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Species with widespread distributions play a crucial role in our understanding of climate change impacts on population structure. In marine species, population structure is often governed by both high connectivity potential and selection across strong environmental gradients. Despite the complexity of factors influencing marine populations, studying species with broad distribution can provide valuable insights into the relative importance of these factors and the consequences of climate-induced alterations across environmental gradients. We used the northern shrimp Pandalus borealis and its wide latitudinal distribution to identify current drivers of population structure and predict the species' vulnerability to climate change. A total of 1514 individuals sampled across 24° latitude were genotyped at high geographic (54 stations) and genetic (14,331 SNPs) resolutions to assess genetic variation and environmental correlations. Four populations were identified in addition to finer substructure associated with local adaptation. Geographic patterns of neutral population structure reflected predominant oceanographic currents, while a significant proportion of the genetic variation was associated with gradients in salinity and temperature. Adaptive landscapes generated using climate projections suggest a larger genomic offset in the southern extent of the P. borealis range, where shrimp had the largest adaptive standing genetic variation. Our genomic results combined with recent observations point to further deterioration in southern regions and an impending vulnerable status in the regions at higher latitudes for P. borealis. They also provide rare insights into the drivers of population structure and climatic vulnerability of a widespread meroplanktonic species, which is crucial to understanding future challenges associated with invertebrates essential to ecosystem functioning., (© 2024 His Majesty the King in Right of Canada and The Authors. Molecular Ecology published by John Wiley & Sons Ltd. Reproduced with the permission of the Minister of Fisheries and Oceans Canada.)

A global decline in seagrass populations has led to renewed calls for their conservation as important providers of biogenic and foraging habitat, shoreline stabilization and carbon storage. Eelgrass ( Zostera marina ) occupies the largest geographic range among seagrass species spanning a commensurately broad spectrum of environmental conditions. In Canada, eelgrass is managed as a single phylogroup despite occurring across three oceans and a range of ocean temperatures and salinity gradients. Previous research has focused on applying relatively few markers to reveal population structure of eelgrass, whereas a whole-genome approach is warranted to investigate cryptic structure among populations inhabiting different ocean basins and localized environmental conditions. We used a pooled whole-genome re-sequencing approach to characterize population structure, gene flow and environmental associations of 23 eelgrass populations ranging from the Northeast United States to Atlantic, subarctic and Pacific Canada. We identified over 500,000 SNPs, which when mapped to a chromosome-level genome assembly revealed six broad clades of eelgrass across the study area, with pairwise F ST ranging from 0 among neighbouring populations to 0.54 between Pacific and Atlantic coasts. Genetic diversity was highest in the Pacific and lowest in the subarctic, consistent with colonization of the Arctic and Atlantic oceans from the Pacific less than 300 kya. Using redundancy analyses and two climate change projection scenarios, we found that subarctic populations are predicted to be potentially more vulnerable to climate change through genomic offset predictions. Conservation planning in Canada should thus ensure that representative populations from each identified clade are included within a national network so that latent genetic diversity is protected, and gene flow is maintained. Northern populations, in particular, may require additional mitigation measures given their potential susceptibility to a rapidly changing climate., Competing Interests: The authors declare no conflict of interest exists., (© 2024 His Majesty the King in Right of Canada and The Authors. Evolutionary Applications published by John Wiley & Sons Ltd. Reproduced with the permission of the Minister of Fisheries and Oceans Canada.)

A key component of the global blue economy strategy is the sustainable extraction of marine resources and conservation of marine environments through networks of marine protected areas (MPAs). Connectivity and representativity are essential factors that underlie successful implementation of MPA networks, which can safeguard biological diversity and ecosystem function, and ultimately support the blue economy strategy by balancing ocean use with conservation. New "big data" omics approaches, including genomics and transcriptomics, are becoming essential tools for the development and maintenance of MPA networks. Current molecular omics techniques, including population-scale genome sequencing, have direct applications for assessing population connectivity and for evaluating how genetic variation is represented within and among MPAs. Effective baseline characterization and long-term, scalable, and comprehensive monitoring are essential for successful MPA management, and omics approaches hold great promise to characterize the full range of marine life, spanning the microbiome to megafauna across a range of environmental conditions (shallow sea to the deep ocean). Omics tools, such as eDNA metabarcoding can provide a cost-effective basis for biodiversity monitoring in large and remote conservation areas. Here we provide an overview of current omics applications for conservation planning and monitoring, with a focus on metabarcoding, metagenomics, and population genomics. Emerging approaches, including whole-genome sequencing, characterization of genomic architecture, epigenomics, and genomic vulnerability to climate change are also reviewed. We demonstrate that the operationalization of omics tools can enhance the design, monitoring, and management of MPAs and thus will play an important role in a modern and comprehensive blue economy strategy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jeffery, Lehnert, Kess, Layton, Wringe and Stanley.)

Marine classification schemes based on abiotic surrogates often inform regional marine conservation planning in lieu of detailed biological data. However, these schemes may poorly represent ecologically relevant biological patterns required for effective design and management strategies. We used a community-level modeling approach to characterize and delineate representative mesoscale (tens to thousands of kilometers) assemblages of demersal fish and benthic invertebrates in the Northwest Atlantic. Hierarchical clustering of species occurrence data from four regional annual multispecies trawl surveys revealed three to six groupings (predominant assemblage types) in each survey region, broadly associated with geomorphic and oceanographic features. Indicator analyses identified 3-34 emblematic taxa of each assemblage type. Random forest classifications accurately predicted assemblage distributions from environmental covariates (AUC > 0.95) and identified thermal limits (annual minimum and maximum bottom temperatures) as important predictors of distribution in each region. Using forecasted oceanographic conditions for the year 2075 and a regional classification model, we projected assemblage distributions in the southernmost bioregion (Scotian Shelf-Bay of Fundy) under a high emissions climate scenario (RCP 8.5). Range expansions to the northeast are projected for assemblages associated with warmer and shallower waters of the Western Scotian Shelf over the 21st century as thermal habitat on the relatively cooler Eastern Scotian Shelf becomes more favorable. Community-level modeling provides a biotic-informed approach for identifying broadscale ecological structure required for the design and management of ecologically coherent, representative, well-connected networks of Marine Protected Areas. When combined with oceanographic forecasts, this modeling approach provides a spatial tool for assessing sensitivity and resilience to climate change, which can improve conservation planning, monitoring, and adaptive management., (© 2022 Her Majesty the Queen in Right of Canada. Ecological Applications published by Wiley Periodicals LLC on behalf of The Ecological Society of America. Reproduced with the permission of the Minister of Fisheries and Oceans Canada.)

The impacts of climate change and the socioecological challenges they present are ubiquitous and increasingly severe. Practical efforts to operationalize climate-responsive design and management in the global network of marine protected areas (MPAs) are required to ensure long-term effectiveness for safeguarding marine biodiversity and ecosystem services. Here, we review progress in integrating climate change adaptation into MPA design and management and provide eight recommendations to expedite this process. Climate-smart management objectives should become the default for all protected areas, and made into an explicit international policy target. Furthermore, incentives to use more dynamic management tools would increase the climate change responsiveness of the MPA network as a whole. Given ongoing negotiations on international conservation targets, now is the ideal time to proactively reform management of the global seascape for the dynamic climate-biodiversity reality., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Objectives: This study aimed to identify, assess and summarize available scientific evidence on tailored text messaging interventions focused on type 2 diabetes self-management. The systematic review concentrated on message design and delivery features, and tailoring strategies. The meta-analysis assessed the moderators of the effectiveness of tailored text messaging interventions., Methods: A comprehensive search strategy included major electronic databases, key journal searches and reference list searching for related studies. PRISMA and Cochrane Collaboration's guidelines and recommended tools for data extraction, quality appraisal and data analysis were followed. Data were extracted on participant characteristics (age, gender, ethnicity), and interventional and methodological characteristics (study design, study setting, study length, choice of modality, comparison group, message type, format, content, use of interactivity, message frequency, message timing, message delivery, tailoring strategies and theory use). Outcome measures included diet, physical activity, medication adherence and glycated hemoglobin data (HbA1C). Where possible, a random effects meta-analysis was performed to pool data on the effectiveness of the tailored text messaging interventions and moderator variables., Results: The search returned 13 eligible trials for the systematic review and 11 eligible trials for the meta-analysis. The majority of the studies were randomized controlled trials, conducted in high-income settings, used multi-modalities, and mostly delivered informative, educational messages through an automated message delivery system. Tailored text messaging interventions produced a substantial effect ( g  = 0.54, 95% CI = 0.08-0.99, p  < 0.001) on HbA1C values for a total of 949 patients. Subgroup analyses revealed the importance of some moderators such as message delivery ( Q B  = 18.72, df = 1, p  = 0.001), message direction ( Q B  = 5.26, df = 1, p  = 0.022), message frequency ( Q B  = 18.72, df = 1, p  = 0.000) and using multi-modalities ( Q B  = 6.18, df = 1, p  = 0.013)., Conclusions: Tailored mobile text messaging interventions can improve glycemic control in type 2 diabetes patients. However, more rigorous interventions with larger samples and longer follow-ups are required to confirm these findings and explore the effects of tailored text messaging on other self-management outcomes.

Objective: This systematic review aims to collect existing literature and summarize the impact of active workstations on the health and work outcomes of participants with overweight or obesity., Methods: Five databases were examined (until March 2018), and the keywords "desk," "workstation," "work station," and "work stations" were used with any one of the following terms: "active," "bik*," "cycling," "height adjustable," "stepping," "stand up," "standing," "treadmill*," "walk*," "elliptical," "bicycl*," "pedaling," "stability ball," "stability balls," "exercise ball," "exercise balls," "swiss ball," "swiss balls," "sit-to-stand," and "sit stand.", Results: Nineteen studies (two with school-aged children) were included in this review. Nine studies used treadmill, three used cycling, one used stepping, and twelve used standing desks. A decrease in sedentary time and an increase in physical activity level and energy expenditure were observed for most of the active workstations. Both the treadmill and the cycle desk improved glycemic control, but the treadmill desk was the only workstation for which improved work performance and help in body-weight management (body fat percentage, body weight, waist and hip circumference) were reported., Conclusions: Active workstations are a promising solution for decreasing occupational sedentariness. Overall, active workstations have a positive impact on energy expenditure and physical activity in individuals with overweight and obesity., (© 2019 The Obesity Society.)

In the northwest Atlantic Ocean, sea scallop (Placopecten magellanicus) has been characterized by a latitudinal genetic cline with a breakpoint between northern and southern genetic clusters occurring at ~45°N along eastern Nova Scotia, Canada. Using 96 diagnostic single-nucleotide polymorphisms (SNPs) capable of discriminating between northern and southern clusters, we examined fine-scale genetic structure of scallops among 27 sample locations, spanning the largest geographic range evaluated in this species to date (~37-51°N). Here, we confirmed previous observations of northern and southern groups, but we show that the boundary between northern and southern clusters is not a discrete latitudinal break. Instead, at latitudes near the previously described boundary, we found unexpected patterns of fine-scale genetic structure occurring between inshore and offshore sites. Scallops from offshore sites, including St. Pierre Bank and the eastern Scotian Shelf, clustered with southern stocks, whereas inshore sites at similar latitudes clustered with northern stocks. Our analyses revealed significant genetic divergence across small spatial scales (i.e., 129-221 km distances), and that spatial structure over large and fine scales was strongly associated with temperature during seasonal periods of thermal minima. Clear temperature differences between inshore and offshore locations may explain the fine-scale structuring observed, such as why southern lineages of scallop occur at higher latitudes in deeper, warmer offshore waters. Our study supports growing evidence that fine-scale population structure in marine species is common, often environmentally associated, and that consideration of environmental and genomic data can significantly enhance the identification of marine diversity and management units.

Domestication is rife with episodes of interbreeding between cultured and wild populations, potentially challenging adaptive variation in the wild. In Atlantic salmon, Salmo salar , the number of domesticated individuals far exceeds wild individuals, and escape events occur regularly, yet evidence of the magnitude and geographic scale of interbreeding resulting from individual escape events is lacking. We screened juvenile Atlantic salmon using 95 single nucleotide polymorphisms following a single, large aquaculture escape in the Northwest Atlantic and report the landscape-scale detection of hybrid and feral salmon (27.1%, 17/18 rivers). Hybrids were reproductively viable, and observed at higher frequency in smaller wild populations. Repeated annual sampling of this cohort revealed decreases in the presence of hybrid and feral offspring over time. These results link previous observations of escaped salmon in rivers with reports of population genetic change, and demonstrate the potential negative consequences of escapes from net-pen aquaculture on wild populations., Competing Interests: The authors declare no competing interests.

Two genetically distinct lineages of European green crabs ( Carcinus maenas ) were independently introduced to eastern North America, the first in the early 19th century and the second in the late 20th century. These lineages first came into secondary contact in southeastern Nova Scotia, Canada (NS), where they hybridized, producing latitudinal genetic clines. Previous studies have documented a persistent southward shift in the clines of different marker types, consistent with existing dispersal and recruitment pathways. We evaluated current clinal structure by quantifying the distribution of lineages and fine-scale hybridization patterns across the eastern North American range (25 locations, ~39 to 49°N) using informative single nucleotide polymorphisms (SNPs; n  = 96). In addition, temporal changes in the genetic clines were evaluated using mitochondrial DNA and microsatellite loci ( n  = 9-11) over a 15-year period (2000-2015). Clinal structure was consistent with prior work demonstrating the existence of both northern and southern lineages with a hybrid zone occurring between southern New Brunswick (NB) and southern NS. Extensive later generation hybrids were detected in this region and in southeastern Newfoundland. Temporal genetic analysis confirmed the southward progression of clines over time; however, the rate of this progression was slower than predicted by forecasting models, and current clines for all marker types deviated significantly from these predictions. Our results suggest that neutral and selective processes contribute to cline dynamics, and ultimately, highlight how selection, hybridization, and dispersal can collectively influence invasion success.

The spatial genetic structure of most species in the open marine environment remains largely unresolved. This information gap creates uncertainty in the sustainable management, recovery, and associated resilience of marine communities and our capacity to extrapolate beyond the few species for which such information exists. We document a previously unidentified multispecies biogeographic break aligned with a steep climatic gradient and driven by seasonal temperature minima in the northwest Atlantic. The coherence of this genetic break across our five study species with contrasting life histories suggests a pervasive macroecological phenomenon. The integration of this genetic structure with habitat suitability models and climate forecasts predicts significant variation in northward distributional shifts among populations and availability of suitable habitat in future oceans. The results of our integrated approach provide new perspective on how cryptic intraspecific diversity associated with climatic variation influences species and community response to climate change beyond simple poleward shifts.

Genetic-environment associations are increasingly revealed through population genomic data and can occur through a number of processes, including secondary contact, divergent natural selection, or isolation by distance. Here, we investigate the influence of the environment, including seasonal temperature and salinity, on the population structure of the invasive European green crab ( Carcinus maenas ) in eastern North America. Green crab populations in eastern North America are associated with two independent invasions, previously shown to consist of distinct northern and southern ecotypes, with a contact zone in southern Nova Scotia, Canada. Using a RAD-seq panel of 9,137 genomewide SNPs, we detected 41 SNPs (0.49%) whose allele frequencies were highly correlated with environmental data. A principal components analysis of 25 environmental variables differentiated populations into northern, southern, and admixed sites in concordance with the observed genomic spatial structure. Furthermore, a spatial principal components analysis conducted on genomic and geographic data revealed a high degree of global structure ( p  < .0001) partitioning a northern and southern ecotype. Redundancy and partial redundancy analyses revealed that among the environmental variables tested, winter sea surface temperature had the strongest association with spatial structuring, suggesting that it is an important factor defining range and expansion limits of each ecotype. Understanding environmental thresholds associated with intraspecific diversity will facilitate the ability to manage current and predict future distributions of this aquatic invasive species.

Clinal variation across replicated environmental gradients can reveal evidence of local adaptation, providing insight into the demographic and evolutionary processes that shape intraspecific diversity. Using 1773 genome-wide single nucleotide polymorphisms we evaluated latitudinal variation in allele frequency for 134 populations of North American and European Atlantic salmon ( Salmo salar ). We detected 84 (4.74%) and 195 (11%) loci showing clinal patterns in North America and Europe, respectively, with 12 clinal loci in common between continents. Clinal single nucleotide polymorphisms were evenly distributed across the salmon genome and logistic regression revealed significant associations with latitude and seasonal temperatures, particularly average spring temperature in both continents. Loci displaying parallel clines were associated with several metabolic and immune functions, suggesting a potential basis for climate-associated adaptive differentiation. These climate-based clines collectively suggest evidence of large-scale environmental associated differences on either side of the North Atlantic. Our results support patterns of parallel evolution on both sides of the North Atlantic, with evidence of both similar and divergent underlying genetic architecture. The identification of climate-associated genomic clines illuminates the role of selection and demographic processes on intraspecific diversity in this species and provides a context in which to evaluate the impacts of climate change., Competing Interests: We have no competing interests.

The ability to detect and characterize hybridization in nature has long been of interest to many fields of biology and often has direct implications for wildlife management and conservation. The capacity to identify the presence of hybridization, and quantify the numbers of individuals belonging to different hybrid classes, permits inference on the magnitude of, and timescale over which, hybridization has been or is occurring. Here, we present an r package and associated workflow developed for the detection, with estimates of efficiency and accuracy, of multigenerational hybrid individuals using genetic or genomic data in conjunction with the program newhybrids. This package includes functions for the identification and testing of diagnostic panels of markers, the simulation of multigenerational hybrids, and the quantification and visualization of the efficiency and accuracy with which hybrids can be detected. Overall, this package delivers a streamlined hybrid analysis platform, providing improvements in speed, ease of use and repeatability over current ad hoc approaches. The latest version of the package and associated documentation are available on GitHub (https://github.com/bwringe/hybriddetective)., (© 2017 John Wiley & Sons Ltd.)

The Northwest Atlantic cod stocks collapsed in the early 1990s and have yet to recover, despite the subsequent establishment of a continuing fishing moratorium. Efforts to understand the collapse and lack of recovery have so far focused mainly on the dynamics of commercially harvested species. Here, we use data from a 33-year scientific trawl survey to determine to which degree the signatures of the collapse and recovery of the cod are apparent in the spatial and temporal dynamics of the broader groundfish community. Over this 33-year period, the groundfish community experienced four phases of change: (i) a period of rapid, synchronous biomass collapse in most species, (ii) followed by a regime shift in community composition with a concomitant loss of functional diversity, (iii) followed in turn by periods of slow compositional recovery, and (iv) slow biomass growth. Our results demonstrate how a community-wide perspective can reveal new aspects of the dynamics of collapse and recovery unavailable from the analysis of individual species or a combination of a small number of species. Overall, we found evidence that such community-level signals should be useful for designing more effective management strategies to ensure the persistence of exploited marine ecosystems., Competing Interests: We declare we have no competing interests.

Genomic studies of invasive species can reveal both invasive pathways and functional differences underpinning patterns of colonization success. The European green crab ( Carcinus maenas ) was initially introduced to eastern North America nearly 200 years ago where it expanded northwards to eastern Nova Scotia. A subsequent invasion to Nova Scotia from a northern European source allowed further range expansion, providing a unique opportunity to study the invasion genomics of a species with multiple invasions. Here, we use restriction-site-associated DNA sequencing-derived SNPs to explore fine-scale genomewide differentiation between these two invasions. We identified 9137 loci from green crab sampled from 11 locations along eastern North America and compared spatial variation to mitochondrial COI sequence variation used previously to characterize these invasions. Overall spatial divergence among invasions was high (pairwise F ST ~0.001 to 0.15) and spread across many loci, with a mean F values >0.05. The majority of the most divergent loci (i.e., outliers, ~1.2%) displayed latitudinal clines in allele frequency highlighting extensive genomic divergence among the invasions. Discriminant analysis of principal components (both neutral and outlier loci) clearly resolved the two invasions spatially and was highly correlated with mitochondrial divergence. Our results reveal extensive cryptic intraspecific genomic diversity associated with differing patterns of colonization success and demonstrates clear utility for genomic approaches to delineating the distribution and colonization success of aquatic invasive species.ST ~0.052 and 52% of loci examined characterized by F ST values >0.05. The majority of the most divergent loci (i.e., outliers, ~1.2%) displayed latitudinal clines in allele frequency highlighting extensive genomic divergence among the invasions. Discriminant analysis of principal components (both neutral and outlier loci) clearly resolved the two invasions spatially and was highly correlated with mitochondrial divergence. Our results reveal extensive cryptic intraspecific genomic diversity associated with differing patterns of colonization success and demonstrates clear utility for genomic approaches to delineating the distribution and colonization success of aquatic invasive species.

Advances in genetic sequencing technologies and techniques have made large, genome-wide data sets comprised of hundreds or even thousands of individuals and loci the norm rather than the exception even for nonmodel organisms. While such data present new opportunities for evaluating population structure and demographic processes, the large size of these genomic data sets brings new computational challenges for researchers needing to parse, convert and manipulate data often into a variety of software-specific formats required of genomic analyses. We developed genepopedit as a flexible tool for the manipulation of multilocus molecular data sets. Functionality can be divided among diagnostic-, manipulation-, sampling-, simulation-, and transformation-based tools. Metadata from large genomic data sets can be efficiently extracted, without the need to view data in a text-editing program. genepopedit provides tools to manipulate loci, individual samples and populations included in genomic data sets, in addition to the ability to convert directly to a variety of software formats. Functions are compiled as an R package, which can integrate into existing analysis workflows. Importantly, genepopedit provides a simple yet robust code-based tool for repeatable genomic data manipulation, which has been proven to be stable for data sets in excess of 200 000 SNPs. The latest version of the package and associated documentation are available on Github (github.com/rystanley/genepopedit)., (© 2016 John Wiley & Sons Ltd.)

Hybridization among populations and species is a central theme in many areas of biology, and the study of hybridization has direct applicability to testing hypotheses about evolution, speciation and genetic recombination, as well as having conservation, legal and regulatory implications. Yet, despite being a topic of considerable interest, the identification of hybrid individuals, and quantification of the (un)certainty surrounding the identifications, remains difficult. Unlike other programs that exist to identify hybrids based on genotypic information, newhybrids is able to assign individuals to specific hybrid classes (e.g. F 1 , F 2 ) because it makes use of patterns of gene inheritance within each locus, rather than just the proportions of gene inheritance within each individual. For each comparison and set of markers, multiple independent runs of each data set should be used to develop an estimate of the hybrid class assignment accuracy. The necessity of analysing multiple simulated data sets, constructed from large genomewide data sets, presents significant computational challenges. To address these challenges, we present parallelnewhybrid, an r package designed to decrease user burden when undertaking multiple newhybrids analyses. parallelnewhybrid does so by taking advantage of the parallel computational capabilities inherent in modern computers to efficiently and automatically execute separate newhybrids runs in parallel. We show that parallelization of analyses using this package affords users several-fold reductions in time over a traditional serial analysis. parallelnewhybrid consists of an example data set, a readme and three operating system-specific functions to execute parallel newhybrids analyses on each of a computer's c cores. parallelnewhybrid is freely available on the long-term software hosting site github (www.github.com/bwringe/parallelnewhybrid)., (© 2016 John Wiley & Sons Ltd.)

Understanding patterns of dispersal and connectivity among marine populations can directly inform fisheries conservation and management. Advances in high-throughput sequencing offer new opportunities for estimating marine connectivity. We used restriction-site-associated DNA sequencing to examine dispersal and realized connectivity in the sea scallop Placopecten magellanicus , an economically important marine bivalve. Based on 245 individuals sampled rangewide at 12 locations from Newfoundland to the Mid-Atlantic Bight, we identified and genotyped 7163 single nucleotide polymorphisms; 112 (1.6%) were identified as outliers potentially under directional selection. Bayesian clustering revealed a discontinuity between northern and southern samples, and latitudinal clines in allele frequencies were observed in 42.9% of the outlier loci and in 24.6% of neutral loci. Dispersal estimates derived using these clines and estimates of linkage disequilibrium imply limited dispersal; 373.1 ± 407.0 km (mean ± SD) for outlier loci and 641.0 ± 544.6 km (mean ± SD) for neutral loci. Our analysis suggests restricted dispersal compared to the species range (>2000 km) and that dispersal and effective connectivity differ. These observations support the hypothesis that limited effective dispersal structures scallop populations along eastern North America. These findings can help refine the appropriate scale of management and conservation in this commercially valuable species.

To understand coastal dispersal dynamics of Atlantic cod (Gadus morhua), we examined spatiotemporal egg and larval abundance patterns in coastal Newfoundland. In recent decades, Smith Sound, Trinity Bay has supported the largest known overwintering spawning aggregation of Atlantic cod in the region. We estimated spawning and dispersal characteristics for the Smith Sound-Trinity Bay system by fitting ichthyoplankton abundance data to environmentally-driven, simplified box models. Results show protracted spawning, with sharply increased egg production in early July, and limited dispersal from the Sound. The model for the entire spawning season indicates egg export from Smith Sound is 13%•day(-1) with a net mortality of 27%•day(-1). Eggs and larvae are consistently found in western Trinity Bay with little advection from the system. These patterns mirror particle tracking models that suggest residence times of 10-20 days, and circulation models indicating local gyres in Trinity Bay that act in concert with upwelling dynamics to retain eggs and larvae. Our results are among the first quantitative dispersal estimates from Smith Sound, linking this spawning stock to the adjacent coastal waters. These results illustrate the biophysical interplay regulating dispersal and connectivity originating from inshore spawning of coastal northwest Atlantic.

Objective: To assess the safety and efficacy of alcohol-facilitated ankylosis of the distal intertarsal (DIT) and tarsometatarsal (TMT) joints in horses with osteoarthritis (bone spavin)., Design: Prospective clinical trial., Animals: 21 horses with DIT or TMT joint-associated hind limb lameness and 5 nonlame horses., Procedures: 11 horses (group 1) underwent lameness, force-plate, and radiographic examinations; following intra-articular analgesia, lameness and force-plate examinations were repeated. Nonlame horses were used for force-plate data acquisition only. Following localization of lameness to the DIT and TMT joints, contrast arthrographic evaluation was performed; when communication with the tibiotarsal joint was not evident or suspected, 70% ethyl alcohol (3 mL) was injected. Group 1 horses underwent lameness, force-plate, and radiographic examinations every 3 months for 1 year. Ten other horses (group 2) underwent lameness and radiographic examinations followed by joint injection with alcohol; follow-up information was obtained from owners or via clinical examination., Results: Significant postinjection reduction in lameness (after 3 days to 3 months) was evident for all treated horses. Twelve months after injection, 10 of 11 group 1 horses were not lame; lameness grade was 0.5 in 1 horse. Follow-up information was available for 9 of 10 group 2 horses; 7 were not lame, and 2 remained mildly lame (1 had a concurrent problem in the injected limb, and the other had DIT joint collapse that precluded needle entry)., Conclusions and Clinical Relevance: Intra-articular alcohol injection in horses with bone spavin resulted in a rapid (usually within 3 months) reduction in lameness and joint space collapse.

Objective: To determine whether intra-articular 70% ethyl alcohol alone (IAEA) or in combination with 2 percutaneously placed transarticular lag screws (EA-TLS) would result in arthrodesis of the equine proximal interphalangeal (PIP) joint., Study Design: Experimental., Animals: Healthy horses (n=6), aged 1.5-3 years, free of lameness, diagonally paired front and hind PIP joints., Methods: Six milliliters 70% ethyl alcohol was injected into randomly selected diagonally paired front and hind PIP joints. Thirty days later, 2 parallel 5.5 mm cortical screws were inserted in lag fashion across the hind PIP joints and the limbs were cast. Horses were confined for 60 days after surgery before free exercise was permitted. Serial lameness examinations were performed at 1, 6, and 10 months. Radiographs of the PIP joints were obtained before injection with alcohol (front, hind PIP joints), at 6 and 10 months (front PIP joints) and 1, 3, 6, and 10 months (hind PIP joints). At 10 months, horses were euthanatized and gross and histopathologic examination of the treated joints was performed., Results: Horses had variable cartilage thinning (more severe in hind PIP joints) and dorsal bone proliferation. One front and 1 hind PIP joint were fused 10 months after alcohol injection., Conclusions: Ethyl alcohol injected alone or in combination with percutaneously placed transarticular lag screws failed to reliably produce fusion of the PIP joint., (© Copyright 2011 by The American College of Veterinary Surgeons.)

Objective: To compare the biomechanical characteristics, failure mode, and effects of side (left or right limb) and end (forelimb or hindlimb) of different screws in 2-screw, parallel-screw proximal interphalangeal joint arthrodesis constructs in horses., Study Design: In vitro experimental study., Sample Population: Twenty limbs from 6 cadavers (4 complete limb sets, 2 partial sets-total of 4 forelimb and 6 hindlimb pairs)., Methods: Two parallel 5.5 mm cortical (AO) screws were inserted in lag fashion in 1 randomly allocated limb of a pair, and 2 parallel headless, tapered, variable-pitched, titanium compression screws (Acutrak-Plus) were inserted in the contralateral limb. Constructs were tested in 3-point bending in a dorsopalmar (plantar) direction using a materials-testing machine at a loading rate of 5.83 mm/s. Maximal bending moment at failure and composite stiffness were calculated from data generated on load-displacement curves. Data were analyzed using a Friedman 2-way analysis of variance and Wilcoxon's signed-rank tests., Results: No significant difference was detected for bending moment or stiffness values in proximal interphalangeal joint arthrodesis constructs using 2 parallel Acutrak-Plus or AO screws for fixation. Mean stiffness values were significantly different between forelimb and hindlimb constructs., Conclusions: Performance of 2 parallel Acutrak-Plus screws was biomechanically comparable with 2 parallel AO 5.5 mm cortical screws in in vitro pastern arthrodesis constructs., Clinical Relevance: Acutrak-Plus screws may provide an alternative means of fixation for proximal interphalangeal joint arthrodesis.

Background: Informed consent is a critical component of clinical research. Different methods of presenting information to potential participants of clinical trials may improve the informed consent process. Audio-visual interventions (presented for example on the Internet, DVD, or video cassette) are one such method., Objectives: To assess the effects of providing audio-visual information alone, or in conjunction with standard forms of information provision, to potential clinical trial participants in the informed consent process, in terms of their satisfaction, understanding and recall of information about the study, level of anxiety and their decision whether or not to participate., Search Strategy: We searched: the Cochrane Consumers and Communication Review Group Specialised Register (searched 20 June 2006); the Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane Library, issue 2, 2006; MEDLINE (Ovid) (1966 to June week 1 2006); EMBASE (Ovid) (1988 to 2006 week 24); and other databases. We also searched reference lists of included studies and relevant review articles, and contacted study authors and experts. There were no language restrictions., Selection Criteria: Randomised and quasi-randomised controlled trials comparing audio-visual information alone, or in conjunction with standard forms of information provision (such as written or oral information as usually employed in the particular service setting), with standard forms of information provision alone, in the informed consent process for clinical trials. Trials involved individuals or their guardians asked to participate in a real (not hypothetical) clinical study., Data Collection and Analysis: Two authors independently assessed studies for inclusion and extracted data. Due to heterogeneity no meta-analysis was possible; we present the findings in a narrative review., Main Results: We included 4 trials involving data from 511 people. Studies were set in the USA and Canada. Three were randomised controlled trials (RCTs) and the fourth a quasi-randomised trial. Their quality was mixed and results should be interpreted with caution. Considerable uncertainty remains about the effects of audio-visual interventions, compared with standard forms of information provision (such as written or oral information normally used in the particular setting), for use in the process of obtaining informed consent for clinical trials. Audio-visual interventions did not consistently increase participants' levels of knowledge/understanding (assessed in four studies), although one study showed better retention of knowledge amongst intervention recipients. An audio-visual intervention may transiently increase people's willingness to participate in trials (one study), but this was not sustained at two to four weeks post-intervention. Perceived worth of the trial did not appear to be influenced by an audio-visual intervention (one study), but another study suggested that the quality of information disclosed may be enhanced by an audio-visual intervention. Many relevant outcomes including harms were not measured. The heterogeneity in results may reflect the differences in intervention design, content and delivery, the populations studied and the diverse methods of outcome assessment in included studies., Authors' Conclusions: The value of audio-visual interventions for people considering participating in clinical trials remains unclear. Evidence is mixed as to whether audio-visual interventions enhance people's knowledge of the trial they are considering entering, and/or the health condition the trial is designed to address; one study showed improved retention of knowledge amongst intervention recipients. The intervention may also have small positive effects on the quality of information disclosed, and may increase willingness to participate in the short-term; however the evidence is weak. There were no data for several primary outcomes, including harms. In the absence of clear results, triallists should continue to explore innovative methods of providing information to potential trial participants. Further research should take the form of high-quality randomised controlled trials, with clear reporting of methods. Studies should conduct content assessment of audio-visual and other innovative interventions for people of differing levels of understanding and education; also for different age and cultural groups. Researchers should assess systematically the effects of different intervention components and delivery characteristics, and should involve consumers in intervention development. Studies should assess additional outcomes relevant to individuals' decisional capacity, using validated tools, including satisfaction; anxiety; and adherence to the subsequent trial protocol.

Migraineurs have specific preferences with regard to migraine therapy. In surveys, they consistently cite several attributes they seek in a migraine medication: rapid pain relief, complete pain relief, ability to return to normal functioning, relief of migraine-associated symptoms, reduction in headache recurrence, and minimal adverse effects. When prescribing medication for patients with migraine, physicians should respect patients' treatment preferences and select drugs that most closely meet patients' needs. As a class, the 5-HT(1B/1D) agonists, or triptans, have many of these attributes, including effectively relieving pain and associated symptoms and allowing patients to return fairly quickly to their normal activities. However, differences have emerged in the ability of specific triptans to satisfy patient preferences. Physicians should consider these differences when prescribing triptans for their patients with migraine.

The present study examined the effect of a range of doses of chronic nicotine (0.75, 1.5, 3.0 and 30.0 mg kg(-1) day(-1), s.c., 14 days) upon striatal dopaminergic nerve terminal survival following 6-hydroxydopamine (6-OHDA; 10 microg intrastriatal unilaterally) in rats; and the effects of acute nicotine (1 mg kg(-1), s.c.) pretreatment upon striatal neurodegeneration induced by methamphetamine (5 mg kg(-1), i.p., three doses at 2 h intervals) in wild-type and alpha4 nicotinic receptor (nAChR) subunit knockout mice. In both models of Parkinsonian-like damage, loss of striatal dopaminergic nerve terminals was assessed by [(3)H]-mazindol autoradiography. In rats, chronic nicotine infusion delivered by osmotic minipump implanted subcutaneously 7 days prior to intrastriatal 6-OHDA injection produced significant and dose-related protection against 6-OHDA-induced neurodegeneration. Low (0.75 and 1.5 mg kg(-1) day(-1)) but not high (3.0 and 30.0 mg kg(-1) day(-1)) nicotine doses significantly inhibited 6-OHDA-induced degeneration. In wild-type mice, acute nicotine treatment produced significant inhibition of methamphetamine-induced neurodegeneration. In alpha4 nAChR subunit knockout mice, acute nicotine treatment failed to inhibit methamphetamine-induced neurodegeneration. Nicotine is capable of protecting dopaminergic neurons against Parkinsonian-like neurodegeneration in vivo. In rats, this neuroprotective effect is critically dependent upon nicotine dose and is consistent with the activation of nAChRs, as high, desensitizing doses of nicotine fail to be neuroprotective. Further, neuroprotection is absent in alpha4 nAChR subunit knockout mice. The current results therefore suggest that activation of alpha4 subunit containing nAChRs constitutes a major component of the neuroprotective effect of nicotine upon Parkinsonian-like damage in vivo.

Recent evidence suggests that alpha7 subunit-containing nicotinic receptors (nAChRs) within the ventral tegmental area (VTA) are involved in the processes underlying nicotine tolerance and withdrawal. The current study used in situ hybridization histochemistry with multiple radiolabelled probes to amplify mRNA signal, to examine the distribution of alpha7 nAChR subunit mRNA both in control brains and following chronic nicotine treatment (1.5 and 30.0 mg/kg/day). Low levels of alpha7 transcript were detected within substantia nigra pars compacta (SNpc), substantia nigra pars reticularis (SNpr) and VTA. Higher levels of alpha7 transcript were found within the cortex and hippocampus. Following chronic nicotine treatment, levels of alpha7 subunit mRNA were significantly elevated in SNpc, SNpr and VTA, but were unchanged in cortex and hippocampus.

Lanepitant, a potent non-peptide neurokinin-1 receptor antagonist, inhibits neurogenic dural inflammation, and may have a role in migraine therapy. This study evaluated the effect of lanepitant taken daily for migraine prevention. Patients with migraine headaches with and without aura by International Headache Society classification criteria were enrolled in a 12-week double-blind, parallel design study comparing the effect of 200 mg qd lanepitant (n = 42) and placebo (n = 42) on reduction of migraine frequency. The primary outcome measure was response rate, i.e. the proportion of patients with a 50% reduction in days of headache. Of the 84 patients enrolled, 90.5% were female. The endpoint response rate for lanepitant-treated patients (41.0%) was not statistically significantly (P = 0.065) greater than that for placebo-treated patients (22.0%). No efficacy variables differed significantly between treatments, except for response rates at month 3 (P = 0.045). Higher plasma concentrations were no more effective than lower concentrations. In this study lanepitant was not effective in preventing migraine, but was well tolerated. These results do not support a role for NK-1 antagonism in migraine prevention.

Recent evidence suggests that aberrant nicotinic receptor (nAChR) expression plays an important role in schizophrenia. The present study sought to examine the distribution of nAChRs within the thalamus and associated cholinergic structures by examining nAChR subunit mRNA expression using in situ hybridization histochemistry. Transcripts for alpha4 and beta2 subunits were found in high levels in all thalamic nuclei and at lower levels in cholinergic nuclei (PPTg and MS/VDB). Distribution of mRNA encoding for additional subunits was restricted; lower alpha3 subunit transcript levels were detected in the anterior thalamic nuclei and portions of the lateral and posterior thalamic nuclei, with alpha7 transcripts being detected in cholinergic nuclei, the IMD and very low levels in the RTN. Low levels of alpha6 and beta3 transcript were found only within the RTN.

The introduction in 1991 of sumatriptan succinate, the first approved 5-HT1B/1D receptor agonist, represented a significant advance in the treatment of acute migraine. The approval of three additional 5-HT receptor agonists, including rizatriptan, has further expanded the options for migraine treatment. Four randomized clinical trials have compared the effects of oral sumatriptan with those of oral rizatriptan. Forty mg rizatriptan was more effective than 100 mg sumatriptan but was associated with a high incidence of adverse events. Five mg rizatriptan was comparable to 50 mg sumatriptan. In two trials, rizatriptan 10 mg, the recommended dose in most countries, had a more rapid onset of action than 50 mg (p<0.05) and 100 mg sumatriptan (p=0.075). In addition, 10 mg rizatriptan resulted in more patients being pain-free after 2 hours than 100 mg sumatriptan (p<0.05), and resulted in fewer drug-related adverse events than sumatriptan.

Headache is an extremely common symptom in primary care practice. Despite the ubiquity of the pain, differential diagnosis of headache is not difficult, provided the clinician obtains a comprehensive history. A complete physical examination and specific testing may be required to rule out other underlying causes, but headache itself falls into 3 main classes that are readily identified. Migraine headache occurs most commonly in women, is of moderate to severe intensity, and is often accompanied by nausea and increased sensitivity to light and sound. Cluster headache describes multiple recurrent attacks of severe unilateral pain and occurs most frequently in men. Tension-type headache is the most common form, characterized by mild to moderate dull pain that is often brought on by stress and/or depression. Understanding the triggers and manifestations of these headache types is essential for effective management.

Objective: To assess the effectiveness of the nonprescription combination of acetaminophen, aspirin, and caffeine in alleviating migraine headache pain., Design: Three double-blind, randomized, parallel-group, single-dose, placebo-controlled studies., Setting: Private practice, referral centers, and general community., Patients: Migraineurs with moderate or severe headache pain who met International Headache Society diagnostic criteria for migraine with aura or without aura. The most severely disabled segment of migraineurs, including those whose attacks usually required bed rest, or who vomited 20% or more of the time, were excluded. Of the 1357 enrolled patients, 1250 took study medication and 1220 were included in the efficacy-evaluable data set., Intervention: Two tablets of the nonprescription combination of acetaminophen, aspirin, and caffeine or placebo taken orally as a single-dose treatment of 1 eligible acute migraine attack., Main Outcome Measures: Pain intensity difference from baseline; percentage of patients with pain reduced to mild or none., Results: Significantly greater reductions in migraine headache pain intensity 1 to 6 hours after dose were seen in patients taking the acetaminophen, aspirin, and caffeine combination than in those taking placebo in each of the 3 studies. Pain intensity was reduced to mild or none 2 hours after dose in 59.3% of the 602 drug-treated patients compared with 32.8% of the 618 placebo-treated patients (P< .001; 95% confidence interval [CI], 55%-63% for drug, 29%-37% for placebo); at 6 hours after dose, 79% vs 52%, respectively, had pain reduced to mild or none (P<.001; 95% CI, 75%-82% vs 48%-56%). In addition, by 6 hours after dose, 50.8% of the drug-treated patients were pain free compared with 23.5% of the placebo-treated patients (P<.001; 95% CI, 47%-55% for drug, 20%-27% for placebo). Other migraine headache characteristics, such as nausea, photophobia, phonophobia, and functional disability, were significantly improved 2 to 6 hours after treatment with the acetaminophen, aspirin, and caffeine combination compared with placebo (P< or =.01)., Conclusions: The nonprescription combination of acetaminophen, aspirin, and caffeine was highly effective for the treatment of migraine headache pain as well as for alleviating the nausea, photophobia, phonophobia, and functional disability associated with migraine attacks. This drug combination also has an excellent safety profile and is well tolerated.

A simple technique based on a Fizeau interferometer to measure the absolute phase shift on reflection for a Fabry-Perot interferometer dielectric stack mirror is described. Excellent agreement between the measured and predicted phase shift on reflection was found. Also described are the salient features of low-order Fabry-Perot interferometers and the demonstration of a near ideal low-order (1-10) Fabry-Perot interferometer through minimizing the phase dispersion on reflection of the dielectric stack. This near ideal performance of a low-order Fabry-Perot interferometer should enable several applications such as compact spectral imagers for solid and gas detection. The large free spectral range of such systems combined with an active control system will also allow simple interactive tuning of wavelength agile laser sources such as CO(2) lasers, external cavity diode lasers, and optical parametric oscillators.

The following is a summary of guidelines created under the auspices of the National Headache Foundation, in an effort to improve the care of headache patients in primary care practice. The guidelines represent the consensus of an advisory panel of practitioners chosen by the NHF for their expertise in four specialty areas. A complete set of guidelines can be obtained by calling the National Headache Foundation at 1-800-843-2256 or by writing to them at 428 W. St. James Pl., 2nd Floor, Chicago, IL 60614-2750; the cost is $10.

The efficacy of BMS 180048, a 5-HT1 agonist in the acute treatment of a migraine headache, was evaluated in 216 patients. Three doses of the study drug were compared to placebo. Patients received a single test dose in the physician's office while being evaluated with a Holter monitor during a headache-free day. They then treated a migraines headache with a single dose of the study drug as an outpatient. The 150 mg- and 200-mg doses of BMS were significantly superior to placebo on change in pain intensity at 2 hours. Patients treated with BMS 180048 had a longer duration of response than placebo-treated patients. At the 24-hour point, only 24% of the 150-mg group and 25% of the 200-mg group had relapsed, compared to placebo which had a 42% relapse rate. It is concluded that BMS 180048 is an effective compound for the treatment of migraine headaches with a prolonged duration of response.

The cysteine proteinase cathepsin B (CB) was isolated from immortalized murine BV-2 microglial cells and examined via sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting to establish physicochemical properties of CB from what is generally considered the resident CNS macrophage. Microglial proteases have been implicated in several pathological processes occurring in the CNS, including neurodegeneration. Murine microglial CB was observed to consist of two major single-chain species of 32 and 34 kDa, with pls of 5.5-5.2 and 5.1-4.5, respectively. In addition, a minor 24-kDa CB species was also observed in some microglial preparations. The major CB isozymes in microglia differed from those observed in murine liver and brain, which consisted of both single- and double-chain CB variants of 31 and 24-25 kDa/5 kDa, respectively, with pl values of 5.5-4.5. A microglial pro-CB of 37 kDa was also isolated, which could be processed to the 34-kDa single-chain CB species. Cystatin was observed to prevent pro-CB processing, whereas E-64 and leupeptin were only partially inhibitory. The 37-kDa pro-CB species was observed to undergo processing into the 34-kDa CB species when incubated at pH 5.5 but remained stable with respect to molecular mass when incubated at pH 7.0. In contrast, the 34-kDa single-chain CB species was observed to autodegrade when incubated at pH 7.0, whereas incubation at pH 5.5 did not affect the integrity of the species as monitored by immunoblotting. Both pro-CB and 32-kDa single-chain CB species were observed extracellularly following lipopolysaccharide activation of BV-2 microglial cells.

Verrucous carcinoma, because of its oftentimes unusual clinical appearance, may be misdiagnosed if there is not good communication between the surgeon and the pathologist. We have reviewed our series of 20 cases of verrucous carcinoma from 1964 through 1974 and have analyzed the results of our therapy. We have concluded that verrucous carcinoma is a slow-growing, locally invasive lesion that does not metastasize to the cervical lymph nodes. Radiation therapy does not seem to be an effective method of treatment; the recurrence rate is high. Conservative laryngeal surgery is the preferred method of treatment in these patients and should prevent loss of life and spare laryngeal function.

Activities of a cathepsin B-like cysteine proteinase have previously been observed to correlate with the malignancy of several animal and human tumors. Plasma membrane fractions of some of these tumors have been found to be enriched in cathepsin B-like activity. We have determined the subcellular distribution of this enzyme and three additional lysosomal hydrolases (cathepsin H, beta-hexosaminidase, and beta-glucuronidase) in normal murine liver and six metastatic variants of the B16 melanoma. The tissues were fractionated initially by differential centrifugation followed by Percoll density gradient centrifugation of the light mitochondrial fraction. Two fractions were obtained: an L-2 fraction enriched in all four lysosomal hydrolases; and an L-1 fraction enriched in a marker enzyme for the plasma membrane. Cathepsin B-like and beta-hexosaminidase activities, but not the other hydrolase activities, were also found to be enriched in the L-1 fractions of the metastatic B16 tumors. We explored the nature of the association of the cathepsin B-like activity with the plasma membrane using fractions from the spontaneously metastatic B16 amelanotic melanoma. Activity could not be dissociated from the plasma membrane fraction by washing with a physiological salt solution suggesting that it was not adsorbed to this fraction nonspecifically, nor could it be displaced by mannose 6-phosphate or other sugars which compete for binding to the known lysosomal receptors. High salt concentrations, low concentrations of the mild detergent saponin, mild acidification, or phosphatidylinositol-specific phospholipase C did not elute the cathepsin B-like activity. However, activity was eluted by exposure to 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate, a detergent used in the purification of integral membrane proteins. The B16 amelanotic melanoma plasma membrane-associated cathepsin B-like activity had a slightly higher pH optimum and was resistant to inactivation by neutral pH and to inhibition by three low molecular weight inhibitors of cysteine proteinases. The Ki values for inhibition by leupeptin and stefin A were 20-fold higher. The presence of a cathepsin B-like cysteine proteinase at the surface of metastatic tumor cells, particularly in a form which can retain activity at physiological pH and retain activity in the presence of extracellular proteinase inhibitors, may contribute to the focal dissolution of the extracellular matrix observed at sites of contact with invading tumor cells.

Because supraglottic cancer usually is diagnosed late and metastasizes early, the cure rate is poorer than for glottic cancer. Supraglottic lesions can spread in any direction. The main method of diagnosis is either indirect or direct laryngoscopy, and the main symptoms are vague throat pain, otalgia, hemoptysis, hoarseness, and enlarged cervical lymph nodes. Roentgenographic examination is useful only as a supplement to other diagnostic measures. Staging of the disease is important in determining the most effective therapy and in predicting the results of treatment. Treatment should be individualized for each patient and should be selected on the basis of lesion size and site, the presence or absence of regional metastasis, the general health of the patient, and the likelihood of faithful follow-up.

Congenital cholesteatoma of the ear is a capricious and challenging problem for the otologist. We present 21 cases managed at the Mayo Clinic from 1961 to 1983. In all but one unusual case, the cholesteatoma developed behind an intact tympanic membrane and there was no history of aural infections. Preoperative symptoms and signs were predominantly conductive deafness with either a normal tympanic membrane or an opaque, whitish appearance to the drum. Disease was located in the middle ear or in the middle ear and mastoid, except in one patient who had cholesteatoma extending into the petrous apex. Surgical management depended on the extent of the lesion, and recurrences were unusual, suggesting that congenital cholesteatoma may not be as aggressive as acquired cholesteatoma.

Forty-eight patients (13 men and 35 women) took part in a double-blind randomized study. All patients received a placebo daily for 4 weeks (period A), at the end of which the frequency and severity of headaches experienced by each patient were assessed. Patients then received an active drug for 12 weeks (period B). Sixteen patients received nadolol, 80 mg/day; 16 received nadolol, 160 mg/day; and 16 received propranolol, 160 mg/day. The frequency and severity of headaches in the three groups were tabulated at the end of period B, as were the side effects. Only three subjects dropped out during the study, and one of these needed abdominal surgery. All three groups reported improvement, the most noticeable being in those patients who received 80 mg of nadolol daily.