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The current epoch in fisheries science has been driven by continual advances in laboratory techniques and  increasingly sophisticated approaches to analysing datasets. We now have the scientific knowledge and tools to proactively identify obstacles to the sustainable management of marine resources. However, in addition to technological advances, there are predicted global environmental changes, each with inherent implications for fisheries. The 2023 symposium of the Fisheries Society of the British Isles called for "open and constructive knowledge exchange between scientists, stakeholders, managers and policymakers" (https://fsbi.org.uk/symposium-2023/), a nexus of collaborative groups best placed to identify issues and solutions. Arguably, the Centre of Environment, Aquaculture and Fisheries Science (Cefas) and their Scientific Advice for Fisheries Management (SAFM) Team sit at the centre of such a network. SAFM regularly engages with managers and stakeholders, undertakes scientific research, provides fisheries advice to the UK government, and are leading experts within the International Council for the Exploration of the Sea (ICES). As such, this paper is an opinion piece, linked to individual authors specialisms, that aims to highlight emerging issues affecting fisheries and suggest where research efforts could be focused that contribute to sustainable fisheries., (© 2024 Fisheries Society of the British Isles.)

Zooplankton are the key intermediary between primary production and the fish community and a cornerstone of marine food webs, but they are often poorly represented in models that tend to focus on fish, charismatic top predators, or ocean biogeochemistry. In this study, we use an intermediate complexity end-to-end food web model of the North Sea with explicit two-way coupling of zooplankton to phytoplankton and higher trophic levels to ask whether this matters. We vary the metabolic rate of omnivorous zooplankton (OZ) as a proxy for uncertainties in our understanding and modeling of zooplankton form and function, and moving beyond previous studies we look at the impacts on the food web in concert with climate warming and fishing. We consider impacts on food web state and time to recover the relevant unfished state after fishing ceases. We also consider potential impacts on pelagic and demersal fishing fleets if we assume that they are constrained by the requirement to allow recovery to an unfished state within a certain period of time as a way of ensuring consistency with Good Environmental Status as required by EU and UK legislation. We find that all three aspects considered are highly sensitive to changes in the treatment of zooplankton, with impacts being larger than for warming of 2 or 4°C across most food web functional groups, particularly for apex predators. We call for a programme of research aimed at improving our understanding of zooplankton ecology and its relationship to the wider food web, and we recommend that improved representations of zooplankton are incorporated in future modeling studies as a priority., (© 2024 Crown copyright. Journal of Fish Biology published by John Wiley & Sons Ltd on behalf of Fisheries Society of the British Isles. This article is published with the permission of the Controller of HMSO and the King's Printer for Scotland.)

Background: There is a need to improve prognostic accuracy for patients with cutaneous melanoma. A 31-gene expression profile (31-GEP) test uses the molecular biology of primary tumors to identify individual patient metastatic risk., Objective: Develop a nomogram incorporating 31-GEP with relevant clinical factors to improve prognostic accuracy., Methods: In an IRB-approved study, 1124 patients from 9 Mohs micrographic surgery centers were prospectively enrolled, treated with Mohs micrographic surgery, and underwent 31-GEP testing. Data from 684 of those patients with at least 1-year follow-up or a metastatic event were included in nomogram development to predict metastatic risk., Results: Logistic regression modeling of 31-GEP results and T stage provided the simplest nomogram with the lowest Bayesian information criteria score. Validation in an archival cohort (n = 901) demonstrated a significant linear correlation between observed and nomogram-predicted risk of metastasis. The resulting nomogram more accurately predicts the risk for cutaneous melanoma metastasis than T stage or 31-GEP alone., Limitations: The patient population is representative of Mohs micrographic surgery centers. Sentinel lymph node biopsy was not performed for most patients and could not be used in the nomogram., Conclusions: Integration of 31-GEP and T stage can gain clinically useful prognostic information from data obtained noninvasively., Competing Interests: Conflicts of interest Drs Covington, Caruso, Quick, and Zolochevska are employees and stockholders at Castle Biosciences. Drs Thorpe, Bricca, Campoli, DeBloom, Fazio, Greenhaw, Kirkland, Machan, Brodland, and Zitelli have no conflicts of interest to disclose., (Copyright © 2021 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

This study investigates the long-term performance of the mesophilic (35 °C) anaerobic mono-digestion of process waters (PW) from the hydrothermal carbonisation (HTC) of spent coffee grounds. At an organic loading rate (OLR) of 0.4 g COD L -1 d -1 , initial instability was seen, but after 40 days and supplementary alkalinity, the digestion stabilised with the chemical oxygen demand (COD) in the untreated PW degraded with 37.8-64.6% efficiency and the yield of methane at 0.16 L g COD -1 . An increase in OLR to 0.8 g COD L -1 d -1 caused a collapse in biogas production, and resulted in severe instability in the reactor, characterised by falling pH and an increasing volatile fatty acid concentration. Comparatively, the digestion of a treated PW (concentrated in nanofiltration and reverse osmosis after removal of the fouling fraction), at OLR between 0.4 and 0.8 g COD L -1 d -1 , was stable over the entire 117 days of treated PW addition, yielded methane at 0.21 L g COD -1 and the COD was degraded with an average efficiency of 93.5% - the highest efficiency the authors have seen for HTC PW. Further anaerobic digestion of untreated PW at an average OLR of 0.95 g COD L -1 d -1 was stable for 38 days, with an average COD degradation of 69.6%, and methane production between 0.15 and 0.19 L g COD -1 . The digestion of treated PW produced significantly higher COD degradation and methane yield than untreated PW, which is likely to be related to the removal of refractory and inhibitory organic material in the post-HTC treatment by adsorption of hydrophobic material., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The aim of this work was to study the potentials and benefits of dynamic biogas production from Anaerobic Digestion (AD) of sewage sludge. The biogas production rate was aimed to match the flexible demand for electricity generation and so appropriate feeding regimes were calculated and tested in both pilot and demonstration scale. The results demonstrate that flexibilization capability exists for both conventional AD and advanced AD using Thermal Hydrolysis Process (THP) as pre-treatment. Whilst the former provides lower capability, flexible biogas production was achieved by the latter, as it provides a quick response. In all scenarios, the value of the biogas converted into electricity is higher than with a steady operational regime, increasing by 3.6% on average (up to 5.0%) in conventional and by 4.8% on average (up to 7.1%) with THP. The process has proven scalable up to 18 m 3 digester capacity in operational conditions like those in full scale., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

This study investigates the recovery of phosphorus from the process water obtained through hydrothermal carbonisation (HTC) of a 'wet' biomass waste, namely spent coffee grounds. HTC was shown to liberate more than 82% of the total phosphorus in the grounds in the form of dissolved ortho-phosphate. Nanofiltration was used to concentrate the inorganic nutrients of the HTC process water, achieving a mass concentration factor of 3.9 times. The natural stoichiometry of phosphorus, magnesium and ammoniacal nitrogen in the nanofiltration retentate was favourable for struvite precipitation. 92.8% of aqueous phosphorus was recovered as struvite through simple pH adjustment, yielding a total phosphorus recovery of 75% from the feedstock spent coffee grounds., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Fish stocks interact through predation and competition for resources, yet stocks are typically managed independently on a stock-by-stock basis. The need to take account of multi-species interactions is widely acknowledged. However, examples of the application of multi-species models to support management decisions are limited as they are often seen as too complex and lacking transparency. Thus there is a need for simple and transparent methods to address stock interactions in a way that supports managers. Here we introduce LeMaRns, a new R-package of a general length-structured fish community model, LeMans, that characterises fishing using fleets that can have different gears and species catch preferences. We describe the model, package implementation, and give three examples of use: determination of multi-species reference points; modelling of mixed-fishery interactions; and examination of the response of community indicators to dynamical changes in fleet effort within a mixed-fishery. LeMaRns offers a diverse array of options for parameterisation. This, along with the speed, comprehensive documentation, and open source nature of the package makes LeMans newly accessible, transparent, and easy to use, which we hope will lead to increased uptake by the fisheries management community., Competing Interests: The authors have declared that no competing interests exist.

The concept of an optimum yield at intermediate levels of fishing (the so called maximum sustainable yield or MSY) has been with us since the 1930s and is now enshrined in legislation as a key objective of fisheries management. The concept seems intuitively reasonable and is readily applicable to a single stock treated in isolation and assuming a constant environment. However, translating this concept into a mixed and multispecies fishery, where there are complex trade-offs between fleets and stocks and in general no simple optimum solution, has been problematic. Here I introduce a framework for thinking about multispecies MSY in terms of an integrated risk of stock depletion and expected long-term yield. Within this framework I consider the performance of a set of simple harvest control rules based upon a single-limit fishing mortality rate (F) which is common to all stocks and a target biomass which is a set fraction of a stock's virgin biomass. Using a multispecies management strategy evaluation, I compare expected outcomes for a set of these harvest control rules with alternative scenarios, in which each stock has its own F based on the assessment process. I find that the simple framework can produce outcomes that are similar to those from the more sophisticated estimates of F. I therefore conclude that achieving multispecies MSY may depend more upon setting reasonable biomass targets and faithfully applying a harvest control rule approach rather than determining the best possible Fs for each stock., (© 2019 Crown copyright. Journal of Fish Biology published by John Wiley & Sons Ltd on behalf of Fisheries Society of the British Isles.)

Background and Objective: The V-to-Y advancement flap, also known as the island pedicle flap, is a single-stage repair option that can be used for defects on the distal nose. We report our experience using this flap for nasal defects following Mohs micrographic surgery, as well as describe optimal patient selection and flap design., Materials and Methods: A retrospective review was conducted of all patient charts and operative photographs of nasal V-to-Y advancement flaps performed over 6 years at the Universtiy of Texas Southwestern Medical Center. Charts were reviewed for age, sex, tumour type and location, defect size, anticoagulation, immunosuppression, postoperative complications, revisions, and outcomes., Results: Thirty-nine patients with defects ranging from 0.7 to 1.7 cm in size (median of 1 cm) were included. Most defects involved the inferior, paramedian nose, and after accounting for 7 postrepair interventions on 6 (15%) patients, 38 (97%) patients were noted to have good to excellent cosmetic outcomes while 1 patient experienced a persistent trapdoor effect., Conclusion: The V-to-Y advancement flap is an excellent single-stage option that can reliably provide good to excellent cosmetic results when used to repair small- to medium-size sized defects on the distal half of the nose.

Bradykinin-induced activation of the pulmonary endothelium triggers a rise in intracellular Ca 2+ that activates nitric oxide (NO)-dependent vasorelaxation. Chronic hypoxia is commonly associated with increased pulmonary vascular tone, which can cause pulmonary hypertension in responsive individuals. In the present study, we tested the hypothesis that long-term high-altitude hypoxia (LTH) diminishes bradykinin-induced Ca 2+ signals and inhibits endothelial nitric oxide synthase (eNOS), prostacyclin (PGI 2 ), and large-conductance K + (BK Ca ) channels in sheep, which are moderately responsive to LTH, resulting in decreased pulmonary arterial vasorelaxation. Pulmonary arteries were isolated from ewes kept near sea level (720 m) or at high altitude (3,801 m) for >100 days. Vessel force was measured with wire myography and endothelial intracellular Ca 2+ with confocal microscopy. eNOS was inhibited with 100 μM N G -nitro-l-arginine methyl ester (l-NAME), PGI 2 production was inhibited with 10 µM indomethacin that inhibits cyclooxygenase, and BK Ca channels were blocked with 1 mM tetraethylammonium. Bradykinin-induced endothelial Ca 2+ signals increased following LTH, but bradykinin relaxation decreased. Furthermore, some vessels contracted in response to bradykinin after LTH. l-NAME sensitivity decreased, suggesting that eNOS dysfunction played a role in uncoupling Ca 2+ signals and bradykinin relaxation. The Ca 2+ ionophore A-23187 (10 µM) elicited an enhanced Ca 2+ response following LTH while relaxation was unchanged although l-NAME sensitivity increased. Additionally, BK Ca function decreased during bradykinin relaxation following LTH. Western analysis showed that BK Ca α-subunit expression was increased by LTH while that for the β 1 subunit was unchanged. Overall, these results suggest that those even moderately responsive to LTH can have impaired endothelial function.

A SULPHUS TM biotrickling filter (BTF) and an ACTUS TM polishing activated carbon filter (ACF) were used at a wastewater treatment plant to treat 2,432 m 3 ·h -1 of air extracted from sewage sludge processes. The project is part of Thames Water's strategy to reduce customer odour impact and, in this case, is designed to achieve a maximum discharge concentration of 1,000 ou E ·m -3 . The odour and hydrogen sulphide concentration in the input air was more influenced by the operation of the sludge holding tank mixers than by ambient temperature. Phosphorus was found to be limiting the performance of the BTF during peak conditions, hence requiring additional nutrient supply. Olfactometry and pollutant measurements demonstrated that during the high rate of change of intermittent odour concentrations the ACF was required to reach compliant stack values. The two stage unit outperformed design criteria, with 139 ou E ·m -3 measured after 11 months of operation. At peak conditions and even at very low temperatures, the nutrient addition considerably increased the performance of the BTF, extending the time before activated carbon replacement over the one year design time. During baseline operation, the BTF achieved values between 266-1,647 ou E ·m -3 even during a 6 day irrigation failure of the biofilm.

In utero hypoxia influences the structure and function of most fetal arteries, including those of the developing cerebral circulation. Whereas the signals that initiate this hypoxic remodeling remain uncertain, these appear to be distinct from the mechanisms that maintain the remodeled vascular state. The present study explores the hypothesis that chronic hypoxia elicits sustained changes in fetal cerebrovascular reactivity to endothelin-1 (ET-1), a potent vascular contractant and mitogen. In fetal lambs, chronic hypoxia (3,820-m altitude for the last 110 days of gestation) had no significant effect on plasma ET-1 levels or ETA receptor density in cerebral arteries but enhanced contractile responses to ET-1 in an ETA-dependent manner. In organ culture (24 h), 10 nM ET-1 increased medial thicknesses less in hypoxic than in normoxic arteries, and these increases were ablated by inhibition of PKC (chelerythrine) in both normoxic and hypoxic arteries but were attenuated by inhibition of CaMKII (KN93) and p38 (SB203580) in normoxic but not hypoxic arteries. As indicated by Ki-67 immunostaining, ET-1 increased medial thicknesses via hypertrophy. Measurements of colocalization between MLCK and SMαA revealed that organ culture with ET-1 also promoted contractile dedifferentiation in normoxic, but not hypoxic, arteries through mechanisms attenuated by inhibitors of PKC, CaMKII, and p38. These results support the hypothesis that chronic hypoxia elicits sustained changes in fetal cerebrovascular reactivity to ET-1 through pathways dependent upon PKC, CaMKII, and p38 that cause increased ET-1-mediated contractility, decreased ET-1-mediated smooth muscle hypertrophy, and a depressed ability of ET-1 to promote contractile dedifferentiation., (Copyright © 2017 the American Physiological Society.)

Long-term hypoxia (LTH) attenuates nitric oxide-induced vasorelaxation in ovine middle cerebral arteries. Because cGMP-dependent protein kinase (PKG) is an important mediator of NO signaling in vascular smooth muscle, we tested the hypothesis that LTH diminishes the ability of PKG to interact with target proteins and cause vasorelaxation. Prominent among proteins that regulate vascular tone is the large-conductance Ca 2+ -sensitive K + (BK) channel, which is a substrate for PKG and is responsive to phosphorylation on multiple serine/threonine residues. Given the influence of these proteins, we also examined whether LTH attenuates PKG and BK channel protein abundances and PKG activity. Middle cerebral arteries were harvested from normoxic and hypoxic (altitude of 3,820 m for 110 days) fetal and adult sheep. These arteries were denuded and equilibrated with 95% O 2 -5% CO 2 in the presence of N -nitro-l-arginine methyl ester (l-NAME) to inhibit potential confounding influences of events upstream from PKG. Expression and activity of PKG-I were not significantly affected by chronic hypoxia in either fetal or adult arteries. Pretreatment with the BK inhibitor iberiotoxin attenuated vasorelaxation induced by 8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphate in normoxic but not LTH arteries. The spatial proximities of PKG with BK channel α- and β1-proteins were examined using confocal microscopy, which revealed a strong dissociation of PKG with these proteins after LTH. These results support our hypothesis that hypoxia reduces the ability of PKG to attenuate vasoconstriction in part through suppression of the ability of PKG to associate with and thereby activate BK channels in arterial smooth muscle. NEW & NOTEWORTHY Using measurements of contractility, protein abundance, kinase activity, and confocal colocalization in fetal and adult ovine cerebral arteries, the present study demonstrates that long-term hypoxia diminishes the ability of cGMP-dependent protein kinase (PKG) to cause vasorelaxation through suppression of its colocalization and interaction with large-conductance Ca 2+ -sensitive K + (BK) channel proteins in cerebrovascular smooth muscle. These experiments are among the first to demonstrate hypoxic changes in BK subunit abundances in fetal cerebral arteries and also introduce the use of advanced methods of confocal colocalization to study interaction between PKG and its targets., (Copyright © 2017 the American Physiological Society.)

Bradykinin-induced activation of the pulmonary endothelium triggers nitric oxide production and other signals that cause vasorelaxation, including stimulation of large-conductance Ca(2+)-activated K(+) (BKCa) channels in myocytes that hyperpolarize the plasma membrane and decrease intracellular Ca(2+). Intrauterine chronic hypoxia (CH) may reduce vasorelaxation in the fetal-to-newborn transition and contribute to pulmonary hypertension of the newborn. Thus we examined the effects of maturation and CH on the role of BKCa channels during bradykinin-induced vasorelaxation by examining endothelial Ca(2+) signals, wire myography, and Western immunoblots on pulmonary arteries isolated from near-term fetal (∼ 140 days gestation) and newborn, 10- to 20-day-old, sheep that lived in normoxia at 700 m or in CH at high altitude (3,801 m) for >100 days. CH enhanced bradykinin-induced relaxation of fetal vessels but decreased relaxation in newborns. Endothelial Ca(2+) responses decreased with maturation but increased with CH. Bradykinin-dependent relaxation was sensitive to 100 μM nitro-L-arginine methyl ester or 10 μM 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, supporting roles for endothelial nitric oxide synthase and soluble guanylate cyclase activation. Indomethacin blocked relaxation in CH vessels, suggesting upregulation of PLA2 pathways. BKCa channel inhibition with 1 mM tetraethylammonium reduced bradykinin-induced vasorelaxation in the normoxic newborn and fetal CH vessels. Maturation reduced whole cell BKCa channel α1-subunit expression but increased β1-subunit expression. These results suggest that CH amplifies the contribution of BKCa channels to bradykinin-induced vasorelaxation in fetal sheep but stunts further development of this vasodilatory pathway in newborns. This involves complex changes in multiple components of the bradykinin-signaling axes., (Copyright © 2016 the American Physiological Society.)

Implementation of an ecosystem approach to fisheries requires advice on trade-offs among fished species and between fisheries yields and biodiversity or food web properties. However, the lack of explicit representation, analysis and consideration of uncertainty in most multispecies models has limited their application in analyses that could support management advice.We assessed the consequences of parameter uncertainty by developing 78 125 multispecies size-structured fish community models, with all combinations of parameters drawn from ranges that spanned parameter values estimated from data and literature. This unfiltered ensemble was reduced to 188 plausible models, the filtered ensemble (FE), by screening outputs against fish abundance data and ecological principles such as requiring species' persistence.Effects of parameter uncertainty on estimates of single-species management reference points for fishing mortality ( F MSY , fishing mortality rate providing MSY, the maximum sustainable yield) and biomass ( B MSY , biomass at MSY) were evaluated by calculating probability distributions of estimated reference points with the FE. There was a 50% probability that multispecies F MSY could be estimated to within ±25% of its actual value, and a 50% probability that B MSY could be estimated to within ±40% of its actual value.Signal-to-noise ratio was assessed for four community indicators when mortality rates were reduced from current rates to F MSY . The slope of the community size spectrum showed the greatest signal-to-noise ratio, indicating that it would be the most responsive indicator to the change in fishing mortality F . Further, the power of an ongoing international monitoring survey to detect predicted responses of size spectrum slope was higher than for other size-based metrics.Synthesis and applications: Application of the ensemble model approach allows explicit representation of parameter uncertainty and supports advice and management by (i) providing uncertainty intervals for management reference points, (ii) estimating working values of reference points that achieve a defined reduction in risk of not breaching the true reference point, (iii) estimating the responsiveness of population, community, food web and biodiversity indicators to changes in F , (iv) assessing the performance of indicators and monitoring programmes and (v) identifying priorities for data collection and changes to model structure to reduce uncertainty.

Prior studies identified T cells, B cells, and macrophages in the inflammatory infiltrate and up-regulation of their protein products in discoid lupus erythematosus (DLE) skin; however, they lacked rigorous analyses to define their specific locations in skin. Thus, we compared expressions of selected T cell, B cell, and macrophage markers in five areas of DLE, psoriasis, and normal skin. Immunostainings for CD3, CD4, CD8, CD20, CD68, CXCR3, CXCL10, and TIA-1 were performed in biopsies of 23 DLE lesional skin, 11 psoriasis lesional skin, and 5 normal skin. Three independent observers used a graded scale to rate each marker's presence in the epidermis, dermatoepidermal junction (DEJ), perivascular area, periadnexal area, and deep dermis. DLE lesional skin contained an increased abundance of CD3(+), CD8(+), and CD68(+) cells at the DEJ, and CD20(+) and CD68(+) cells in the periadnexal area versus psoriasis and normal skin. CXCR3, CXCL10, and TIA-1 were elevated in periadnexal sites of DLE lesional skin versus psoriasis lesional skin. The aggregation of T cells, B cells, macrophages, and their protein products (CXCR3, CXCL10, and TIA-1) in the DEJ and periadnexal area of DLE lesional skin may contribute to the pathology of DLE through a coordinated, sophisticated process.

The UK Water Industry currently generates approximately 800GWh pa of electrical energy from sewage sludge. Traditionally energy recovery from sewage sludge features Anaerobic Digestion (AD) with biogas utilisation in combined heat and power (CHP) systems. However, the industry is evolving and a number of developments that extract more energy from sludge are either being implemented or are nearing full scale demonstration. This study compared five technology configurations: 1 - conventional AD with CHP, 2 - Thermal Hydrolysis Process (THP) AD with CHP, 3 - THP AD with bio-methane grid injection, 4 - THP AD with CHP followed by drying of digested sludge for solid fuel production, 5 - THP AD followed by drying, pyrolysis of the digested sludge and use of the both the biogas and the pyrolysis gas in a CHP. The economic and environmental Life Cycle Assessment (LCA) found that both the post AD drying options performed well but the option used to create a solid fuel to displace coal (configuration 4) was the most sustainable solution economically and environmentally, closely followed by the pyrolysis configuration (5). Application of THP improves the financial and environmental performance compared with conventional AD. Producing bio-methane for grid injection (configuration 3) is attractive financially but has the worst environmental impact of all the scenarios, suggesting that the current UK financial incentive policy for bio-methane is not driving best environmental practice. It is clear that new and improving processes and technologies are enabling significant opportunities for further energy recovery from sludge; LCA provides tools for determining the best overall options for particular situations and allows innovation resources and investment to be focused accordingly., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Chronic hypoxia attenuates soluble guanylate cyclase-induced vasorelaxation in serotonin (5-HT)-contracted ovine carotid arteries. Because protein kinase G (PKG) mediates many effects of soluble guanylate cyclase activation through phosphorylation of multiple kinase targets in vascular smooth muscle, we tested the hypothesis that chronic hypoxia reduces the ability of PKG to phosphorylate its target proteins, which attenuates the ability of PKG to induce vasorelaxation. We also tested the hypothesis that hypoxia attenuates PKG expression and/or activity. Arteries from normoxic and chronically hypoxic (altitude of 3,820 m for 110 days) fetal and adult sheep were denuded of endothelium and equilibrated with 95% O2-5% CO2 in the presence of nitro-l-arginine methyl ester (l-NAME) and N(G)-nitro-l-arginine (l-NNA) to inhibit residual endothelial nitric oxide synthase. Concentration-response relations for 5-HT were determined in the presence of prazosin to minimize activation of α-adrenergic receptors. The PKG activator 8-(p-chlorophenylthio)-guanosine 3',5'-cyclic monophosphate (8-pCTP-cGMP) reduced agonist binding affinity of the 5-HT receptor in a concentration-dependent manner that was attenuated by hypoxia. Expression and activity of PKG-I was not significantly affected by chronic hypoxia in either fetal or adult arteries, although PKG-I abundance was greater in fetal arteries. Pretreatment with the large conductance calcium-sensitive potassium channel (BK) inhibitor iberiotoxin attenuated the vasorelaxation induced by 8-pCPT-cGMP in normoxic but not chronically hypoxic arteries. These results support the hypothesis that hypoxia attenuates the vasorelaxant effects of PKG through suppression of the ability of PKG to activate large conductance calcium-sensitive potassium channels in arterial smooth muscle. The results also reveal that this hypoxic effect is greater in fetal than adult arteries and that chronic maternal hypoxia can profoundly affect fetal vascular function.

Chronic hypoxia increases vascular endothelial growth factor (VEGF) and thereby promotes angiogenesis. The present study explores the hypothesis that hypoxic increases in VEGF also remodel artery wall structure and contractility through phenotypic transformation of smooth muscle. Pregnant and nonpregnant ewes were maintained at sea level (normoxia) or 3,820 m (hypoxia) for the final 110 days of gestation. Common carotid arteries harvested from term fetal lambs and nonpregnant adults were denuded of endothelium and studied in vitro. Stretch-dependent contractile stresses were 32 and 77% of normoxic values in hypoxic fetal and adult arteries. Hypoxic hypocontractility was coupled with increased abundance of nonmuscle myosin heavy chain (NM-MHC) in fetal (+37%) and adult (+119%) arteries. Conversely, hypoxia decreased smooth muscle MHC (SM-MHC) abundance by 40% in fetal arteries but increased it 123% in adult arteries. Hypoxia decreased colocalization of NM-MHC with smooth muscle α-actin (SM-αA) in fetal arteries and decreased colocalization of SM-MHC with SM-αA in adult arteries. Organ culture with physiological concentrations (3 ng/ml) of VEGF-A(165) similarly depressed stretch-dependent stresses to 37 and 49% of control fetal and adult values. The VEGF receptor antagonist vatalanib ablated VEGF's effects in adult but not fetal arteries, suggesting age-dependent VEGF receptor signaling. VEGF replicated hypoxic decreases in colocalization of NM-MHC with SM-αA in fetal arteries and decreases in colocalization of SM-MHC with SM-αA in adult arteries. These results suggest that hypoxic increases in VEGF not only promote angiogenesis but may also help mediate hypoxic arterial remodeling through age-dependent changes in smooth muscle phenotype and contractility.

Hyaluronic acid (HA) is a significant component of the extracellular matrix (ECM), particular interest being shown herein in synovial fluid. The present study aims to investigate the degrading effects of X-ray radiation on HA at radiotherapy doses. Measurements of viscosity and shear stresses on HA solutions have been made at different shear rates using various types of viscometer for different concentrations in the range 0.01-1% w/v of HA. The HA has been subjected to doses of 6 MV photon radiation ranging from 0 to 20 Gy, the major emphasis being on doses below 5 Gy. It is found that there is a dose-dependent relationship between viscosity and shear rate, viscosity reducing with radiation dose, this being related to polymer scissions via the action of radiation-induced free radicals. The dependency appears to become weaker at higher concentrations, possibly due to the contribution to viscosity from polymer entanglement becoming dominant over that from mean molecular weight. Present results, for HA solutions in the concentration range 0.01% to 1% w/v, show reduced viscosity with dose over the range 0-4 Gy, the latter covering the dose regime of interest in fractionated radiotherapy. The work also shows agreement with previous Raman microspectrometry findings by others, the possible bond alterations being defined by comparison with available published data., (Copyright 2009 Elsevier Ltd. All rights reserved.)

To determine if adjuvant methotrexate (MTX), escalated weekly to toxicity, could improve disease-free survival (DFS) and overall survival by preventing recurrent disease, 60 patients with potentially resectable stage III or IV squamous head and neck carcinomas were stratified by primary site, stage, and nutritional status, then randomized by pairs to receive or not receive adjuvant MTX. All received standard surgery and postoperative radiation therapy. Five patients were taken off study because of unresectability at the time of surgery, leaving 55 evaluable patients. There were no statistically significant imbalances in known prognostic factors between the two treatment arms. MTX was begun at 40 mg/m2 and escalated 10 mg/m2 weekly (four doses preoperatively; four doses postoperatively, preradiation therapy; eight doses postradiation therapy) to mucosal or hematologic toxicity. The median peak MTX dose achieved was 80 mg/m2. Although three patients were hospitalized with MTX toxicity, none died of MTX toxicity. No patient receiving MTX had disease progression during treatment, and there was no increase in postoperative complications. Thirty-two patients died (median survival, 19 months); 23 patients are alive with median follow-up of 43 months. There was no statistically significant difference in actuarial DFS (P = 1.0) or overall survival (P = .61). Although patients on the MTX arm appeared to have less local and regional recurrences at first recurrence (thus more distant metastases), this did not reach statistical significance (P = .06). There was no significant difference between the sites of recurrence at death or last follow-up (P = .38).