Expected-value bias in routine third-trimester growth scans.

OBJECTIVES: Operators performing fetal growth scans are usually aware of the gestational age of the pregnancy, which may lead to expected-value bias when performing biometric measurements. We aimed to evaluate the incidence of expected-value bias in routine fetal growth scans and assess its impact on standard biometric measurements. METHODS: We collected prospectively full-length video recordings of routine ultrasound growth scans coupled with operator eye tracking. Expected value was defined as the gestational age at the time of the scan, based on the estimated due date that was established at the dating scan. Expected-value bias was defined as occurring when the operator looked at the measurement box on the screen during the process of caliper adjustment before saving a measurement. We studied the three standard biometric planes on which measurements of head circumference (HC), abdominal circumference (AC) and femur length (FL) are obtained. We evaluated the incidence of expected-value bias and quantified the impact of biased measurements. RESULTS: We analyzed 272 third-trimester growth scans, performed by 16 operators, during which a total of 1409 measurements (354 HC, 703 AC and 352 FL; including repeat measurements) were obtained. Expected-value bias occurred in 91.4% of the saved standard biometric plane measurements (85.0% for HC, 92.9% for AC and 94.9% for FL). The operators were more likely to adjust the measurements towards the expected value than away from it (47.7% vs 19.7% of measurements; P < 0.001). On average, measurements were corrected by 2.3 ± 5.6, 2.4 ± 10.4 and 3.2 ± 10.4 days of gestation towards the expected gestational age for the HC, AC, and FL measurements, respectively. Additionally, we noted a statistically significant reduction in measurement variance once the operator was biased (P = 0.026). Comparing the lowest and highest possible estimated fetal weight (using the smallest and largest biased HC, AC and FL measurements), we noted that the discordance, in percentage terms, was 10.1% ± 6.5%, and that in 17% (95% CI, 12-21%) of the scans, the fetus could be considered as small-for-gestational age or appropriate-for-gestational age if using the smallest or largest possible measurements, respectively. Similarly, in 13% (95% CI, 9-16%) of scans, the fetus could be considered as large-for-gestational age or appropriate-for-gestational age if using the largest or smallest possible measurements, respectively. CONCLUSIONS: During routine third-trimester growth scans, expected-value bias frequently occurs and significantly changes standard biometric measurements obtained. © 2019 the Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Effect of summer daylight exposure and genetic background on growth in growth hormone-deficient children.

The response to growth hormone in humans is dependent on phenotypic, genetic and environmental factors. The present study in children with growth hormone deficiency (GHD) collected worldwide characterised gene-environment interactions on growth response to recombinant human growth hormone (r-hGH). Growth responses in children are linked to latitude, and we found that a correlate of latitude, summer daylight exposure (SDE), was a key environmental factor related to growth response to r-hGH. In turn growth response was determined by an interaction between both SDE and genes known to affect growth response to r-hGH. In addition, analysis of associated networks of gene expression implicated a role for circadian clock pathways and specifically the developmental transcription factor NANOG. This work provides the first observation of gene-environment interactions in children treated with r-hGH.

Pharmacogenomics of insulin-like growth factor-I generation during GH treatment in children with GH deficiency or Turner syndrome.

Individual responses to growth hormone (GH) treatment are variable. Short-term generation of insulin-like growth factor-I (IGF-I) is recognized as a potential marker of sensitivity to GH treatment. This prospective, phase IV study used an integrated genomic analysis to identify markers associated with 1-month change in IGF-I (ΔIGF-I) following initiation of recombinant human (r-h)GH therapy in treatment-naïve children with GH deficiency (GHD) (n=166) or Turner syndrome (TS) (n=147). In both GHD and TS, polymorphisms in the cell-cycle regulator CDK4 were associated with 1-month ΔIGF-I (P<0.05). Baseline gene expression was also correlated with 1-month ΔIGF-I in both GHD and TS (r=0.3; P<0.01). In patients with low IGF-I responses, carriage of specific CDK4 alleles was associated with MAPK and glucocorticoid receptor signaling in GHD, and with p53 and Wnt signaling pathways in TS. Understanding the relationship between genomic markers and early changes in IGF-I may allow development of strategies to rapidly individualize r-hGH dose.

Discovering Salient Anatomical Landmarks by Predicting Human Gaze.

Anatomical landmarks are a crucial prerequisite for many medical imaging tasks. Usually, the set of landmarks for a given task is predefined by experts. The landmark locations for a given image are then annotated manually or via machine learning methods trained on manual annotations. In this paper, in contrast, we present a method to automatically discover and localize anatomical landmarks in medical images. Specifically, we consider landmarks that attract the visual attention of humans, which we term visually salient landmarks. We illustrate the method for fetal neurosonographic images. First, full-length clinical fetal ultrasound scans are recorded with live sonographer gaze-tracking. Next, a convolutional neural network (CNN) is trained to predict the gaze point distribution (saliency map) of the sonographers on scan video frames. The CNN is then used to predict saliency maps of unseen fetal neurosonographic images, and the landmarks are extracted as the local maxima of these saliency maps. Finally, the landmarks are matched across images by clustering the landmark CNN features. We show that the discovered landmarks can be used within affine image registration, with average landmark alignment errors between 4.1% and 10.9% of the fetal head long axis length.

Spatio-Temporal Partitioning and Description of Full-Length Routine Fetal Anomaly Ultrasound Scans.

This paper considers automatic clinical workflow description of full-length routine fetal anomaly ultrasound scans using deep learning approaches for spatio-temporal video analysis. Multiple architectures consisting of 2D and 2D + t CNN, LSTM, and convolutional LSTM are investigated and compared. The contributions of short-term and long-term temporal changes are studied, and a multi-stream framework analysis is found to achieve the best top-1 accuracy=0.77 and top-3 accuracy=0.94. Automated partitioning and characterisation on unlabelled full-length video scans show high correlation (ρ=0.95, p=0.0004) with workflow statistics of manually labelled videos, suggesting practicality of proposed methods.

Recombinant human growth hormone for children born small for gestational age: meta-analysis confirms the consistent dose-effect relationship on catch-up growth.

BACKGROUND: The optimal treatment regimen of recombinant human GH (r-hGH) for short children born small for gestational age (SGA) is still under discussion. METHODS: A meta-analysis was performed of existing clinical trials that investigated the treatment of r-hGH in short children diagnosed SGA or with intrauterine growth retardation to determine the relationship between the daily r-hGH dose (placebo/no treatment; 0.033 mg/kg/day; 0.067 mg/kg/day) and the effect on growth [change in height-SD score (SDS) for chronological age]. A mathematical model describing the dose-response relationship was produced, and growth response (gain in height-SDS) to 2 yr of r-hGH 0.033 mg/kg/day [somatropin (rDNA origin) for injection; Serono] was estimated and compared with the response to other r-hGH formulations. RESULTS: The relationship between r-hGH dose and 2-yr growth response was described by an equation. The equation yielded a mean difference in height- SDS gain of 0.48 (0.35) between r-hGH 0.033 and 0.067 mg/kg/day in favor of the higher dose. The height-SDS gain after 2 yr of Serono r-hGH formulation, 0.033 mg/kg/day was estimated as 1.2. Comparison of this estimate to the growth response to 2-yr treatment at 0.033 mg/kg/day of other r-hGH formulations (mean difference in height-SDS 0.05, lower limit of the 95% confidence interval=-0.15) confirmed that growth response to Serono r-hGH formulation 0.033 mg/kg/day is an inferred response estimated to be within the range of observed responses to a (non-Serono formulation) r-hGH dose of 0.033 mg/kg/day. CONCLUSION: There is a clear dose-response relationship for r-hGH in the treatment of short children born SGA and the analysis confirmed that treatment with Serono r-hGH formulation 0.033 mg/kg/day should provide a meaningful therapeutic response.

Changes in insulin sensitivity and glucose metabolism during therapy with recombinant human growth hormone in short children born small for gestational age show a negative correlation with baseline measurements.

Recombinant human growth hormone (rhGH) is an effective therapy for children with short stature born small for gestational age (SGA); however, insulin resistance can develop during treatment. This retrospective analysis assessed the effect of rhGH treatment (0.067 mg/kg/day) on glucose metabolism and insulin secretion in children with short stature born SGA, and measured whether baseline characteristics correlated with changes in insulin resistance or glucose sensitivity during treatment. Baseline glucose area under the concentration-time curve (AUC) was negatively correlated with the change in glucose AUC (p<0.001). Similar negative correlations were seen between baseline insulin AUC and the change in insulin AUC during treatment (p<0.001); and between baseline HOMA-IR (homeostatic model of insulin resistance) and the change in HOMA-IR during treatment (p<0.001). Small but significant changes, not thought to be clinically significant, were seen in indicators of insulin sensitivity during rhGH treatment. Glucose levels remained within the normal range during oral glucose tolerance testing.

SonoEyeNet: Standardized Fetal Ultrasound Plane Detection Informed by Eye Tracking.

We present a novel automated approach for detection of standardized abdominal circumference (AC) planes in fetal ultrasound built in a convolutional neural network (CNN) framework, called SonoEyeNet, that utilizes eye movement data of a sonographer in automatic interpretation. Eye movement data was collected from experienced sonographers as they identified an AC plane in fetal ultrasound video clips. A visual heatmap was generated from the eye movements for each video frame. A CNN model was built using ultrasound frames and their corresponding visual heatmaps. Different methods of processing visual heatmaps and their fusion with image feature maps were investigated. We show that with the assistance of human visual fixation information, the precision, recall and F1-score of AC plane detection was increased to 96.5%, 99.0% and 97.8% respectively, compared to 73.6%, 74.1% and 73.8% without using eye fixation information.

Detection of carbapenemase activity in Pseudomonas aeruginosa by Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS).

A new MALDI-TOF MS imipenem hydrolysis assay was developed to optimize detection of carbapenemase-producing strains of Pseudomonas aeruginosa. The method correctly discriminated carbapenemase producers (n=74) from non-producers (n=95) in 99.4% of cases, and successfully detected 100% GES-5 strains (n=5).

Deletion of mitochondrial DNA in a case of early-onset diabetes mellitus, optic atrophy, and deafness (Wolfram syndrome, MIM 222300).

The Wolfram syndrome (MIM 222300) is a disease of unknown origin consisting of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. Here we report on a generalized deficiency of the mitochondrial respiratory enzyme activities in skeletal muscle and lymphocyte homogenate of a girl suffering from the Wolfram syndrome. In addition, we provide evidence for a 7.6-kilobase pair heteroplasmic deletion (spanning nucleotides 6465-14135) of the mitochondrial DNA in the two tissues and show that directly repeated sequences (11 bp) were present in the wild-type mitochondrial genome at the boundaries of the deletion. Neither of the patient's parents was found to bear rearranged molecules. This study supports the view that a respiratory chain defect can present with insulin-dependent diabetes mellitus as the onset symptom. It also suggests that a defect of oxidative phosphorylation should be considered when investigating other cases of Wolfram syndrome, especially because this syndrome fulfills the criteria for a genetic defect of the mitochondrial energy supply: (a) an unexplained association of symptoms (b) with early onset and rapidly progressive course, (c) involving seemingly unrelated organs and tissues.

Peripheral and central H1 histamine receptor occupancy by levocetirizine, a non-sedating antihistamine; a time course study in the guinea pig.

BACKGROUND AND PURPOSE: The H(1) receptor occupancy (H1RO) in brain is an indicator of central side effects of antihistamines. Here, we determined the kinetics of central and peripheral H1RO by levocetirizine in relation to its brain and plasma concentration, and investigated the role of the blood-brain barrier in any delay in brain H1RO. EXPERIMENTAL APPROACH: Concentration-time profiles in plasma and brain were obtained after 0.1 and 1 mg kg(-1) oral doses of levocetirizine in guinea pigs. H1RO in brain was measured ex vivo using [3H]-mepyramine and, in the periphery, by measuring the degree of inhibition of histamine-induced contractions of isolated guinea pig ileum. KEY RESULTS: The concentration-time profile of levocetirizine indicated lower levels (partition coefficient, K(p)=0.06-0.08), higher t(max) (2-4 h vs 1-1.5 h) and longer terminal half-life (4-5.6 h vs 2.1-2.8 h) in brain than plasma. The H1RO at 0.1 and 1 mg kg(-1) were 75% and 97%, respectively, at 1 hr in the periphery and, in the brain, were <20% and 28-67% respectively, at all time points studied. Brain H1RO vs plasma concentrations profile showed a delay, but not when compared to brain concentrations. CONCLUSIONS AND IMPLICATIONS: This study demonstrates an effective peripheral antihistamine effect of levocetirizine without central adverse effects at the dose close to human therapeutic dose. The slow increase in H1RO in the brain with time was caused by slow blood-brain barrier transport of levocetirizine. This demonstrates the importance of measuring time course of brain H1RO in relation to brain concentrations of drugs.

Growth hormone therapy for short children born small for gestational age.

Children born small for gestational age may demonstrate continued growth retardation, resulting in persistent short stature. In the majority of the cases, this is linked with abnormal growth hormone secretion and also abnormal insulin-like growth factor levels. This review discusses the treatment of such children with recombinant human growth hormone. It illustrates the importance of starting therapy early, the dose-dependent response, and the advantages of continuous therapy and describes safety considerations.

Solubilization and immunopurification of rat brain synaptic vesicle protein 2A with maintained binding properties.

This study reports the solubilization of the rat synaptic vesicle protein SV2A, the brain binding site for the antiepileptic drug levetiracetam (LEV), and its characterization. N-dodecyl-beta-D-maltoside (DDM) was the best detergent at achieving a high percentage of SV2A solubilization and at maintaining the binding characteristics of a tritiated form of a more potent analogue of LEV, [3H]ucb 30889 ((2S)-2-[4-(3-azidophenyl)-2-oxopyrrolidin-1-yl]butanamide). Scatchard analysis revealed that approximately 25% of SV2A proteins from brain membranes are solubilized by DDM under optimal conditions. Competition binding experiments with a variety of LEV analogues indicated that [3H]ucb 30889 labels the same binding site in both crude homogenates and soluble extracts, with still high stereoselectivity. After immunoprecipitation of SV2A from solubilized rat brain membranes, binding properties of [3H]ucb 30889 to SV2A and association with synaptotagmin I were maintained. The two other isoforms SV2B and SV2C were found to be co-immunoprecipitated with SV2A. The solubilization and immunopurification of SV2A with unmodified ligand affinities and synaptotagmin I interaction provides the starting point for future protein-protein interactions and structural studies.

Modulation of subcellular distribution of doxorubicin in multidrug-resistant P388/ADR mouse leukemia cells by the chemosensitizer ((2-isopropyl-1-(4-[3-N-methyl-N-(3,4-dimethoxy-beta- phenethyl)amino]propyloxy)-benzenesulfonyl))indolizine.

The impact of the novel chemosensitizer ((2-isopropyl-1-(4-[3-N-methyl-N-(3,4-dimethoxy-beta- phenethyl)amino]propyloxy)benzenesulfonyl))indolizine (SR33557) on the intracellular distribution of doxorubicin (DOX) within the multidrug-resistant murine P388/ADR leukemia cell line was studied by fluorescence microscopy. We found that under conditions which modulated multidrug-resistant (30 microM SR33557 for 1 h), P388/ADR cells presented an original sequestration of DOX in large intracellular vesicles, where SR33557 is itself sequestered, as seen by colocalization studies. Colocalization experiments with lysosomal and mitochondrial probes suggest that these vesicles are neither mitochondrial in nature nor functional lysosomes. To investigate the biochemical basis for this effect, we studied the impact of SR33557 on the sphingolipid metabolism of P388/ADR cells. We observed that although P388/ADR cells normally catabolized exogenous [3H]sphingomyelin, when pretreated with SR33557 they showed almost complete inhibition of sphingomyelin breakdown. Finally, in order to demonstrate that the inability of P388/ADR cells to degrade sphingomyelin in the presence of SR33557 (which is a potent inhibitor of acid lysosomal sphingomyelinase) leads to phospholipid accumulation, we performed electron microscopy where we observed laminated inclusions. These morphological modifications are similar to those observed in Niemann-Pick disease lymphoblastoid cell lines which are inherently deficient in acid sphingomyelinase activity. The observation that, in the absence of SR33557, these Niemann-Pick disease cell lines presented similar DOX sequestration to that of SR33557-treated P388/ADR cells strongly suggests that DOX accumulates in SR33557-induced myeloid bodies. The redistribution of DOX within these vesicles, perhaps by preventing its expulsion by P-glycoprotein, may be a key in discovering the mechanism of action of SR33557.

In vitro and in vivo enhancement of ricin-A chain immunotoxin activity by novel indolizine calcium channel blockers: delayed intracellular degradation linked to lipidosis induction.

With regard to increasing the clinical potential of ricin A-chain immunotoxins (RTA-ITs), a novel class of calcium channel blockers, indolizines SR33557 [2-isopropyl-1-[4-(3-N-methyl-N-(3,4-dimethoxy-beta- phenethyl)amino)propyloxy)benzenesulfonyl))indolizine] and SR33287 [isopropyl-2-((1-butylamino-3-propyl)oxy-4-benzoyl)-3-indolizine], were evaluated for their ability to enhance RTA-IT activity in vitro and in vivo. Five microM SR33287 and 5 microM SR33557 were potent enhancers of both anti-Thy 1.2 AT15E RTA-IT (84- and 64-fold, respectively) on T2 cells and anti-CD5 T101 (622- and 538-fold) and T101 F(ab')2 RTA-IT (34- and 28-fold) on CEM III cells. This was superior to the effect achieved by both 10 microM verapamil and 10 mM NH4Cl, albeit slightly inferior to that of 50 nM monensin and 5 microM perhexiline. Murine T2 lymphoma cells bearing the Thy 1.2 antigen were injected i.v. in Thy 1.2 (-) BL. 1.1 mice (median survival time, 17.7 days). Intravenous treatment with 10 micrograms of AT15E RTA-IT prolonged the survival of mice (median survival time, 26.8 days). When 400 micrograms of SR33287 were coinjected i.v. with 10 micrograms of AT15E RTA-IT, mouse survival was further increased, with 5 of 6 mice surviving, disease free, over 42 days. SR33287 had a significant impact on the intracellular routing of 125I-AT15E RTA-IT, which induced a greater than 2-fold increase in intracellular intact AT15E RTA-IT at 90 min. This effect on RTA-IT half-life was distinctly different from that observed with either NH4Cl or monensin and may be linked to the inhibition of acid lysosomal sphingomyelinase by SR33287, leading to cellular lipidosis. In conclusion, indolizines appear to be promising agents not only for immunotoxin enhancement but also for increasing the activity of any number of targeted therapeutic agents where modifying either the intracellular routing or increasing the intracellular half-life of the ligand would be beneficial to its cytotoxic activity.

Semi-empirical conformational analysis of propranolol interacting with dipalmitoylphosphatidylcholine.

A semi-empirical conformational analysis is used to compute the conformation of (+)-propranolol inserted in dipalmitoylphosphatidylcholine. In a first step, the minimal conformational energy of the isolated molecule at the hydrocarbon-water interface is calculated as the sum of the contributions resulting from the Van der Waals, the torsional, the electrostatic and the transfer energies. Five pairs of conformers of minimal energy are determined. They are compared to data available from other experimental approaches. In a second step, they are assembled with dipalmitoylphosphatidylcholine at the interface. Although propranolol is considered in its protonated form, the electrostatic interaction with dipalmitoylphosphatidylcholine is negligible as compared to the Van der Waals interaction. The area occupied per propranolol molecule is between 0.53 and 0.64 nm2/molecule. In the most probable modes of insertion of propranolol into the lipid layer, the naphthyl moiety of the compound interacts with the lipid acyl chains. The protonated amino group is located in the vicinity of the phosphate residue possibly causing an electrostatic interaction.

Fusion and lipid exchange in vesicles containing lipophilic spin labels.

Lipophilic non-electrolyte spin labels greatly accelerate the fusion of unilamellar vesicles of dipalmitoylphosphatidylcholine when the system is maintained below the lipid phase transition. Differential scanning calorimetry and centrifugation measurements show that the transformed vesicles are large and probably unilamellar. Differential scanning calorimetry and fluorescence depolarization measurements were also carried out on mixtures of labeled dipalmitoylphosphatidylcholine vesicles and of vesicles composed of pure dimyristoylphosphatidylcholine. A mixing of the membrane components is observed when the vesicles are incubated above the transition temperature of the two constituent lipids. However, the process does not involve a real fusion of the entire vesicles. An exchange of lipid and label monomers between the two lipid phases seems to occur. These observations are discussed in view of the molecular organization of the spin label within the dipalmitoylphosphatidylcholine matrix below and above the lipid transition temperature.

Binding of vasoactive intestinal peptide and its stimulation of adenylate cyclase through two classes of receptors in rat liver membranes. Effects of 12 secretin analogues and 2 secretin fragments.

1. Vasoactive intestinal peptide (VIP) receptors were identified in crude rat hepatic membranes by 125I-labelled VIP binding and by the ability of VIP to stimulate adenylate cyclase activity. The specificity of these receptors was evaluated by the capacity of secretin, synthetic secretin analogues, and secretin fragments to inhibit 125I-labelled VIP binding and to stimulate adenylate cyclase. 2. The results were compatible with the existence of two classes of VIP binding sites that could be distinguished according to their affinity for VIP and their specificity. High-affinity sites were more specific for VIP as secretin was 175 times less potent than VIP for recognition of these sites while being only 33 times less potent than VIP for recognition of low-affinity sites. 3. Secretin analogues, monosubstituted in position 2, 3, 4 or 6 were less potent than secretin for adenylate cyclase stimulation as well as for the recognition of the two classes of receptors. [Val5]secretin was more potent than secretin and appeared definitely more VIP-like than secretin; [Ala4, Val5] and [D-Ala4,Val5]secretin were equipotent to secretin. 4. The fragment secretin (7-27) was unable to recognize VIP receptors and to stimulate adenylate cyclase. The substituted fragment [Gln9,Asn15]secretin (5-27) recognized these receptors with weak potency but could not activate the enzyme.

Spin label partitioning in lipid vesicles. A model study for drug encapsulation.

In this paper we attempt to outline some features which determine the encapsulation of small molecules into lipid vesicles. Spin labels derived from five carboxylic acids of different lengths were synthesized and incorporated in varying amounts into multilamellar and unilamellar vesicles made up of four different phosphatidylcholines. The influence on the release process of the bilayer rigidity and of the hydrophobicity of the entrapped molecule was systematically studied. The hydrophobicity is of critical importance and was estimated by measuring the partition coefficient (P) between octanol and buffer. In multilamellar vesicles, molecules characterized by extreme P values (log P less than -0.3 and log P greater than 5) can be efficiently entrapped. The rate of leakage is related to the P value according to a bell-shaped curve. Moreover, gel state of the bilayer and long acyl chains of the lipids are properties which favor a good entrapment. Small unilamellar vesicles may be formed in the presence of high concentrations of hydrophilic and lipophilic spin labels. However, the formation of unilamellar vesicles produces a significant reduction of the internal volume and of the entrapped water-soluble spin lables. High fractions of lipid-soluble spin labels can be incorporated in unilamellar vesicles but the vesicle stability is diminished.

Evidence of a specific complex between adriamycin and negatively-charged phospholipids.

Membrane-model systems (monolayers, small unilamellar vesicles) were used to study the interaction between adriamycin (ADM) and phospholipids. Adsorption of 3H-labeled adriamycin on different phospholipid monolayers demonstrated the specificity of adriamycin for negatively-charged phospholipids (cardiolipin, phosphatidylserine, phosphatidic acid). The stoichiometry has been found to be approx. 2 mol (1.8) adriamycin per mol cardiolipin and approx. 1 mol (0.75) adriamycin per mol phosphatidylserine and phosphatidic acid. No adsorption was detected with neutral lipids. Surface-potential measurements confirm the formation of a complex stabilized by electrostatic interactions without penetration of the drug into the lipid lipophilic phase. Some adriamycin derivatives were used to discriminate between the ionized hydrophilic and hydrophobic contributions in the complex formation. The absorption spectrum of adriamycin in the presence of cardiolipin resembles the behavior of the ADM-DNA complex. Moreover, the association constants of the two complexes are very similar (cardiolipin-ADM, 1.6 . 10(6) . M-1; ADM-DNA, 2.4 . 10(6) . M-1). To explain the high affinity of cardiolipin for adriamycin, we proposed that two essential interactions are responsible for the complex stabilization: an electrostatic interaction between the protonated amino groups of the sugar residues and the ionized phosphate residues, and an interaction between adjacent anthraquinone chromophores. These data strongly suggest competitive behavior between a membrane site and the target. Consequently, it must be assumed that the lipidic components of the cell membrane structure may be an important determinant in the behavior of adriamycin. This observation should be kept in mind in the building of new derivatives.