13+/-11% of the data were rejected because of sighs, apneas, and cycles with the fraction of inspired oxygen above 0.17. Using the remaining validated breaths, the response to ABT was calculated for the CR, for all breaths in the TR (TR(T)), and for the first 50 breaths of the TR (TR50). During the ABTs oxygen saturation did not fall below 96%, and heart rate was not affected. Inspired and end-tidal CO2 fractions remained unchanged during the ABTs. FetO2 oscillated in TRs at a lower values than in CRs and differed significantly between breaths of air and hypoxic breaths of TRs. All infants responded to ABT with percentage alternation coefficients of TRs significantly greater than those of CRs for all respiratory variables. The values of the coefficients were not significantly different between both ABT, and between TR50 and TR(T). The greatest values of the coefficients were for timing variables compared with flows and volume. We conclude that the ABT is a reproducible test of peripheral chemoreceptor function under standardized conditions.