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Long-term repeated-dose toxicity is mainly assessed in animals despite poor concordance of animal data with human toxicity. Nowadays advanced human in vitro systems, eg, metabolically competent HepaRG cells, are used for toxicity screening. Extrapolation of in vitro toxicity to in vivo effects is possible by reverse dosimetry using pharmacokinetic modeling. We assessed long-term repeated-dose toxicity of bosentan and valproic acid (VPA) in HepaRG cells under serum-free conditions. Upon 28-day exposure, the EC50 values for bosentan and VPA decreased by 21- and 33-fold, respectively. Using EC10 as lowest threshold of toxicity in vitro, we estimated the oral equivalent doses for both test compounds using a simplified pharmacokinetic model for the extrapolation of in vitro toxicity to in vivo effect. The model predicts that bosentan is safe at the considered dose under the assumed conditions upon 4 weeks exposure. For VPA, hepatotoxicity is predicted for 4% and 47% of the virtual population at the maximumrecommended daily dose after 3 and 4 weeks of exposure, respectively. We also investigated the changes in the central carbon metabolism of HepaRG cells exposed to orally bioavailable concentrations of both drugs. These concentrations are below the 28-day EC10 and induce significant changes especially in glucose metabolism and urea production. These metabolic changes may have a pronounced impact in susceptible patients such as those with compromised liver function and urea cycle deficiency leading to idiosyncratic toxicity. We show that the combination of modeling based on in vitro repeated-dose data and metabolic changes allows the prediction of human relevant in vivo toxicity with mechanistic insights. [ABSTRACT FROM AUTHOR]

This article summarizes some of my accomplishments during a 45-year career in fisheries science that ranged from conducting fish stock assessments, working for an international marine science organization, and managing a variety of scientific projects and activities, to finally serving as a scientific editor. In doing so, I have tried to focus on lessons learned. Starting my working life as a high-school math teacher, I soon opted for a different career, returned to the university, and received a PhD in fisheries biology. The first 15 years of my career were at the Woods Hole Laboratory of the National Marine Fisheries Service (NMFS) doing fish stock assessments, where my main interest was Atlantic mackerel (Scomber scombrus). Until the USA declared a 200-mile Exclusive Economic Zone (EEZ) in early 1977, the focal point of my work was the International Commission for the Northwest Atlantic Fisheries (ICNAF). Lasting friendships with scientists from other countries developed during the ICNAF meetings and continued for years thereafter, some to the present day. During 1977 -1985, my assessment activities were confined to domestic fisheries and interactions with regional fishery management councils, where I found that a cooperative attitude and the use of nontechnical language made a positive impression and helped build trust. Involvement in ICES assessment working groups led, in 1985, to being appointed Statistician in the ICES Secretariat in Copenhagen and the start of an 8-year life in the international community that culminated in becoming General Secretary. Some major changes in ICES in which I was intimately involved are discussed. After my return to the USA in 1994, my career included managing a variety of activities and projects in Woods Hole and at NOAA/NMFS headquarters in Silver Spring, MD (where I was NMFS liaison to the National Sea Grant Office), finally concluding, after my retirement from NMFS in 2004, with continued engagement in fisheries science as an editor for ICES. Having benefited from experiences in science and administration and the lessons learned therein, it is a pleasure, via this article, to offer advice to young scientists contemplating potential paths to pursue in their careers. [ABSTRACT FROM AUTHOR]

The World Conference on Stock Assessment Methods (July 2013) included a workshop on testing assessment methods through simulations. The exercise was made up of two steps applied to datasets from 14 representative fish stocks from around the world. Step 1 involved applying stock assessments to datasets with varying degrees of effort dedicated to optimizing fit. Step 2 was applied to a subset of the stocks and involved characteristics of given model fits being used to generate pseudo-data with error. These pseudo-data were then provided to assessment modellers and fits to the pseudo-data provided consistency checks within (self-tests) and among (cross-tests) assessment models. Although trends in biomass were often similar across models, the scaling of absolute biomass was not consistent across models. Similar types of models tended to perform similarly (e.g. age based or production models). Self-testing and cross-testing of models are a useful diagnostic approach, and suggested that estimates in the most recent years of time-series were the least robust. Results from the simulation exercise provide a basis for guidance on future large-scale simulation experiments and demonstrate the need for strategic investments in the evaluation and development of stock assessment methods. [ABSTRACT FROM PUBLISHER]

The biological mechanisms of autism spectrum disorders (ASDs) are largely unknown in spite of extensive research. ASD is characterized by altered function of multiple brain areas including the temporal cortex and by an increased synaptic excitation:inhibition ratio. While numerous studies searched for evidence of increased excitation in ASD, fewer have investigated the possibility of reduced inhibition. We characterized the cortical γ-amino butyric acid (GABA)ergic system in the rat temporal cortex of an ASD model [offspring of mothers prenatally injected with valproic acid (VPA)], by monitoring inhibitory post-synaptic currents (IPSCs) with patch-clamp. We found that numerous features of inhibition were severely altered in VPA animals compared to controls. Among them were the frequency of miniature IPSCs, the rise time and decay time of electrically-evoked IPSCs, the slope and saturation of their input/output curves, as well as their modulation by adrenergic and muscarinic agonists and by the synaptic GABAA receptor allosteric modulator zolpidem (but not by the extra-synaptic modulator gaboxadol). Our data suggest that both pre- and post-synaptic, but not extra-synaptic, inhibitory transmission is impaired in the offspring of VPA-injected mothers. We speculate that impairment in the GABAergic system critically contributes to an increase in the ratio between synaptic excitation and inhibition, which in genetically predisposed individuals may alter cortical circuits responsible for emotional, communication and social impairments at the core of ASD. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction. Dyspareunia in women, defined as persistent or recurrent genital pain associated with sexual intercourse, is hypothesized to be related to (fear associated) pelvic floor hyperactivity and to diminished sexual arousal. Psychophysiological research to support these hypotheses is scarce and concentrates mostly on the role of either pelvic floor activity or sexual arousal. To investigate both factors, a measurement device that enables simultaneous assessment of pelvic floor muscle activity and genital sexual arousal would be most optimal. Aim. The aim of this study was to test a new vaginal device-a vaginal photoplethysmograph with build-in surface electromyography (EMG)-that allows simultaneous assessment of pelvic floor muscle activity and vaginal blood flow. Main Outcome Measures. Genital arousal measured as vaginal pulse amplitude (VPA) and vaginal surface EMG. Methods. Thirty-six sexually functional women participated. To investigate the sensitivity of the device for changes in genital blood flow and involuntary changes in pelvic floor activity, VPA and vaginal surface EMG were monitored during exposure to sexual and anxiety-evoking film clips. In addition, vaginal surface EMG was monitored during voluntary flick and hold contractions. Results. VPA increased in response to the sexual film, and EMG values were significantly higher in response to the anxiety-evoking film. Higher EMG values in response to the anxiety film were associated with lower VPA. EMG during the instructed 3-second hold pelvic floor contractions showed, as expected, higher values during pelvic floor contractions with support of surrounding muscle groups, compared with pelvic floor muscles alone. Conclusion. The device is sensitive to changes in vaginal blood flow in response to sexual stimuli, and it is able to pick up small, involuntary changes in pelvic floor activity associated with anxiety. Also, the device is able to record changes in pelvic floor activity during voluntary pelvic floor contractions. This new device will be a valuable tool in further research on superficial dyspareunia. Both S, van Lunsen R, Weijenborg P, and Laan E. A new device for simultaneous measurement of pelvic floor muscle activity and vaginal blood flow: A test in a nonclinical sample. J Sex Med 2012;9:2888-2902. [ABSTRACT FROM AUTHOR]

The hydro-acoustic target strength (TS) of herring (Clupea harengus L.) was estimated from the catch composition of 19 pelagic-trawl hauls and from simultaneous recordings with a split-beam, 38kHz echosounder. The data were collected in September 2000 during a Bothnian Sea survey in the northern Baltic Sea. The dependence of TS (in dB) on fish length (L, cm) was modelled with the equation TS=alog10 L+b. The fitted model was TS=16.8log10 L−60.0. With a predefined slope of 20 the TS vs. log-fish length relationship was TS=20log10 L−63.9. The analyses suggested that TS was higher in the Bothnian Sea than is assumed in most studies in the Baltic Sea. Applying the revised TS–length dependence considerably enhanced the agreement between the biomass estimates from hydroacoustics and those from a catche-at-age analysis (VPA). [Copyright &y& Elsevier]

The data sets required for constructing age-based models for the Northeast Arctic cod stock are extended back to 1930 and critically reviewed. The full data set (1930–1994) is interpreted by both a standard virtual population analysis (VPA) and a version that allows for cannibalism. The resulting extended time-series of population abundance-at-age is used to reconsider the parent stock, temperature, and predation relationships described earlier. Results from the version of the VPA with cannibalism based on the new data confirm the earlier findings that temperature and spawning-stock biomass had a significant positive effect on recruitment. This is not the case with the extended time-series as interpreted by the standard VPA because, while significant temperature and juvenile predation effects are still found, a parent stock effect is no longer statistically significant. Moreover, the general level of explanation provided by the multiple regression is far less with the extended time-series. [ABSTRACT FROM PUBLISHER]

The eastern stock of gemfish in south-eastern Australia is currently assessed to be overfished and to be depleted below the performance criterion established by the Australian Fisheries Management Authority (AFMA). Assessments of the stock indicate that there was a substantial decline in abundance during the late 1970s and early 1980s and that the year classes spawned at the end of the 1980s were much weaker than expected from the (estimated) stock–recruitment relationship. The performances of a variety of alternative management procedures are contrasted. The factors considered in the operating models include uncertainty about historical catches, the comparability of recent survey estimates, the form of the stock–recruitment relationship, whether variations in recruitment about the stock–recruitment relationship are auto-correlated, and the quantity and quality of the data available for assessment purposes. The management procedures differ in terms of their data needs (survey data only, survey and age-composition data) and their target levels. The results indicate that, even though yields from the fishery are likely to be low, the benefits of conducting annual surveys exceed the costs. The value of collecting age-composition data is less clear. Management procedures based on Virtual Population Analysis achieve more variable catches and are less likely to satisfy AFMA performance criteria than management procedures based on a Schaefer production model, but they achieve higher levels of “guaranteed” catch for the industry. [ABSTRACT FROM PUBLISHER]

A simple model relating catchability to maturity is presented, which allows for computation of annual age-specific correction factors for groundfish survey indices. The model is based on the hypothesis that mature fish are less catchable than immature fish during the spawning season and are therefore less available to groundfish surveys carried out during that period. The effect modelled is an interaction effect – its operation requires both a change in catchability at maturity and temporal changes in maturity at age in the stock. In recent years, assessments of the Icelandic cod stock have relied on VPAs calibrated (tuned) with bottom trawl c.p.u.e. data. The c.p.u.e. data are from the commercial trawler fleet and from the Marine Research Institute's annual groundfish survey conducted in March, covering the entire distribution area of the stock around Iceland. At the time of the survey, most of the year's spawners have migrated towards the spawning grounds. Independent data from commercial catches indicate that the proportions of fish mature at age in the Icelandic cod stock have increased substantially in recent years. Furthermore, comparison of proportions mature in the catches with survey indices for mature and immature fish indicate that immature fish are substantially more catchable than mature fish of the same age. The effects of changes in proportion mature on estimated stock numbers are discussed with reference to limitations in the available data. [ABSTRACT FROM PUBLISHER]

The analysis of multiple time series of indices of recruitment to fish stocks by means of calibration regression is discussed, together with the use of the relationships so fitted for the prediction of year class strength. A simple method for the combination of the estimates derived from different index series using inverse variance weighted averages is proposed, and methods for the estimation of the overall error in the prediction are discussed. The method used has been shown to perform well in simulation tests, and is well adapted for use on real datasets with time series of variable length and missing data. It has been implemented in a computer program (RCT3, superseding RCRTINX2) which is available for operational use, and has been endorsed by the ICES Working Group on the Methods of Fish Stock Assessment as being satisfactory for operational use until more complex methods have been shown to have superior performance.opyright 1997 International Council for the Exploration of the Sea [ABSTRACT FROM PUBLISHER]

The approach suggested is in the class of cohort methods; it is a new technique for processing catch-at-age data on species having short (within a year) periods of fishery. The method can also be regarded as an approximation to more general conditions when fishery varies continuously during the year. In many cases it enables a more complete extraction of information on exploited populations and fishery from the catch-at-age matrices, including the natural mortality coefficient and terminal fishing parameters, without using any auxiliary data (survey data, fishing effort series etc.). A number of numerical experiments using simulated data illustrate the methodology and demonstrate the merits of the suggested method. [ABSTRACT FROM PUBLISHER]