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The current gold standard of identifying yield points from stress strain curves involves identifying a significant change in elastic modulus or using an arbitrary strain offset (0.1%, 0.2% or 2%) of the elastic modulus. The development of the offset method was due to the ambiguous definitions of yield point. The result is an arbitrary yield point which is prone to various human-related errors. This article presents a method to identify a unique yield point consistently using energy absorbed by the material up to first peak stress. This mathematical process idealises the stress strain curve for easy identification of the yield point. The method was tested on three possible types of stress strain curves with either a distinct yield point or without a distinct yield point (with peak stress closer to elastic region or closer to fracture). The yield points obtained by the proposed method are shown to be robust, consistent and unaffected by variations of the stress strain curves and data noises.

Purpose To evaluate factors associated with response to intravitreal bevacizumab (IVB) and intravitreal triamcinolone acetonide (IVTA) in diabetic macular edema (DME).Methods Ninety-one eyes of 88 patients diagnosed with DME were enrolled in this retrospective chart review. Group 1 included eyes that showed good response to IVB. Group 2 included eyes that did not respond to IVB but responded to IVTA. Group 3 included eyes that responded to neither. Clinical factors, HbA1c, and optical coherence tomography (OCT) findings including patterns of macular edema were compared among the 3 groups.Results A total of 44, 27, and 20 eyes were included in groups 1, 2, and 3, respectively. HbA1c was higher in group 3 than in the other groups. Proportion of full (combination of all patterns) type edema was higher in group 3 than in the other 2 groups. In group 1, the proportion of sponge-like diffuse retinal thickening type was higher and cystoid macular edema type was lower than in the other groups.Conclusions The degree of diabetic control and morphologic subtypes with OCT should be considered to better predict the prognosis after treatment in DME.

An integrated finite element analysis–evolutionary algorithm simulation approach is proposed in this work to model the density characteristics of the three-dimensional printing, specifically for selective laser sintering process. The approach consists of modeling sintering phenomenon by finite element analysis simulation, which is further fed into an evolutionary algorithm cluster comprising genetic programming. The integrated approach is useful to model the functional relationship of density characteristic of selective laser sintering–fabricated components with respect to laser power, scan velocity and scan spacing. Performance of the proposed model is evaluated against the actual results obtained from the literature. We find that our proposed finite element analysis–evolutionary algorithm model is able to model the selective laser sintering process very well, which can be used to complement the analytically and experimentally obtained results. For the validation of the robustness of the model, we also conducted sensitivity and parametric analyses and investigated the specific influence, and variation, of each of the input process parameters on the density of the selective laser sintering–fabricated component. It was found that scan spacing has the least influence, whereas scan velocity has the highest influence on the density of the selective laser sintering–fabricated component. Non-linear relationships unveiled between the process parameters highlight the capability of the model in simulating the density characteristic of the complex selective laser sintering process in uncertain input conditions.

The approach of probability collectives (PC) in the collective intelligence (COIN) framework is one of the emerging artificial intelligence tools dealing with the complex problems in a distributed way. It decomposes the entire system into subsystems and treats them as a multi-agent system (MAS). These agents iteratively select their strategies to optimise their local goals which make the system to achieve the global optimum. This paper demonstrates the ability of PC solving discrete as well as mixed variable problems. The approach has produced competent and sufficiently robust results with comparatively higher computational cost. The associated strengths, weaknesses and possible real world extensions are also discussed.

Rapid prototyping (RP) is a promising product development technology due to its unique characteristic of fabricating functional products timely and efficiently. Fused deposition modelling (FDM) process based on RP technology is used in industries for prototype fabrication and its properties testing. The properties of the RP fabricated prototypes such as wear strength, tensile strength, dimensional accuracy, etc. depends on the parameter settings of the RP machines. For selecting the appropriate parameter settings, various mathematical models developed based on physics and data can be formulated. In the present work, we introduced an ensemble method of genetic programming (GP) and artificial neural network for formulating a model for predicting the wear strength of the FDM fabricated prototype. The results indicate that ensemble model have performed better than that of the standardised GP, which may be then used by experts for optimising the performance of the FDM process.

The National Aeronautics and Space Administration Global Modeling and Assimilation Office (NASA/GMAO) observing system simulation experiment (OSSE) framework is used to explore the response of analysis error and forecast skill to observation quality. In an OSSE, synthetic observations may be created that have much smaller error than real observations, and precisely quantified error may be applied to these synthetic observations. Three experiments are performed in which synthetic observations with magnitudes of applied observation error that vary from zero to twice the estimated realistic error are ingested into the Goddard Earth Observing System Model (GEOS‐5) with Gridpoint Statistical Interpolation (GSI) data assimilation for a 1 month period representing July. The analysis increment and observation innovation are strongly impacted by observation error, with much larger variances for increased observation error. The analysis quality is degraded by increased observation error, but the change in root‐mean‐square error of the analysis state is small relative to the total analysis error. Surprisingly, in the 120 h forecast, increased observation error only yields a slight decline in forecast skill in the extratropics and no discernible degradation of forecast skill in the tropics. Analysis increments are strongly impacted by observation error.Analysis quality is modestly impacted by observation error.Forecast skill is minimally impacted by observation error.

Torsional vibration control can be crucial for applications of smart materials and structures. In this paper, the problem of topology optimization of collocated piezoelectric sensor/actuator (S/A) pairs for torsional vibration control of a laminated composite plate is directly addressed. Both isotropic and anisotropic PZT S/A pairs are considered and it is highlighted that the torsional vibration can be more effectively damped out by employing the topological optimal design of the S/A pairs than by using the conventional designs. To implement this topology optimization, a genetic algorithm (GA) based on a bit-array representation method is presented and a finite element (FE) simulation model based on the first-order shear theory and an output feedback control law is adopted. Numerical experiments are used to verify the present algorithm and show that the present optimal topology design can achieve significantly better active damping effect than the one using a continuously distributed PZT S/A pair, which was often adopted by many other researchers. Together with the progress in laser cutting and micromachining techniques, topology optimization of piezoelectric sensors and/or actuators would be promising in active vibration control of smart structures.

Autism is a disorder of neurodevelopment resulting in pervasive abnormalities in social interaction and communication, repetitive behaviours and restricted interests. There is evidence for functional abnormalities and metabolic dysconnectivity in ‘social brain’ circuitry in this condition, but its structural basis has proved difficult to establish reliably. Explanations for this include replication difficulties inherent in ‘region of interest’ approaches usually adopted, and variable inclusion criteria for subjects across the autism spectrum. Moreover, despite a consensus that autism probably affects widely distributed brain regions, the issue of anatomical connectivity has received little attention. Therefore, we planned a fully automated voxel-based whole brain volumetric analysis in children with autism and normal IQ. We predicted that brain structural changes would be similar to those previously shown in adults with autism spectrum disorder and that a correlation analysis would suggest structural dysconnectivity. We included 17 stringently diagnosed children with autism and 17 age-matched controls. All children had IQ >80. Using Brain Activation and Morphological Mapping (BAMM) software, we measured global brain and tissue class volumes and mapped regional grey and white matter differences across the whole brain. With the expectation that volumes of interconnected regions correlate positively, we carried out a preliminary exploration of ‘connectivity’ in autism by comparing the nature of inter-regional grey matter volume correlations with control. Children with autism had a significant reduction in total grey matter volume and significant increase in CSF volume. They had significant localized grey matter reductions within fronto-striatal and parietal networks similar to findings in our previous study, and additional decreases in ventral and superior temporal grey matter. White matter was reduced in the cerebellum, left internal capsule and fornices. Correlation analysis revealed significantly more numerous and more positive grey matter volumetric correlations in controls compared with children with autism. Thus, using similar diagnostic criteria and image analysis methods in otherwise healthy populations with an autistic spectrum disorder from different countries, cultures and age groups, we report a number of consistent findings. Taken together, our data suggest abnormalities in the anatomy and connectivity of limbic–striatal ‘social’ brain systems which may contribute to the brain metabolic differences and behavioural phenotype in autism.

Nucleotide sequencing after TA cloning of the amplicon of the almost-full length recA gene from three strains of UPTC (A1, A2, and A3) isolated from seagulls in Northern Ireland, the phenotypical and genotypical characteristics of which have been demonstrated to be indistinguishable, clarified nucleotide differences at three nucleotide positions among the three strains. In conclusion, the nucleotide sequences of the recA gene were found to discriminate among the three strains of UPTC, A1, A2, and A3, which are indistinguishable phenotypically and genotypically. Thus, the present study strongly suggests that nucleotide sequence data of the amplicon of a suitable gene or region could aid in discriminating among isolates of the UPTC group, which are indis- tinguishable phenotypically and genotypically. (© 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Computer simulation methods spanning several temporal and spatial scales are reviewed, focusing on their applications on the neuromuscular synapse. Quantum mechanics treats the enzymatic catalysis of neurotransmitters on the picometer scale. Molecular dynamics reveals conformational changes of the enzyme acetylcholinesterase for nanoseconds. Brownian dynamics follow the substrate molecule in its diffusion on the microsecond level. Methods such as finite elements describe the diffusion of neurotransmitters as a changing concentration continuum in the synapse. Promising directions for future research include integration of methods on several scales, and applying these methods to the acetylcholine receptor.

Molecular dynamics simulations are leading to a deeper understanding of the activity of the enzyme acetylcholinesterase. Simulations have shown how breathing motions in the enzyme facilitate the displacement of substrate from the surface of the enzyme to the buried active site. The most recent work points to the complex and spatially extensive nature of such motions and suggests possible modes of regulation of the activity of the enzyme.

A series of 4-aryl substituted 7-hydroxy-flavones were prepared using the three-step Baker-Venka-taraman synthesis in good overall yields. The flavones were all evaluated in vitrofor inhibitory activity against aromatase (P450AROM/ CYP19), using human placental microsomes, and for inhibitory activity against 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD-1) using human placental cytosol. The phenyl, 4-fluoro-phenyl and 4-bromo-phenyl derivatives displayed moderate inhibitory activity against P450AROM(IC5017.2, 13.5 and 10.1 μM, respectively), none of the flavones, including the standard genistein, displayed any inhibitory activity against 17β-HSD type 1 at 100 μM concentration.

Overexpression of ErbB2 has been found in approximately 25–30% of human breast cancers and has been shown to render the cancer cells more resistant to chemotherapy. However, it is not clear whether ErbB2 overexpression renders the cells more resistant to specific anti-cancer drugs or renders the cells more resistant to a broad range of anti-cancer drugs. It is not clear how the function of ErbB2 in drug resistance is related to expression and activation of the other ErbB receptors. In this communication, we showed that several breast cancer cell lines including BT20, BT474, MCF-7, MDA-MB-453, and SKBR-3 cells had a similar pattern of resistance to a broad range of anti-cancer drugs including 5-Fluorouracil, Cytoxan, Doxorubincin, Taxol, and Vinorelbin, suggesting a mechanism of multidrug resistance. High expression of P-glycoprotein and the ErbB receptors contribute to drug resistance of these breast cancer cells; however, overexpression of ErbB2 alone is not a major factor in determining drug resistance. To further determine the role of the ErbB receptors in drug resistance, we selected various NIH 3T3 cell lines that specifically expressed EGF receptor (EGFR), ErbB2, ErbB3, EGFR/ErbB2, EGFR/ErbB3, or ErbB2/ErbB3. A cytotoxicity assay showed that expression of ErbB2 alone did not significantly enhance drug resistance, whereas coexpression of either EGFR or ErbB3 with ErbB2 significantly enhanced drug resistance. Moreover, ErbB2 was highly phosphorylated in NIH 3T3 cells that coexpress ErbB2 with either EGFR or ErbB3, but not in NIH 3T3 cells that express ErbB2 alone. Together, our results suggest that coexpression of EGFR or ErbB3 with ErbB2 induces high phosphorylation of ErbB2 and renders the cells more resistant to various anti-cancer drugs.

In the course of our studies on retinoic acid receptor (RAR) agonists, we have designed and synthesized a series of benzofuran and benzothiophene derivatives. Some of these compounds (1a,b,e,f,j) markedly inhibited LPS-induced B-lymphocyte proliferation and exerted RARα selectivity. One of them, 4-[5-(4,7-dimethylbenzofuran-2-yl)pyrrol-2-yl]benzoic acid (1b), when orally administered significantly inhibited mouse antibody production and delayed type hypersensitivity (DTH) responses from a dose of 0.1 mg/kg.

In the course of our studies on retinoic acid receptor (RAR) agonists, we have designed and synthesized a series of quinoxaline derivatives. One of them, 4-[5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-quinoxalinyl)-1H-2-pyrrolyl]benzoic acid (3a), which possesses a 2,5-disubstituted pyrrole moiety, showed selectivity for the RARα receptor and exerted highly potent cell-differentiating activity on HL-60 cells.

Epidermal growth factor (EGF) stimulates the homodimerization of EGF receptor (EGFR) and the heterodimerization of EGFR and ErbB2. The EGFR homodimers are quickly endocytosed after EGF stimulation as a means of down-regulation. However, the results from experiments on the ability of ErbB2 to undergo ligand-induced endocytosis are very controversial. It is unclear how the EGFR–ErbB2 heterodimers might behave. In this research, we showed by subcellular fractionation, immunoprecipitation, Western blotting, indirect immunofluorescence, and microinjection that, in the four breast cancer cell lines MDA453, SKBR3, BT474, and BT20, the EGFR–ErbB2 heterodimerization levels were positively correlated with the ratio of ErbB2/EGFR expression levels. ErbB2 was not endocytosed in response to EGF stimulation. Moreover, in MDA453, SKBR3, and BT474 cells, which have very high levels of EGFR–ErbB2 heterodimerization, EGF-induced EGFR endocytosis was greatly inhibited compared with that in BT20 cells, which have a very low level of EGFR–ErbB2 heterodimerization. Microinjection of an ErbB2 expression plasmid into BT20 cells significantly inhibited EGF-stimulated EGFR endocytosis. Coexpression of ErbB2 with EGFR in 293T cells also significantly inhibited EGF-stimulated EGFR endocytosis. EGF did not stimulate the endocytosis of ectopically expressed ErbB2 in BT20 and 293T cells. These results indicate that ErbB2 and the EGFR–ErbB2 heterodimers are impaired in EGF-induced endocytosis. Moreover, when expressed in BT20 cells by microinjection, a chimeric receptor composed of the ErbB2 extracellular domain and the EGFR intracellular domain underwent normal endocytosis in response to EGF, and this chimera did not block EGF-induced EGFR endocytosis. Thus, the endocytosis deficiency of ErbB2 is due to the sequence of its intracellular domain.

The cytotoxicity of Taxol represents both inhibition of cell proliferation and cell death. The drug blocked cells in the G2/M phase of the cell cycle. It has also been reported that Taxol induced cell apoptosis; however, the mode of action of Taxol is far from clear. In this communication, the cytotoxicity of Taxol in various breast cancer cell lines was carefully examined. We showed that Taxol treatment induced a biphasic decrease of viable cells. While the first phase of decrease occurred over concentrations ranging from 0.005 to 0.05 μM and the second phase of decrease occurred at concentrations ranging from 5 to 50 μM, there was a plateau between these ranges. We determined that the biphasic response was due to two different mechanisms. In the lower concentration range (0.005–0.05 μM), Taxol stabilized the spindle during mitosis, thereby blocking mitosis. This mitotic block led to the inhibition of cell proliferation and the induction of apoptosis. In the higher concentration range (5–50 μM), Taxol mainly increased the polymerization of microtubule and stimulated the formation of microtubule bundles, which blocked entry into S phase. This inhibition of S phase entry led to the inhibition of cell proliferation and the induction of necrosis. These findings may have profound clinical implications.

A new separation process of saturated fatty acids (lauric acid−myristic acid) using crystallization from an aqueous ethanol solution has been examined. There were two vessels in this separation process:  an extraction vessel and a crystallization vessel. The fatty acids in the aqueous phase were first extracted from their organic phase (melt) in the extraction vessel. The fatty acids in the aqueous phase were continuously introduced to the crystallization vessel, and then the fatty acids were crystallized there. The crystals of the fatty acids were collected continuously above the aqueous phase in the crystallization vessel. In this process, the yield and the purity of the crystals over time were measured, and it was found that the purity of lauric acid increased unsteadily up to 0.98 mole fraction of lauric acid with an increase in the yield of the low yield range. The mole fraction of ethanol in the aqueous phase could be significant to control the relationship between the yield and the purity of the crystals. Three different mole fractions of lauric acid in the organic phase were used to be separated in this process. Moreover, we have considered the effective separations of this process, and the maximum yield and purity of the crystals have been estimated by a simple mass balance.

The imaging findings of focal intrahepatic extramedullary haematopoiesis (EMH) in a 51-year-old woman with beta-thalassaemia intermedia are described with particular reference to MRI and CT. Bone marrow colloid scintigraphy was unhelpful in confirming the diagnosis, which was made from fine needle aspiration. This is the first description of stellate scars occurring in an EMH lesion. A review of the radiological appearances of this rare condition is presented.

The ability of a series of antimalarial drugs to impair the metabolism of metoprolol in rat and man has been examined. Chloroquine was a potent inhibitor in rat liver microsomes (Kjvalue for metoprolol α-hydroxylation = 0.18 μM and for O-demethylation = 0.36 μM). The other antimalarial drugs also inhibited metoprolol oxidation. Quinine was similar to chloroquine in potency, while quinidine, primaquine and mefloquine were slightly less potent. Chloroquine also inhibited metoprolol oxidation in human liver microsomes, although it was about two orders of magnitude less potent than in the rat and the extent of impairment varied greatly between individual livers. Intraperitoneal administration of chloroquine to anaesthetized rats decreased the clearance of metoprolol (40 mg tartrate salt kg−1i.p.) to 54, 34, 20 and 26% of the control value at doses of 2.5, 4.0, 25 and 40 mg kg−1, respectively. We conclude that antimalarial treatment might have contributed to a previously reported difference in the metabolic pattern of metoprolol between Caucasians and Nigerians.

In order to enhance the resolution of the ultrasonic B-mode image, digital techniques for dynamic focusing and steering have been receiving a great deal of attention for a long time. In this paper, we present the theory and preliminary experimental results for a new architecture of a fully digital B-mode imaging system with this desired feature. The system employs the Pipelined-Sampled-Delay-Focusing (PSDF) scheme to eliminate the bulky memory addressing and interpolation circuits which are needed in conventional digital imaging systems. To reduce hardware requirements and the bandwidth required for digital processings, we describe an efficient method to generate the sampling clocks for dynamic focusing and steering and some modified bandwidth sampling techniques to reduce the sampling rate for signal digitization. Using these methods, it is possible to achieve dynamic focusing and steering in real-time sector imaging using a linear phased array.

In this paper, a new focusing method for ultrasonic annular array imaging systems is presented. The technique minimizes the lateral resolution for a specified sidelobe suppression over the depth of interest, using a nonspherical lens for line focusing in transmit in combination with continuous dynamic focusing in receive. For this purpose, an effective analysis model is developed for calculating the impulse response of an annulus with an arbitrarily-shaped lens in the whole imaging plane. Using this analysis method, an iterative technique is then applied to obtain an optimum transmit delay profile when continuous receive focusing is employed at all imaging points along the depth of view. The delay profile is optimum in the sense that the lateral beam width is minimized under a specified sidelobe suppression at three depths of the imaging field. The continuous receive focusing is realized in a new digital focusing system which enables arbitrary control of transmit time delays and dynamic focusing in the receive mode. In the proposed system, focusing is achieved by adjusting the sampling time for each array element according to the arrival time differences among array elements for a given focal point. Experimental results show the validity of the analysis model and the optimum lens design.

In this paper, we describe a new method of estimating the ultrasound attenuation coefficient of soft tissue based on the entropy difference between two adjacent envelope segments of narrowband ultrasound pulse echoes. Assuming uniform attenuation in the region under investigation, the attenuation is estimated by minimizing the difference of entropies in the two segments as the attenuation is continuously compensated for. The simulation and experimental results with a tissue equivalent (TE) phantom show that the proposed estimator is quite robust to receiver noise and requires considerably less data length as compared with conventional methods. At present, an experimental result with a TE phantom shows that a resolution of 10 mm × 10 mm can be attained with echoes from a depth of 3 cm using a 2.25 MHz transducer.

A numerical study is made of analytical differentiation (AD) and finite difference (FD) approaches to the computation of sensitivity derivatives required in shape design optimization problems. Based on the boundary element method for linear elastostatics, numerical solutions for response and sensitivity analysis are illustrated for the AD technique and the FD schemes with different step sizes. By solving the problem of an annular disc under internal pressure (for which analytical solutions are available), an indication of the absolute level of accuracy achievable by the FD procedure can be obtained. As there are advantages in using the FD technique for shape optimization, it is desirable to check its accuracy and effectiveness compared to the AD approach. An optimization problem based on the annular disc is then formulated and solved using the various analytical, AD and FD sensitivity values to show how the differing accuracies of the derivatives will affect the efficiency and performance of the optimization process, and whether the FD values used are sufficiently accurate for converging upon the correct optimum solution.

As part of our studies to develop novel retinoids with increased affinity and selectivity for the retinoid X receptor (RXR) subfamily, we have designed and synthesized a series of (E,E,E)-7-(1,2,3,4-tetrahydroquinolin-6-yl)-7-alkyl-6-fluoro-3-methylhepta-2,4,6-trienoic acid derivatives. These tetrahydroquinolines, generated by introducing a polar N atom into the hydrophobic part of the retinoid skeleton, showed high binding affinity to RXRs. Addition of fluorine at the 6-position of the 2,4,6-trienoic acid moiety afforded compounds which elicit potent and selective transactivation of the RXRs. Compound 14b (ER-35794), which possesses an ethyl substituent at the 7-position and fluorine at the 6-position of the triene moiety, is one of the most potent and selective RXR agonists reported to date.

The effects of chronic injection of U50,488H (trans-3,4-dichloro-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeacetamidel++ +), a selective kappa opioid agonist, on the properties of the binding sites of tritiated U69593 [(5 alpha,7 alpha,8 beta)-(-)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro (4,5)dec-8-yl)benzeneacetamide], another selective kappa opioid agonist, and mechanical responses to U50,488H of the heart were studied. Rats received injection twice a day with U50,488H for 4 days. Binding studies on the crude membrane homogenates revealed that there was no change in maximum binding, but a significant increase in Kd after the treatment, indicating that the number of kappa binding sites remained unchanged whereas the affinity of the binding sites to kappa-agonist decreased. The study on the mechanical responses to U50,488H in the isolated perfused heart preparation showed that although the agonist at 10(-6) M caused MR2266 reversible reductions in heart rate and force of contraction as well as ventricular ectopic beat in the heart of rats in the control group, its effects were absent in the U50,488H-treated group, indicating the development of tolerance to the mechanical effects of U50,488H on the heart. The results indicate that the development of tolerance to the mechanical effects of a kappa-agonist after chronic treatment with the agonist was not accompanied by down-regulation, but only a slight and significant reduction in affinity of kappa binding sites in the rat heart.

The protective activity of the bisdioxopiperazine ICRF-187 against the cardiotoxicity of doxorubicin was evaluated in the rat using both functional and histological assays. Animals that had received a single i. v. dose of doxorubicin (4 mg/kg) alone were compared with those that had been pretreated with a single i. v. injection of saline or ICRF-187 (40 or 60 mg/kg). All rats showed a transient reduction in body weight during the first 3 weeks after drug administration. The greatest reduction (~16%) was observed in animals that had received a combination of ICRF-187 (40 or 60 mg/kg) and doxorubicin. Deaths related to cardiotoxicity were observed only in rats that had received doxorubicin alone and in those treated with saline; most of the deaths occurred at between 8 and 13 weeks after drug administration. Sequential assessments of heart function showed a persistent depression of cardiac output in animals that had received doxorubicin, with or without pretreatment with ICRF-187. The reduction in cardiac output observed in rats that had been pretreated with ICRF-187 (40 or 60 mg/kg) amounted to ~15% and ~30% after 12 and 20 weeks, respectively, indicating that cardioprotection was only partial. Nevertheless, this represented a marked improvement as compared with the ~35% reduction in cardiac output measured at 12 weeks in animals that had received doxorubicin but without pretreatment with ICRF-187. Histological examination of animals that had died during the course of the study and had received doxorubicin after pretreatment with saline revealed severe myocardial lesions typical of doxorubicin-induced damage. In contrast, animals that had been pretreated with ICRF-187 and survived for up to 20 weeks after treatment showed a marked amelioration of these lesions. The present findings may be interpreted as a true cardioprotection or a delay in the onset of the cardiotoxicity of doxorubicin resulting from pretreatment with the bisdioxopiperazine ICRF-187. Although prior and ongoing clinical trials clearly indicate that ICRF-187 protects patients well against doxorubicin-induced heart damage, further investigations are required beforehigh doses of ICRF-187 can be used as a means of increasing the protective activity of this drug against doxorubicin-induced cardiotoxicity.