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The present study describes physiologically based kinetic (PBK) models for the alkenylbenzene myristicin that were developed by extension of the PBK models for the structurally related alkenylbenzene safrole in rat and human. The newly developed myristicin models revealed that the formation of the proximate carcinogenic metabolite 1'-hydroxymyristicin in liver is at most 1.8 fold higher in rat than in human and limited for the ultimate carcinogenic metabolite 1'-sulfoxymyristicin to (2.8-4.0)-fold higher in human. In addition, a comparison was made between the relative importance of bioactivation for myristicin and safrole. Model predictions indicate that for these related compounds, the formation of the 1'-sulfoxy metabolites in rat and human liver is comparable with a difference of <2.2-fold over a wide dose range. The results from this PBK analysis support that risk assessment of myristicin may be based on the BMDL 10 derived for safrole of 1.9-5.1 mg/kg bw per day. Using an estimated daily intake of myristicin of 0.0019 mg/kg bw per day resulting from the use of herbs and spices, this results in MOE values for myristicin that amount to 1000-2700, indicating a priority for risk management. The results obtained illustrate that PBK modeling provides insight into possible species differences in the metabolic activation of myristicin. Moreover, they provide an example of how PBK modeling can facilitate a read-across in risk assessment from a compound for which in vivo toxicity studies are available to a related compound for which tumor data are not reported, thus contributing to alternatives in animal testing., Competing Interests: Prof. IMCM Rietjens declares she is a member of the Expert Panel of the Flavour and Extract Manufacturers Association (FEMA). Other authors declare that no conflict of interest exists.

Our in situ X-ray study shows that a silicon substrate in contact with an undersaturated In(Ge) solution is wetted by an approximately 1 nm thin germanium film, which does not grow any thicker. The results can be understood by the use of thickness-dependent correlated interfacial energies. This near-equilibrium heterogeneous interface structure marks the initial stage of crystal growth before the formation of bulk material, which can only form under conditions of supersaturation. This finding uncovers a fundamental aspect of the thermodynamics at solid-liquid interfaces relevant for understanding the transition from equilibrium to supersaturation and is of importance for nanoscale solution growth methods.

The aim of this study was to evaluate the effect of a supraseasonal drought on the ecological attributes of Plagioscion squamosissimus . The fish were caught quarterly from February 2010 to November 2014 using gill nets in the reservoir of Santa Cruz, Rio Grande do Norte, Brazil. The abundance of the species was evaluated with the catch per unit effort (CPUE) metric and then correlated with the accumulated rainfall and water volume of the reservoir. The diet of the fish was evaluated using the feeding index (IAi). The proportional similarity index (PS i ) was used to evaluate the variation in the niches of the fish. The body condition was inferred through the relative condition factor, and its variation was assessed with ANOVA. A reduction in the abundance of the species that were positively correlated with the reservoir water volume was observed. The diet of the fish comprised shrimp, gastropods, fish, insects, shrimp larvae, and vegetable matter, with shrimp being the major component. PS i showed the occurrence of individual specialization during November 2013 and November 2014. The relative condition factor was not correlated with a reduction in the water volume of the reservoir. The supraseasonal drought did not affect the relative condition factor, diet, and the trophic niche, but it did affect the species abundance., Competing Interests: The authors declare that they have no competing interests.

The solid-liquid interface formed by single terminated muscovite mica in contact with two different ionic solutions is analyzed using surface X-ray diffraction. Specular and nonspecular crystal truncation rods of freshly cleaved mica immersed in CsCl or RbBr aqueous solution were measured. The half monolayer of the surface potassium ions present after the cleavage is completely replaced by the positive ions (Cs + or Rb + ) from the solution. These ions are located in the ditrigonal surface cavities with small outward relaxations with respect to the bulk potassium position. We find evidence for the presence of a partly ordered hydration shell around the surface Cs + or Rb + ions and partly ordered negative ions in the solution. The lateral liquid ordering induced by the crystalline surface vanishes at distances larger than 5 Å from the surface.

Sub-chronic toxicity studies of 163 non-genotoxic chemicals were evaluated in order to predict the tumour outcome of 24-month rat carcinogenicity studies obtained from the EFSA and ToxRef databases. Hundred eleven of the 148 chemicals that did not induce putative preneoplastic lesions in the sub-chronic study also did not induce tumours in the carcinogenicity study (True Negatives). Cellular hypertrophy appeared to be an unreliable predictor of carcinogenicity. The negative predictivity, the measure of the compounds evaluated that did not show any putative preneoplastic lesion in de sub-chronic studies and were negative in the carcinogenicity studies, was 75%, whereas the sensitivity, a measure of the sub-chronic study to predict a positive carcinogenicity outcome was only 5%. The specificity, the accuracy of the sub-chronic study to correctly identify non-carcinogens was 90%. When the chemicals which induced tumours generally considered not relevant for humans (33 out of 37 False Negatives) are classified as True Negatives, the negative predictivity amounts to 97%. Overall, the results of this retrospective study support the concept that chemicals showing no histopathological risk factors for neoplasia in a sub-chronic study in rats may be considered non-carcinogenic and do not require further testing in a carcinogenicity study., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

In an exercise designed to reduce animal use, we analyzed the results of rat subchronic toxicity studies from 289 pharmaceutical compounds with the aim to predict the tumor outcome of carcinogenicity studies in this species. The results were obtained from the assessment reports available at the Medicines Evaluation Board of the Netherlands for 289 pharmaceutical compounds that had been shown to be non-genotoxic. One hundred forty-three of the 239 compounds not inducing putative preneoplastic lesions in the subchronic study did not induce tumors in the carcinogenicity study [true negatives (TNs)], whereas 96 compounds were categorized as false negatives (FNs) because tumors were observed in the carcinogenicity study. Of the remaining 50 compounds, 31 showed preneoplastic lesions in the subchronic study and tumors in the carcinogenicity study [true positives (TPs)], and 19 only showed preneoplastic lesions in subchronic studies but no tumors in the carcinogenicity study [false positives (FPs)]. In addition, we then re-assessed the prediction of the tumor outcome by integrating the pharmacological properties of these compounds. These pharmacological properties were evaluated with respect to the presence or absence of a direct or indirect proliferative action. We found support for the absence of cellular proliferation for 204 compounds (TN). For 67 compounds, the presence of cellular hyperplasia as evidence for proliferative action could be found (TP). Therefore, this approach resulted in an ability to predict non-carcinogens at a success rate of 92% and the ability to detect carcinogens at 98%. The combined evaluation of pharmacological and histopathological endpoints eventually led to only 18 unknown outcomes (17 categorized as FN and 1 as FP), thereby enhancing both the negative and positive predictivity of an evaluation based upon histopathological evaluation only. The data show the added value of a consideration of the pharmacological properties of compounds in relation to potential class effects, both in the negative and positive direction. A high negative and a high positive predictivity will both result in waiving the need for conducting 2-year rat carcinogenicity studies, if this is accepted by Regulatory Authorities, which will save large numbers of animals and reduce drug development costs and time.

This review highlights the recent research into the biotransformations and rearrangement of the sulfonylhydrazine-alkylating agent laromustine. Incubation of [(14)C]laromustine with rat, dog, monkey, and human liver microsomes produced eight radioactive components (C-1 to C-8). There was little difference in the metabolite profile among the species examined, partly because NADPH was not required for the formation of most components, which instead involved decomposition and/or hydrolysis. The exception was C-7, a hydroxylated metabolite, largely formed by CYP2B6 and CYP3A4/5. Liquid chromatography-multistage mass spectrometry (LC-MS(n)) studies determined that collision-induced dissociation, and not biotransformation or enzyme catalysis, produced the unique mass spectral rearrangement. Accurate mass measurements performed with a Fourier-transform ion cyclotron resonance mass spectrometer (FTICR-MS) significantly aided determination of the elemental compositions of the fragments and in the case of laromustine revealed the possibility of rearrangement. Further, collision-induced dissociation produced the loss of nitrogen (N2) and methylsulfonyl and methyl isocyanate moieties. The rearrangement, metabolite/decomposition products, and conjugation reactions were analyzed utilizing hydrogen-deuterium exchange, exact mass, (13)C-labeled laromustine, nuclear magnetic resonance spectroscopy (NMR), and LC-MS(n) experiments to assist with the assignments of these fragments and possible mechanistic rearrangement. Such techniques produced valuable insights into these functions: 1) Cytochrome P450 is involved in C-7 formation but plays little or no role in the conversion of [(14)C]laromustine to C-1 through C-6 and C-8; 2) the relative abundance of individual degradation/metabolite products was not species-dependent; and 3) laromustine produces several reactive intermediates that may produce the toxicities seen in the clinical trials., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Nucleic acid purification methods are of importance when performing microbiota studies and especially when analysing the intestinal microbiota as we here find a wide range of different microbes. Various considerations must be taken to lyse the microbial cell wall of each microbe. In the present article, we compare several tissue lysis steps and commercial purification kits, to achieve a joint RNA and DNA purification protocol for the purpose of investigating the microbiota and the microbiota-host interactions in a single colonic mucosal tissue sample., Results: A further optimised tissue homogenisation and lysis protocol comprising mechanical bead beating, lysis buffer replacement and enzymatic treatment, in combination with the AllPrep DNA/RNA Mini Kit (Qiagen, Hilden, Germany) resulted in efficient and simultaneous purification of microbial and human RNA and DNA from a single mucosal colonic tissue sample., Conclusions: The present work provides a unique possibility to study RNA and DNA from the same mucosal biopsy sample, making a direct comparison between metabolically active microbes and total microbial DNA. The protocol also offers an opportunity to investigate other members of a microbiota such as viruses, fungi and micro-eukaryotes, and moreover the possibility to extract data on microbiota and host interactions from one single mucosal biopsy.

The present study developed physiologically-based kinetic (PBK) models for the alkenylbenzene apiol in order to facilitate risk assessment based on read-across from the related alkenylbenzene safrole. Model predictions indicate that in rat liver the formation of the 1'-sulfoxy metabolite is about 3 times lower for apiol than for safrole. These data support that the lower confidence limit of the benchmark dose resulting in a 10% extra cancer incidence (BMDL10) that would be obtained in a rodent carcinogenicity study with apiol may be 3-fold higher for apiol than for safrole. These results enable a preliminary risk assessment for apiol, for which tumor data are not available, using a BMDL10 value of 3 times the BMDL10 for safrole. Based on an estimated BMDL10 for apiol of 5.7-15.3 mg/kg body wt per day and an estimated daily intake of 4 × 10(-5) mg/kg body wt per day, the margin of exposure (MOE) would amount to 140,000-385,000. This indicates a low priority for risk management. The present study shows how PBK modelling can contribute to the development of alternatives for animal testing, facilitating read-across from compounds for which in vivo toxicity studies on tumor formation are available to compounds for which these data are unavailable., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Schizophrenia is associated with deficits in face perception and emotion recognition. Despite consistent behavioural results, the neural mechanisms underlying these cognitive abilities have been difficult to isolate, in part due to differences in neuroimaging methods used between studies for identifying regions in the face processing system. Given this problem, we aimed to validate a recently developed fMRI-based dynamic functional localizer task for use in studies of psychiatric populations and specifically schizophrenia. Previously, this functional localizer successfully identified each of the core face processing regions (i.e. fusiform face area, occipital face area, superior temporal sulcus), and regions within an extended system (e.g. amygdala) in healthy individuals. In this study, we tested the functional localizer success rate in 27 schizophrenia patients and in 24 community controls. Overall, the core face processing regions were localized equally between both the schizophrenia and control group. Additionally, the amygdala, a candidate brain region from the extended system, was identified in nearly half the participants from both groups. These results indicate the effectiveness of a dynamic functional localizer at identifying regions of interest associated with face perception and emotion recognition in schizophrenia. The use of dynamic functional localizers may help standardize the investigation of the facial and emotion processing system in this and other clinical populations., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The common bean, Phaseolus vulgaris (L.), is one of the most important sources of protein worldwide, and Latin America is one of the recognized centers of diversity of this species. However, storage of this product after harvest is not feasible because of bruchid attacks. This study determined the accumulated normalized rate of emergence and the daily emergence rate of Zabrotes subfasciatus (Boheman) (Coleoptera: Chrysomelidae:Bruchinae) in five landrace varieties of common bean (BRL 01, SNA 01, RDR 01, RBC 01, and RBC 13) that occurin southwestern Amazonia. These varieties were selected for this study because they are well-distributed throughout the Amazonian communities. Beans of each variety were infested with 50 unsexed adults, and the insects were removed 13 d after beginning the bioassays. The adult progeny obtained from the feeding substrate were counted and removed every other day after the first emergence, until the end of the emergence period. Differences were observed in the calculated rates of development; however, the time required for development and emergence of the insects was independent. Of the five varieties of bean investigated, we observed that the RDR 01, BRL 01, and SNA 01 cultivars are resistant to Z. subfasciatus; the results indicate that the use of these three varieties can reduce problems associated with bruchid attacks and enable storage of the product after harvesting.

The size of an individual organism is a key trait to characterize its physiology and feeding ecology. Size-based scaling laws may have a limited size range of validity or undergo a transition from one scaling exponent to another at some characteristic size. We collate and review data on size-based scaling laws for resource acquisition, mobility, sensory range, and progeny size for all pelagic marine life, from bacteria to whales. Further, we review and develop simple theoretical arguments for observed scaling laws and the characteristic sizes of a change or breakdown of power laws. We divide life in the ocean into seven major realms based on trophic strategy, physiology, and life history strategy. Such a categorization represents a move away from a taxonomically oriented description toward a trait-based description of life in the oceans. Finally, we discuss life forms that transgress the simple size-based rules and identify unanswered questions.

Background: Genomic nursing education requires an assessment to capture understanding of genetic-genomic concepts that are critical to competent nursing practice. The Genomic Nursing Concept Inventory (GNCI) was designed for that purpose. Advanced psychometric analyses were applied to GNCI responses to assess dimensionality and item and scale functioning and to inform inventory refinement., Method: The 31-item GNCI was administered to baccalaureate nursing students (N = 758), and exploratory factor analysis (EFA) was applied to explore scale dimensionality and construct validity. Item response theory was applied to explore individual item and overall scale functioning., Results: Unidimensionality of the GNCI was supported. Internal consistency reliability was sufficient for the intended use of the scale. Although a few items were identified for review and potential revision, evidence supports GNCI score accuracy across a wide range of genomic knowledge ability., Conclusion: Validity evidence provided support for the use of GNCI scores for the intended purposes., (Copyright 2016, SLACK Incorporated.)

Aminoacyl-phosphatidylglycerol synthases (aaPGSs) are membrane proteins that utilize aminoacylated tRNAs to modify membrane lipids with amino acids. Aminoacylation of membrane lipids alters the biochemical properties of the cytoplasmic membrane and enables bacteria to adapt to changes in environmental conditions. aaPGSs utilize alanine, lysine and arginine as modifying amino acids, and the primary lipid recipients have heretofore been defined as phosphatidylglycerol (PG) and cardiolipin. Here we identify a new pathway for lipid aminoacylation, conserved in many Actinobacteria, which results in formation of Ala-PG and a novel alanylated lipid, Alanyl-diacylglycerol (Ala-DAG). Ala-DAG formation in Corynebacterium glutamicum is dependent on the activity of an aaPGS homolog, whereas formation of Ala-PG requires the same enzyme acting in concert with a putative esterase encoded upstream. The presence of alanylated lipids is sufficient to enhance the bacterial fitness of C. glutamicum cultured in the presence of certain antimicrobial agents, and elucidation of this system expands the known repertoire of membrane lipids acting as substrates for amino acid modification in bacterial cells., (© 2015 John Wiley & Sons Ltd.)

Background: Human brucellosis is a preventable zoonoses that may become persistent, causing, if left untreated, severe localized disease. Occupational exposure to infected animals or animal products and consumption of fresh contaminated dairy are main risk factors., Methods: One hundred farmworkers employed at two cattle farms one in Khartoum North and one in Omdurman were screened for the presence of specific antibodies and seropositive workers were invited to donate a blood sample for blood culture. Molecular typing was used to characterize Brucella isolates., Results: Ten percent of farmworkers tested seropositive and while Brucella melitensis biovar 1 was isolated from the blood of three individuals, an isolate identical to the B. abortus S19 vaccine strain was isolated from a fourth person. All four bacteremic individuals were employed as milkers and did not have obvious disease., Conclusions: The isolation of the highly infectious pathogen B. melitensis from seropositive workers is consistent with the notion that the pathogen may persist in the blood without causing overt disease. While vaccination with strain S19 is essential for the control of bovine brucellosis the vaccine strain may be transmitted to the human population and protective measures remain important to prevent exposure also in view of the presence of B. melitensis. To create awareness for this potentially severe disease more information on the prevalence of the pathogen in different risk groups and in livestock in the Sudan is needed.

The intraparietal sulcus (IPS) is recruited during tasks requiring attention, maintenance and manipulation of information in working memory (WM). While WM tasks often show broad bilateral engagement along the IPS, topographic maps of contralateral (CL) visual space have been identified along the IPS, similar to retinotopic maps in visual cortex. In the present study, we asked how these visuotopic IPS regions are differentially involved in the maintenance and manipulation of spatial information in WM. Visuotopic mapping was performed in 26 participants to define regions of interest along the IPS, corresponding to previously described IPS0-4. In a separate task, we showed that while maintaining the location of a briefly flashed target in WM preferentially engaged CL IPS, manipulation of spatial information by mentally rotating the target around a circle engaged bilateral IPS, peaking in IPS1 in most participants. Functional connectivity analyses showed increased interaction between the IPS and prefrontal regions during manipulation, as well as interhemispheric interactions. Two control tasks demonstrated that covert attention shifts, and nonspatial manipulation (arithmetic), engaged patterns of IPS activation and connectivity that were distinct from WM manipulation. These findings add to our understanding of the role of IPS in spatial WM maintenance and manipulation., (© The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objective: To investigate the possible association between periodontal changes and osteoporosis in postmenopausal women through a longitudinal study., Methods: This longitudinal study included 33 patients. The participants were divided into three groups according to the bone mineral density assessed in the lumbar region: normal bone (G1, n = 15), osteopenia (G2, n = 12) and osteoporosis (G3, n = 6). Periodontal evaluation included clinical attachment level, probing depth, gingival bleeding index and visible plaque index, evaluated by two examiners blinded to systemic bone condition. The statistical process included the t-test for paired samples, with a significance level of 5% to check for changes in periodontal parameters considered at initial and final systemic bone density., Results: The results showed that, after follow-up, there was a significant increase in gingival bleeding index in the group of women who had normal initial bone condition and progressed to osteopenia (after 3 years, 59.89%, p = 0.010) and osteoporosis (after 3 years, 74.37%, p = 0.035). In addition, the group diagnosed with osteopenia at baseline who progressed to osteoporosis after 3 years also showed a significant increase in gingival bleeding index (p < 0.001)., Conclusions: The findings suggest that periodontal changes can be associated with osteoporosis in postmenopausal women.

Remote brain regions show correlated spontaneous activity at rest within well described intrinsic connectivity networks (ICNs). Meta-analytic coactivation studies have uncovered networks similar to resting ICNs, suggesting that in task states connectivity modulations may occur principally within ICNs. However, it has also been suggested that specific "hub" regions dynamically link networks under different task conditions. Here, we used functional magnetic resonance imaging at rest and a continuous visual attention task in 16 participants to investigate whether a shift from rest to attention was reflected by within-network connectivity modulation, or changes in network topography. Our analyses revealed evidence for both modulation of connectivity within the default-mode (DMN) and dorsal attention networks (DAN) between conditions, and identified a set of regions including the temporoparietal junction (TPJ) and posterior middle frontal gyrus (MFG) that switched between the DMN and DAN depending on the task. We further investigated the temporal nonstationarity of flexible (TPJ and MFG) regions during both attention and rest. This showed that moment-to-moment differences in connectivity at rest mirrored the variation in connectivity between tasks. Task-dependent changes in functional connectivity of flexible regions may, therefore, be understood as shifts in the proportion of time specific connections are engaged, rather than a switch between networks per se. This ability of specific regions to dynamically link ICNs under different task conditions may play an important role in behavioral flexibility., (© 2014 Wiley Periodicals, Inc.)

Background: Benign paroxysmal positional vertigo (BPPV) is the most common disorder of the vestibular system of the inner ear, which is a vital part of maintaining balance. Although the efficacy of the Epley maneuver-also known as the canalith repositioning maneuver (CRM)-is well established, data comparing CRM versus a hybrid treatment are lacking., Purpose: The purpose of this study was to determine the effect of a hybrid treatment, the Gans repositioning maneuver (GRM) either with or without postmaneuver restrictions, compared with CRM on treatment of posterior canal BPPV (PC-BPPV)., Research Design: Study design was a randomized controlled trial., Study Sample: A total of 45 patients (30 males and 15 females) with unilateral PC-BPPV were randomly allocated to one of three equal groups on the basis of the date of the first visit with matched assignment for gender: a GRMR group (GRM with postmaneuver restrictions), a GRM group, and a CRM group., Intervention: Patients received weekly administration of the maneuver until resolution of symptoms. The Dix-Hallpike test was performed before treatment at every appointment, and finally after 1 mo from the last maneuver., Data Collection and Analysis: Nystagmus duration and vertigo intensity were recorded. The supine roll test was performed in case the Dix-Hallpike test was negative to test otoconial migration. Data were analyzed with repeated-measures analysis of variance, paired t-tests with a Bonferroni correction, and the Spearman rank correlation coefficient., Results: All patients showed improvement within the groups, and PC-BPPV symptoms were resolved by an average of 2, 1.7, and 1.6 maneuvers for GRMR, GRM, and CRM, respectively, with no statistical differences among the three groups (p > 0.05). Only two patients had recurrence, and one patient had horizontal BPPV at 1 mo follow-up., Conclusion: We demonstrated that the GRM as a new treatment is effective in treating PC-BPPV with no benefits to postmaneuver restrictions., (American Academy of Audiology.)

The world is experiencing the popularization of mobile devices. This was made possible by the increasing technological advances and the advent of the Internet as a communication and information tool. These facts demonstrate that the development of applications compatible with such devices is an effective way to provide content to diverse audiences. In the educational field, these devices can be seen as technological support artifacts for distance education, serving as strategy for continuous and permanent education for health professionals. The Open University of Brazilian National Health System (UNA-SUS) offers distance learning courses, including specializating on free access. In order to increase the public reach, UNA-SUS developed mobile applications as supporting material for students. These applications can be accessed in offline mode, increasing the accessibility and therefore, improving the efficiency of the material. The 28 applications developed with responsive online books format currently reached the milestone of over 6,000 downloads. This number shows the positive acceptance of the format used, accentuated by the ease of having material downloaded from the device, not requiring the user to be connected to access content.

Developmental topographical disorientation (DTD) is a newly discovered cognitive disorder in which individuals experience a lifelong history of getting lost in both novel and familiar surroundings. Recent studies have shown that such a selective orientation defect relies primarily on the inability of the individuals to form cognitive maps, i.e., mental representations of the surrounding that allow individuals to get anywhere from any location in the environment, although other orientation skills are additionally affected. To date, the neural correlates of this developmental condition are unknown. Here, we tested the hypothesis that DTD may be related to ineffective functional connectivity between the hippocampus (HC; known to be critical for cognitive maps) and other brain regions critical for spatial orientation. A group of individuals with DTD and a group of control subjects underwent a resting-state functional magnetic resonance imaging (rsfMRI) scan. In addition, we performed voxel-based morphometry to investigate potential structural differences between individuals with DTD and controls. The results of the rsfMRI study revealed a decreased functional connectivity between the right HC and the prefrontal cortex (PFC) in individuals with DTD. No structural differences were detected between groups. These findings provide evidence that ineffective functional connectivity between HC and PFC may affect the monitoring and processing of spatial information while moving within an environment, resulting in the lifelong selective inability of individuals with DTD to form cognitive maps that are critical for orienting in both familiar and unfamiliar surroundings., (Copyright © 2014 Wiley Periodicals, Inc.)

While the widely studied allocentric spatial representation holds a special status in neuroscience research, its exact nature and neural underpinnings continue to be the topic of debate, particularly in humans. Here, based on a review of human behavioral research, we argue that allocentric representations do not provide the kind of map-like, metric representation one might expect based on past theoretical work. Instead, we suggest that almost all tasks used in past studies involve a combination of egocentric and allocentric representation, complicating both the investigation of the cognitive basis of an allocentric representation and the task of identifying a brain region specifically dedicated to it. Indeed, as we discuss in detail, past studies suggest numerous brain regions important to allocentric spatial memory in addition to the hippocampus, including parahippocampal, retrosplenial, and prefrontal cortices. We thus argue that although allocentric computations will often require the hippocampus, particularly those involving extracting details across temporally specific routes, the hippocampus is not necessary for all allocentric computations. We instead suggest that a non-aggregate network process involving multiple interacting brain areas, including hippocampus and extra-hippocampal areas such as parahippocampal, retrosplenial, prefrontal, and parietal cortices, better characterizes the neural basis of spatial representation during navigation. According to this model, an allocentric representation does not emerge from the computations of a single brain region (i.e., hippocampus) nor is it readily decomposable into additive computations performed by separate brain regions. Instead, an allocentric representation emerges from computations partially shared across numerous interacting brain regions. We discuss our non-aggregate network model in light of existing data and provide several key predictions for future experiments.

Trait neuroticism is suggested to be related to measures of volume and function of the hippocampus, a brain structure located in the medial temporal lobe that is critical for human navigation and orientation. In this study, we assessed whether measures of trait neuroticism and self-concept are correlated with the human ability to orient by means of cognitive maps (i.e. mental representations of an environment that include landmarks and their spatial relationships). After controlling for gender differences, which are well-known in spatial orientation abilities, we found that measures of neuroticism (i.e. negative affect, emotional stability) and self-concept (i.e. self-esteem) were correlated with individual differences in the rate at which cognitive maps were formed; the same measures were generally unrelated to the ability to make use of cognitive maps, as well as the ability to orient using visual path integration. The relationships (and lack thereof) between personality traits and the spatial orientation skills, as reported in the present study, are consistent with specific neural correlates underlying these factors, and may have important implications for treatment of disorders related to them., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Path integration is a fundamental skill for navigation in both humans and animals. Despite recent advances in unraveling the neural basis of path integration in animal models, relatively little is known about how path integration operates at a neural level in humans. Previous attempts to characterize the neural mechanisms used by humans to visually path integrate have suggested a central role of the hippocampus in allowing accurate performance, broadly resembling results from animal data. However, in recent years both the central role of the hippocampus and the perspective that animals and humans share similar neural mechanisms for path integration has come into question. The present study uses a data driven analysis to investigate the neural systems engaged during visual path integration in humans, allowing for an unbiased estimate of neural activity across the entire brain. Our results suggest that humans employ common task control, attention and spatial working memory systems across a frontoparietal network during path integration. However, individuals differed in how these systems are configured into functional networks. High performing individuals were found to more broadly express spatial working memory systems in prefrontal cortex, while low performing individuals engaged an allocentric memory system based primarily in the medial occipito-temporal region. These findings suggest that visual path integration in humans over short distances can operate through a spatial working memory system engaging primarily the prefrontal cortex and that the differential configuration of memory systems recruited by task control networks may help explain individual biases in spatial learning strategies.

Spatial orientation is a complex cognitive process requiring the integration of information processed in a distributed system of brain regions. Current models on the neural basis of spatial orientation are based primarily on the functional role of single brain regions, with limited understanding of how interaction among these brain regions relates to behavior. In this study, we investigated two sources of variability in the neural networks that support spatial orientation--network configuration and efficiency--and assessed whether variability in these topological properties relates to individual differences in orientation accuracy. Participants with higher accuracy were shown to express greater activity in the right supramarginal gyrus, the right precentral cortex, and the left hippocampus, over and above a core network engaged by the whole group. Additionally, high-performing individuals had increased levels of global efficiency within a resting-state network composed of brain regions engaged during orientation and increased levels of node centrality in the right supramarginal gyrus, the right primary motor cortex, and the left hippocampus. These results indicate that individual differences in the configuration of task-related networks and their efficiency measured at rest relate to the ability to spatially orient. Our findings advance systems neuroscience models of orientation and navigation by providing insight into the role of functional integration in shaping orientation behavior.

As neuropsychologists and psychologists specializing in the assessment and treatment of pediatric mental health concerns, one of the most prominent diagnoses we encounter is attention-deficit hyperactivity disorder (ADHD). Following a pediatric neuropsychological evaluation, parents often request recommendations for treatment. This article addresses our approach to the treatment of ADHD from the private practice perspective. We will review our primary treatment methodology as well as integrative and alternative treatment approaches.

Objectives: The purpose of the study was to examine the relationship between self-reported stress levels among new mothers in São Paulo, Brazil and two biomarkers of stressful experience, oxytocin (OT) and Epstein-Barr Virus antibody level (EBV-ab), with planned pregnancy hypothesized as a moderator of biological response to stressful conditions., Methods: Sixty-three first-time mothers between the ages of 15 and 45 were recruited from neighborhoods in São Paulo, Brazil. Quantitative and qualitative data were collected longitudinally, bi-weekly between two and 12 weeks postpartum. OT level was assessed from breast milk samples and EBV-ab from blood spot samples. An Interpersonal Satisfaction scale was developed, validated, and administered, along with the Cohen perceived stress scale (PSS)., Results: In-depth interview data revealed unplanned pregnancy to be a significant stressor in the lives of first-time mothers. In linear regression, OT level was negatively associated with interpersonal satisfaction score (P = 0.022) and positively associated with PSS score (P = 0.007). When splitting the sample by planned status of the pregnancy, women with an unplanned pregnancy showed a strengthened positive association between OT level and PSS (P = 0.001; Adj R(2) = 0.44) and negative association with interpersonal satisfaction (P = 0.017; Adj R(2) = 0.15), while no associations existed for women with a planned pregnancy. EBV-ab level was not correlated or associated with stress/satisfaction measures., Conclusion: OT is an effective biomarker in the measurement of stress in the body, and additionally reflects differential experiences with difficult interpersonal circumstances, such as unplanned pregnancy. By contrast, EBV-ab failed to reflect differences in self-reported stress levels between mothers., (Copyright © 2013 Wiley Periodicals, Inc.)

The intraparietal sulcus (IPS) contains topographically organized regions, similar to retinotopic maps in visual cortex. These regions, referred to as IPS1-4, show similar functional responses to the mapping tasks used to define them, yet differing responses to tests of other posterior parietal cortex (PPC) functions such as short-term memory, eye movements and object viewing, suggesting that they may have distinct patterns of structural connectivity to other parts of the brain. The present study combined functional magnetic resonance imaging (fMRI) mapping with diffusion tensor imaging (DTI) to describe white matter connections of visuotopic regions along the IPS, in 25 neurotypical young-adult participants. We found that posterior IPS more likely connects to retinotopically defined visual regions, and superior temporal gyrus, relative to anterior IPS. Anterior IPS regions 3 and 4 had higher connection probabilities to prefrontal regions, relative to posterior IPS. All four IPS regions showed inter-hemispheric connections to analogous regions in the opposite hemisphere, as well as consistent connections to the thalamus and regions of the striatum. Multivariate pattern classification at the group level reliably distinguished IPS regions from one another on the basis of connectivity patterns, especially for the most distal pairs of regions; occipital and prefrontal regions provided the most discriminating information. These findings advance our understanding of the structure of visuotopic IPS, with implications for functional differences between regions, and possible homologies between humans and macaques. Visuospatial functions dependent on the parietal cortex are frequently impaired in individuals with developmental disorders and those afflicted by cerebrovascular disease; the findings described here can be used as a basis for comparing connectivity differences in these populations., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Building on an integration of research findings on intergroup behavior from multiple fields of scientific inquiry (biological and cultural paleoanthropology, social psychology), as well as research on the HEXACO personality framework (e.g., Ashton & Lee, 2007), 3 independent studies (total N = 1,007) were conducted to introduce and test a fresh personality perspective on human xenophilia. Even though the studies focused on different criteria (Study 1: favorable attitudes toward contact with immigrants, Study 2: habitual cross-cultural exploration, Study 3: favorable attitudes toward contact with indigenous people) and employed different operationalizations of major personality traits (the HEXACO Personality Inventory-Revised [HEXACO-PI-R], the 10-item Big Five Inventory [BFI-10]) results were remarkably similar. First, path analyses confirmed that major personality traits were significant and direct predictors of xenophilia that were independent of the contributions of individual differences commonly predicting xenophobic reactions across studies. Second, and in line with the authors' more specific hypotheses, hierarchical regression analyses also corroborated that individual differences in the levels of endeavor-related personality traits (i.e., eXtraversion, Openness, and Conscientiousness) had a substantially greater power in predicting individual differences in xenophilia than individual differences in levels of altruism/cooperation-related traits (i.e., Honesty-Humility, Emotionality, and Agreeableness). The implications of these findings for more general psychological theorizing on human sociality are discussed., (PsycINFO Database Record (c) 2013 APA, all rights reserved)

This study presents a consumer and farmer safety evaluation on the use of four botanical pesticides in pepper berry crop protection. The pesticides evaluated include preparations from clove, tuba root, sweet flag and pyrethrum. Their safety evaluation was based on their active ingredients being eugenol, rotenone, β-asarone and pyrethrins, respectively. Botanical pesticides from Acorus calamus are of possible concern because of the genotoxic and carcinogenic ingredient β-asarone although estimated margins of exposure (MOE) for consumers indicate a low priority for risk management. For the other three botanical pesticides the margin of safety (MOS) between established acute reference doses and/or acceptable daily intake values and intake estimates for the consumer, resulting from their use as a botanical pesticide are not of safety concern, with the exception for levels of rotenone upon use of tuba root extracts on stored berries. Used levels of clove and pyrethrum as botanical pesticides in pepper berry crop production is not of safety concern for consumers or farmers, whereas for use of tuba root and sweet flag some risk factors were defined requiring further evaluation and/or risk management. It seems prudent to look for alternatives for use of sweet flag extracts containing β-asarone., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Human orientation in novel and familiar environments is a complex skill that can involve numerous different strategies. To date, a comprehensive account of how these strategies interrelate at the behavioural level has not been documented, impeding the development of elaborate systems neuroscience models of spatial orientation. Here, we describe a virtual environment test battery designed to assess five of the core strategies used by humans to orient. Our results indicate that the ability to form a cognitive map is highly related to more basic orientation strategies, supporting previous proposals that encoding a cognitive map requires inputs from multiple domains of spatial processing. These findings provide a topology of numerous primary orientation strategies used by humans during orientation and will allow researchers to elaborate on neural models of spatial cognition that currently do not account for how different orientation strategies integrate over time based on environmental conditions.

The development of thermoplastic materials based on starch has become a promising alternative for reducing plastic waste. To this end, plasma treatments were used to enhance the hydrophobicity of cornstarch films. Cornstarch films plasticized using glycerol and distilled water were prepared by casting. A surface modification method was employed using different precursor gases, HMDSO and SF(6), and a combined treatment using HMDSO followed by SF(6) (HMDSO/SF(6)) and then the reverse, using SF(6) first followed by HMDSO (SF(6)/HMDSO). The results indicated that the induced surface morphology determines the contact angle. It was observed that all films became hydrophobic, and films that were initially treated with SF(6) showed the greatest hydrophobicity if no further coating was applied, or if the treated surface was further coated using HMDSO. Under both of these treatment conditions the contact angle was greater than 110°., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Grid refinement is introduced in a numerical groundwater model to increase the accuracy of the solution over local areas without compromising the run time of the model. Numerical methods developed for grid refinement suffered certain drawbacks, for example, deficiencies in the implemented interpolation technique; the non-reciprocity in head calculations or flow calculations; lack of accuracy resulting from high truncation errors, and numerical problems resulting from the construction of elongated meshes. A refinement scheme based on the divergence theorem and Taylor's expansions is presented in this article. This scheme is based on the work of De Marsily (1986) but includes more terms of the Taylor's series to improve the numerical solution. In this scheme, flow reciprocity is maintained and high order of refinement was achievable. The new numerical method is applied to simulate groundwater flows in homogeneous and heterogeneous confined aquifers. It produced results with acceptable degrees of accuracy. This method shows the potential for its application to solving groundwater heads over nested meshes with irregular shapes., (© 2012, British Geological Survey © NERC 2012. Ground Water © 2012, National GroundWater Association.)

The present study describes physiologically based kinetic (PBK) models for the alkenylbenzene elemicin (3,4,5-trimethoxyallylbenzene) in rat and human, based on the PBK models previously developed for the structurally related alkenylbenzenes estragole, methyleugenol, and safrole. Using the newly developed models, the level of metabolic activation of elemicin in rat and human was predicted to obtain insight in species differences in the bioactivation of elemicin and read across to the other methoxy allylbenzenes, estragole and methyleugenol. Results reveal that the differences between rat and human in the formation of the proximate carcinogenic metabolite 1'-hydroxyelemicin and the ultimate carcinogenic metabolite 1'-sulfoxyelemicin are limited (<3.8-fold). In addition, a comparison was made between the relative importance of bioactivation for elemicin and that of estragole and methyleugenol. Model predictions indicate that compound differences in the formation of the 1'-sulfoxymetabolites are limited (<11-fold) in rat and human liver. The insights thus obtained were used to perform a risk assessment for elemicin using the margin of exposure (MOE) approach and read across to the other methoxy allylbenzene derivatives for which in vivo animal tumor data are available. This reveals that elemicin poses a lower priority for risk management as compared to its structurally related analogues estragole and methyleugenol. Altogether, the results obtained indicate that PBK modeling provides an important insight in the occurrence of species differences in the metabolic activation of elemicin. Moreover, they provide an example of how PBK modeling can facilitate a read across in risk assessment from compounds for which in vivo toxicity studies are available to a compound for which only limited toxicity data have been described, thus contributing to the development of alternatives for animal testing.

Attention-deficit hyperactivity disorder (ADHD) is a heavily studied topic in neuropsychology and general psychology, psychiatry, and pediatrics. The Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition, Text Revision (DSM-IV) is used to diagnose ADHD, but its criteria are behaviorally defined, while ADHD is a neurological dysfunction. The DSM-IV diagnostic criteria do not differentiate between attention and inhibition or executive functions (EF). As well, there is little agreement in the field about what constitutes ADHD and EFs or how to measure or diagnose them, let alone rule them out. When rendering an ADHD diagnosis, the responsible clinician considers DSM-IV criteria along with other reasons why an individual may express symptoms of ADHD, for reasons other than ADHD. This article discusses postulated mechanisms of action for some medications prescribed for ADHD, the variance of medication outcomes in research, the variance of assessment measures used in identifying ADHD subjects for research, and flaws with DSM-IV-based diagnosis. An argument is posed that the field of neuropsychology needs a cohesive and agreed-upon definition of ADHD and EF and how to measure it to more exactly research the topic, accurately diagnose the disorder, and assist prescribing professionals to use medications with improved first-trial precision.

Alkaloid-containing plants are an intrinsic part of the regular Western diet. The present paper summarizes the occurrence of alkaloids in the food chain, their mode of action and possible adverse effects including a safety assessment. Pyrrolizidine alkaloids are a reason for concern because of their bioactivation to reactive alkylating intermediates. Several quinolizidine alkaloids, β-carboline alkaloids, ergot alkaloids and steroid alkaloids are active without bioactivation and mostly act as neurotoxins. Regulatory agencies are aware of the risks and have taken or are considering appropriate regulatory actions for most alkaloids. These vary from setting limits for the presence of a compound in feed, foods and beverages, trying to define safe upper limits, advising on a strategy aiming at restrictions in use, informing the public to be cautious or taking specific plant varieties from the market. For some alkaloids known to be present in the modern food chain, e.g., piperine, nicotine, theobromine, theophylline and tropane alkaloids risks coming from the human food chain are considered to be low if not negligible. Remarkably, for many alkaloids that are known constituents of the modern food chain and of possible concern, tolerable daily intake values have so far not been defined., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Fungus-growing ants (tribe Attini) engage in a mutualism with a fungus that serves as the ants' primary food source, but successful fungus cultivation is threatened by microfungal parasites (genus Escovopsis). Actinobacteria (genus Pseudonocardia) associate with most of the phylogenetic diversity of fungus-growing ants; are typically maintained on the cuticle of workers; and infection experiments, bioassay challenges and chemical analyses support a role of Pseudonocardia in defence against Escovopsis through antibiotic production. Here we generate a two-gene phylogeny for Pseudonocardia associated with 124 fungus-growing ant colonies, evaluate patterns of ant-Pseudonocardia specificity and test Pseudonocardia antibiotic activity towards Escovopsis. We show that Pseudonocardia associated with fungus-growing ants are not monophyletic: the ants have acquired free-living strains over the evolutionary history of the association. Nevertheless, our analysis reveals a significant pattern of specificity between clades of Pseudonocardia and groups of related fungus-growing ants. Furthermore, antibiotic assays suggest that despite Escovopsis being generally susceptible to inhibition by diverse Actinobacteria, the ant-derived Pseudonocardia inhibit Escovopsis more strongly than they inhibit other fungi, and are better at inhibiting this pathogen than most environmental Pseudonocardia strains tested. Our findings support a model that many fungus-growing ants maintain specialized Pseudonocardia symbionts that help with garden defence.

Tubal ligation provides an effective and reliable method by which women can choose to limit the number of children they will bear. However, because of the irreversibility of the procedure and other potential disadvantages, it is important to understand factors associated with women's choice of this method of birth control. Between May 1999 and August 2000, data were collected from 755 women aged 40 to 60 years from a cross-section of neighborhoods of varying socio-economic make-up in Puebla, Mexico, finding a tubal ligation rate of 42.2%. Multiple logistic regression models were utilized to examine demographic, socio-economic, and reproductive history characteristics in relation to women's choice of tubal ligation. Regression analyses were repeated with participants grouped by age to determine how the timing of availability of tubal ligation related to the decision to undergo the procedure. The results of this study suggest that younger age, more education, use of some forms of birth control, and increased parity were associated with women's decisions to undergo tubal ligation. The statistically significant difference of greater tubal ligation and lower hysterectomy rates across age groups reflect increased access to tubal ligation in Mexico from the early 1970s, supporting the idea that women's choice of tubal ligation was related to access.

Laromustine (VNP40101M; 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(methylamino) carbonylhydrazine) is a novel sulfonylhydrazine alkylating agent. Phase 1 metabolism of laromustine was reported recently and showed that laromustine undergoes rearrangement, dehalogenation, and hydrolysis at physiological pH to form active moieties. (1) A mechanism for the rearrangement was proposed on the basis of fragmentation ions. (1) (,) (2) In this article, we report the phase II conjugates of VNP40101M and VNP4090CE which were formed after incubation of VNP40101M or VNP4090CE with pooled human liver microsomes (HLM) and cofactors nicotinamide adenine dinucleotide phosphate (NADPH), glutathione (GSH), N-acetylecysteine (NAC), and cysteine (CYS). Eight novel phase II conjugates (M-1 to M-8) were identified and characterized by hydrogen-deuterium exchange (H-D), stable isotope ((13)C-labeled VNP40101M), and MS(n) experiments. M-4 and M-5 were further confirmed by nuclear magnetic resonance spectroscopy (NMR). The short-lived CH(3)SO(2)CH(2)CH(2)-, methylformamide and CH(3)SO(2)NHN═CHCH(2)- moieties were generated from VNP40101M. The reactive intermediates CH(3)SO(2)CH(2)CH(2)- and methylformamide formed conjugates with GSH, CYS, and NAC. The CH(3)SO(2)NHN═CHCH(2)- moiety formed conjugates with GSH and NAC. M-2, M-4, and M-6 were only detected from the incubation of VNP40101M because VNP4090CE does not contain a methylformamide group. All other conjugates were formed by both VNP40101M and VNP4090CE. The in vitro studies found that VNP40101M and VNP4090CE undergo activation in human liver microsomes. The results from this study showed that laromustine produces several reactive intermediates that may play a role in the toxicities seen in the clinical trials.

We report an in situ surface X-ray diffraction study of liquid AuIn metal alloys in contact with zinc-blende InP (111)(B) substrates at elevated temperatures. We observe strong layering of the liquid metal alloy in the first three atomic layers in contact with the substrate. The first atomic layer of the alloy has a higher indium concentration than in bulk. In addition, in this first layer we find evidence for in-plane ordering at hollow sites, which could sterically hinder nucleation of zinc-blende InP. This can explain the typical formation of the wurtzite crystal structure in InP nanowires grown from AuIn metal particles.

The objective of this study was to determine the influence of powdered coconut water (ACP-318(®)) diluted in high glucose (11.0 mM) TCM199 in the achievement of nuclear in vitro maturation (IVM) of canine oocytes. Cumulus oocyte complexes (COCs) (n = 632) were randomly allocated into three experimental groups named as group 1 (control group), group 2 (5% powdered coconut water) and group 3 (10% powdered coconut water). The percentage of meiotic resumption (MR) (GVBD to MII) was 39.1% (81/207), 50.2% (108/215) and 46.6% (98/210) for groups 1, 2 and 3 respectively (p < 0.05). There were no differences in MR rates among groups 2 and 3. The medium with ACP-318(®) slightly enhanced the nuclear maturation of canine oocytes when a comparison was established with rates of maturation exhibited by oocytes in the experimental group 1 without ACP-318(®) (p < 0.05). The results suggest that oocytes' nuclear morphology integrity and meiosis achievement were positively influenced when exposed to high glucose TCM199 supplemented with 5% powdered coconut water. Further investigation must be performed for a better understanding of powdered coconut water influence in cellular events during IVM of dog oocytes., (© 2009 Blackwell Verlag GmbH.)

Host-parasite associations are potentially shaped by evolutionary reciprocal selection dynamics, in which parasites evolve to overcome host defences and hosts are selected to counteract these through the evolution of new defences. This is expected to result in variation in parasite-defence interactions, and the evolution of resistant parasites causing increased virulence. Fungus-growing ants maintain antibiotic-producing Pseudonocardia (Actinobacteria) that aid in protection against specialized parasites of the ants' fungal gardens, and current evidence indicates that both symbionts have been associated with the ants for millions of years. Here we examine the extent of variation in the defensive capabilities of the ant-actinobacterial association against Escovopsis (parasite-defence interactions), and evaluate how variation impacts colonies of fungus-growing ants. We focus on five species of Acromyrmex leaf-cutting ants, crossing 12 strains of Pseudonocardia with 12 strains of Escovopsis in a Petri plate bioassay experiment, and subsequently conduct subcolony infection experiments using resistant and non-resistant parasite strains. Diversity in parasite-defence interactions, including pairings where the parasites are resistant, suggests that chemical variation in the antibiotics produced by different actinobacterial strains are responsible for the observed variation in parasite susceptibility. By evaluating the role this variation plays during infection, we show that infection of ant subcolonies with resistant parasite strains results in significantly higher parasite-induced morbidity with respect to garden biomass loss. Our findings thus further establish the role of Pseudonocardia-derived antibiotics in helping defend the ants' fungus garden from the parasite Escovopsis, and provide evidence that small molecules can play important roles as antibiotics in a natural system.

Elevated plasma cholesterol, a well-known risk factor for cardiovascular diseases, is the result of the activity of many genes and their encoded proteins in a complex physiological network. We aim to develop a minimal kinetic computational model for predicting plasma cholesterol levels. To define the scope of this model, it is essential to discriminate between important and less important processes influencing plasma cholesterol levels. To this end, we performed a systematic review of mouse knockout strains and used the resulting dataset, named KOMDIP, for the identification of key genes that determine plasma cholesterol levels. Based on the described phenotype of mouse knockout models, 36 of the 120 evaluated genes were marked as key genes that have a pronounced effect on the plasma cholesterol concentration. The key genes include well-known genes, e.g., Apoe and Ldlr, as well as genes hardly linked to cholesterol metabolism so far, e.g., Plagl2 and Slc37a4. Based on the catalytic function of the genes, a minimal conceptual model was defined. A comparison with nine conceptual models from literature revealed that each of the individual published models is less complete than our model. Concluding, we have developed a conceptual model that can be used to develop a physiologically based kinetic model to quantitatively predict plasma cholesterol levels., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Laromustine (VNP40101M, also known as Cloretazine) is a novel sulfonylhydrazine alkylating (anticancer) agent. Laromustine generates two types of reactive intermediates: 90CE and methylisocyanate. When incubated with rat, dog, monkey, and human liver microsomes, [(14)C]laromustine was converted to 90CE (C-8) and seven other radioactive components (C-1-C-7). There was little difference in the metabolite profile among the species examined, in part because the formation of most components (C-1-C-6 and 90CE) did not require NADPH but involved decomposition and/or hydrolysis. The exception was C-7, a hydroxylated metabolite, largely formed by CYP2B6 and CYP3A4/5. Laromustine caused direct inhibition of CYP2B6 and CYP3A4/5 (the two enzymes involved in C-7 formation) as well as of CYP2C19. K(i) values were 125 microM for CYP2B6, 297 muM for CYP3A4/5, and 349 microM for CYP2C19 and were greater than the average clinical plasma C(max) of laromustine (25 microM). There was evidence of time-dependent inhibition of CYP1A2, CYP2B6, and CYP3A4/5. Treatment of primary cultures of human hepatocytes with up to 100 microM laromustine did not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4/5, but the highest concentration of laromustine decreased the activity and levels of immunoreactive CYP3A4. The results of this study suggest the laromustine has 1) negligible victim potential with respect to metabolism by cytochrome P450 enzymes, 2) negligible enzyme-inducing potential, and 3) the potential in some cases to cause inhibition of CYP2B6, CYP3A4, and possibly CYP2C19 during and shortly after the duration of intravenous administration of this anticancer drug, but the clinical effects of such interactions are likely to be insignificant.