Aprepitant is a novel, selective activator of the K2P channel TRAAK.

TRAAK (KCNK4, K2P4.1) is a mechanosensitive two-pore domain potassium (K2P) channel. Due to its expression within sensory neurons and genetic link to neuropathic pain it represents a promising potential target for novel analgesics. In common with many other channels in the wider K2P sub-family, there remains a paucity of small molecule pharmacological tools. Specifically, there is a lack of molecules selective for TRAAK over the other members of the TREK subfamily of K2P channels. We developed a thallium flux assay to allow high throughput screening of compounds and facilitate the identification of novel TRAAK activators. Using a library of ∼1200 drug like molecules we identified Aprepitant as a small molecule activator of TRAAK. Aprepitant is an NK-1 antagonist used to treat nausea and vomiting. Close structural analogues of Aprepitant and a range of NK-1 antagonists were also selected or designed for purchase or brief chemical synthesis and screened for their ability to activate TRAAK. Electrophysiology experiments confirmed that Aprepitant activates both the 'long' and 'short' transcript variants of TRAAK. We also demonstrated that Aprepitant is selective and does not activate other members of the K2P superfamily. This work describes the development of a high throughput assay to identify potential TRAAK activators and subsequent identification and confirmation of the novel TRAAK activator Aprepitant. This discovery identifies a useful tool compound which can be used to further probe the function of TRAAK K2P channels.

Neuroendocrine regulation of reproduction in Atlantic cod (Gadus morhua): Evidence of Eya3 as an integrator of photoperiodic cues and nutritional regulation to initiate sexual maturation.

Evidence from mammals and aves alludes to a possibly conserved seasonal photoperiod induced neuroendocrine cascade which stimulates subsequent sexual maturation however our understanding of this mechanism in teleosts is lacking. Unlike all teleosts studied to date, the Atlantic cod (Gadus morhua) is a short day breeder with the reduction in day-length from the summer solstice stimulating gametogenesis. Cod specific orthologues of eya3, tshß and dio2 were identified and their expression was monitored in the brain and pituitary of cod held under either stimulated or inhibited photoperiod conditions. While no differential expression was apparent in brain dio2 & tshß and pituitary tshß, there was significant temporal variation in expression of pituitary eya3 under the SNP treatment, with expression level elevating in association with active gametogenesis. Under the LL treatment, sexual maturation was inhibited and there was a corresponding suppression of eya3 expression. In a second study the impact of size/energetic status on the initiation of sexual maturation was investigated. In the feed restricted population maturation was significantly suppressed (5% sexually mature) compared to the ab libitum fed stock (95% sexually mature) with there being a concomitant significant suppression in pituitary eya3 expression. Overall, these results suggest that pituitary eya3 has the potential to act as an integrator of both environmental and energetic regulation of sexual maturation of cod. Being the first account of eya3 induction in a short day breeding teleost, the conserved association with stimulation of reproduction and not seasonal state indicates that the upstream drivers which initiate the pathway differ among vertebrates according to their breeding strategies, but the pathway itself and its role in the reproductive cascade appears to be conserved across the vertebrate clade.

From an assessment of multiple chelators, clodronate has potential for use in continuous chelation.

AIM: To identify chelators which when mixed with sodium hypochlorite (NaOCl) are stable, exhibiting minimal loss of free available chlorine (FAC) over 80 min and to further investigate potential mixtures by assessing FAC over 18 h and the capacity to remove smear layer. METHODOLOGY: 0.25 mol L-1 EDTA (10%), 0.25 mol L-1 EGTA (egtazic acid), 0.25 mol L-1 CDTA (cyclohexanediaminetetraacetic acid), 0.25 mol L-1 DTPA (pentetic acid), 0.5 mol L-1 ATMP (aminotri(methylene phosphonic acid)) and 1 mol L-1 HPAA, (hydroxyphosphonoacetic acid), all at alkaline pH, were mixed equally with 5% NaOCl. 0.5 mol L-1 alkaline clodronate and 0.5 mol L-1 Na4 etidronate (15%) were mixed equally with 10% NaOCl. For all mixtures, the pH and temperature were measured over 80 min and additionally for the clodronate mixture over 18 h. Iodometric titration was used to measure the FAC of all mixtures except for HPAA. The following were compared with respect to their ability to remove smear layer: 1 mol L-1 clodronate + 10% NaOCl, 0.5 mol L-1 clodronate + 10% NaOCl, 1 mol L-1 etidronate + 10% NaOCl, 0.5 mol L-1 clodronate + 10% NaOCl and the sequences 5% NaOCl/17% EDTA/5% NaOCl and 5% NaOCl/17% EDTA. The area fraction occupied by open dentinal tubules as a percentage of the total area (% AF) from scanning electron microscopy micrographs was calculated using Image J. The results were statistically analysed with alpha set at 0.05. RESULTS: Compared to its control, the mixture 0.5 mol L-1 clodronate + 10% NaOCl lost no FAC over 18 h (P > 0.05). The FAC of 0.25 mol L-1 CDTA mixed with 5% NaOCl fell to 96%, 92%, 75% and 4.9% at 20, 40, 60 and 80 min, respectively. Temperature rises were observed in all cases except in the etidronate and clodronate mixtures. Only in the clodronate mixture did the pH remain above pH 12 for the whole experiment. Although smear layer was removed, the % AF in 1 mol L-1 clodronate + 10% NaOCl, 0.5 mol L-1 clodronate + 10% NaOCl, 1 mol L-1 etidronate + 10% NaOCl was less than for 0.5 mol L-1 etidronate + 10% NaOCl and 5% NaOCl/17% EDTA/5% NaOCl and 5% NaOCl/17% EDTA. CONCLUSION: Alkaline 0.5 mol L-1 clodronate mixed equally with 10% NaOCl has potential for use in continuous chelation, based on this assessment of stability and smear layer removal. Further research is needed to establish its efficacy and safety.

Emersion behaviour underlies variation in gill morphology and aquatic respiratory function in the amphibious fish Kryptolebias marmoratus.

Fishes acclimated to hypoxic environments often increase gill surface area to improve O2 uptake. In some species, surface area is increased via reduction of an interlamellar cell mass (ILCM) that fills water channels between gill lamellae. Amphibious fishes, however, may not increase gill surface area in hypoxic water because these species can, instead, leave water and breathe air. To differentiate between these possibilities, we compared wild amphibious mangrove rivulus Kryptolebias marmoratus from two habitats that varied in O2 availability - a hypoxic freshwater pool versus nearly anoxic crab burrows. Fish captured from crab burrows had less gill surface area (as ILCMs were enlarged by ∼32%), increased rates of normoxic O2 consumption and increased critical O2 tension compared with fish from the freshwater pool. Thus, wild mangrove rivulus do not respond to near-anoxic water by decreasing metabolism or increasing O2 extraction. Instead, fish from the crab burrow habitat spent three times longer out of water, which probably caused the observed changes in gill morphology and respiratory phenotype. We also tested whether critical O2 tension is influenced by genetic heterozygosity, as K. marmoratus is one of only two hermaphroditic vertebrate species that can produce both self-fertilized (inbred) or out-crossed (more heterozygous) offspring. We found no evidence for inbreeding depression, suggesting that self-fertilization does not impair respiratory function. Overall, our results demonstrate that amphibious fishes that inhabit hypoxic aquatic habitats can use a fundamentally different strategy from that used by fully aquatic water-breathing fishes, relying on escape behaviour rather than metabolic depression or increased O2 extraction ability.

Outcomes of endoscopic ultrasound-guided pancreatic FNAC diagnosis for solid and cystic lesions at Manchester Royal Infirmary based upon the Papanicolaou Society of Cytopathology pancreaticobiliary terminology classification scheme.

OBJECTIVE: To compare endoscopic ultrasound (EUS)-FNAC diagnosis of pancreatic lesions with patient outcome based upon the Papanicolaou Society of Cytopathology pancreaticobiliary terminology classification scheme diagnostic categories: Panc 1 (non-diagnostic); Panc 2 (negative for malignancy/neoplasia); Panc 3 (atypical); Panc 4B (neoplastic, benign); Panc 4O (neoplastic, other); Panc 5 (suspicious of malignancy); and Panc 6 (positive/malignant). METHODS: All EUS-FNA pancreas specimens taken at Manchester Royal Infirmary in 2015 were prospectively classified according to the above scheme at the time of cytology reporting and data recorded prospectively. Subsequently, outcomes based on clinical follow-up or histopathology diagnosis were compared with the cytology diagnosis. RESULTS: 120 EUS-FNA pancreas specimens from 111 patients were received, of which 112 (93.3%) specimens had follow-up data. There were 79 and 41 EUS-FNA pancreas specimens from solid and cystic lesions, respectively. Based on the cytology diagnosis the specimens were classified as Panc 1 (7.5%), Panc 2 (33.3%), Panc 3 (2.5%), Panc 4B (2.5%), Panc 4O (15.0%), Panc 5 (3.3%) and Panc 6 (35.9%). The performance indicators for diagnosis of malignancy or neoplasia with malignant potential, included sensitivity (95.4%), specificity (100%), positive predictive value (100%), negative predictive value (92.3%), false positive rate (0%) and false negative rate (4.6%). CONCLUSIONS: The Papanicolaou Society of Cytopathology pancreaticobiliary terminology classification scheme is a logical system that can easily be introduced in a diagnostic cytopathology service. This classification scheme acts as an aid to diagnostic reporting, clear communication of significant results including risk of neoplasia/malignancy to clinicians, clinical audit and comparison of results with other centres.

Socioeconomic deprivation and the burden of head and neck cancer-Regional variations of incidence and mortality in Merseyside and Cheshire, North West, England.

OBJECTIVES: The aim of this longitudinal study was to examine the distribution of head and neck cancer (HANC) disease burden across the region comparing it to national trends. DESIGN: We undertook a retrospective study of routine data combining it with indicators of deprivation and lifestyle at small geographical areas within the 9 Local Authorities (LAs) of Merseyside and Cheshire Network (MCCN) for head and neck cancers. Data from the North West of England and England were used as comparator regions. SETTING: This research was undertaken by the Cheshire and Merseyside Public Health Collaborative, UK. PARTICIPANTS: The Merseyside and Cheshire region serves a population of 2.2 million. Routine data allowed us to identify HANC patients diagnosed with cancers coded ICD C00-C14 and C30-C32 within 3 cohorts 1998-2000, 2008-2010 and 2009-2011 for our analysis. MAIN OUTCOME MEASURES: Directly age-standardised incidence rates and directly age-standardised mortality rates in the LAs and comparator regions were measured. Lifestyle and deprivation indicators were plotted against them and measured by Pearson's correlation coefficients. RESULTS: The incidence of head and neck cancer has increased across the region from 1998-2000 to 2008-2010 with a peak incidence for Liverpool males at 35/100 000 population. Certain Middle Super Output Areas contribute disproportionately to the significant effect of incidence and mortality within LAs. Income deprivation had the strongest correlation with incidence (r = .59) and mortality (r = .53) of head and neck cancer. CONCLUSION: Our study emphasises notable geographical variations within the region which need to be addressed through public health measures.

A qualitative metasynthesis exploring the impact of prostate cancer and its management on younger, unpartnered and gay men.

Prostate cancer (PCa) can negatively impact on men's sexual, urinary and emotional functioning, affecting quality of life. Most men with PCa are older (≥65 years), married and heterosexual and little is known about the impact on men who are younger, unpartnered or gay. We aimed to synthesise existing qualitative research on these three groups of men. A systematic metasynthesis was undertaken that included data on the unique impacts of PCa on younger (<65 years) (n = 7 papers), unpartnered (n = 17 papers) or gay or bisexual men (n = 11 papers) using a modified meta-ethnographic approach. The three overarching constructs illustrated the magnified disruption to men's biographies, that included: marginalisation, isolation and stigma-relating to men's sense of being "out of sync"; the burden of emotional and embodied vulnerabilities and the assault on identity-illustrating the multiple threats to men's work, sexual and social identities; shifting into different communities of practice-such as the shift from being part of a sexually active community to celibacy. These findings suggest that PCa can have a particular impact on the quality of life of younger, unpartnered and gay men. This has implications for the provision of tailored support and information to these potentially marginalised groups.

Effect of size on spawning time in the lesser sandeel Ammodytes marinus.

Ovarian development was examined in relation to size and temperature in late pre-spawning Ammodytes marinus over 5 years. Oocyte diameter was positively related to length indicating that larger females spawned earlier. Age and temperature, whilst accounting for the effect of length, were not found to affect oocyte development, although the thermal range examined was only 1·3° C.

Characterization of KIR intermediate promoters reveals four promoter types associated with distinct expression patterns of KIR subtypes.

The human killer cell immunoglobulin-like receptor (KIR) genes contain multiple promoters that control the process of gene activation and variegated expression of KIR on natural killer (NK) and T cells. Specific subfamilies of KIR genes have differences in the timing and tissue specificity of expression: however, previous studies of the proximal KIR promoters have not shown significant differences in activity between differentially expressed KIR gene subsets. The recent identification of an intermediate KIR promoter (ProI) associated with KIR2DL1 expression suggested a central role for this element in KIR expression. The current study identifies ProI elements in all of the KIR genes, revealing four classes of ProI that correspond with four distinct expression phenotypes of KIR subgroups: KIR2DL2/S2/L3 that are expressed early in reconstituting NK after transplant; KIR2DL4 that is expressed by CD56-bright NK in a non-variegated manner; KIR3DL3 that is not expressed by circulating NK cells; and the remaining KIR that are expressed by subsets of CD56-dim NK. The four classes of ProI are structurally diverse and display distinct functional properties. Altogether, these results indicate that KIR ProI elements contribute to the tissue/cell-type specificity of KIR transcription and cooperate with the probabilistic proximal promoter to control KIR expression.

The impact of human immune deficiency virus and hepatitis C coinfection on white matter microstructural integrity.

The purpose of the present study is to examine the integrity of white matter microstructure among individuals coinfected with HIV and HCV using diffusion tensor imaging (DTI). Twenty-five HIV+ patients, 21 HIV+/HCV+ patients, and 25 HIV- controls were included in this study. All HIV+ individuals were stable on combination antiretroviral therapy (cART; ≥3 months). All participants completed MRI and neuropsychological measures. Clinical variables including liver function, HIV-viral load, and CD4 count were collected from the patient groups. DTI metrics including mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), and fractional anisotropy (FA) from five subregions of the corpus callosum were compared across groups. The HIV+/HCV+ group and HIV+ group were similar in terms of HIV clinical variables. None of the participants met criteria for cirrhosis or fibrosis. Within the anterior corpus callosum, significant differences were observed between both HIV+ groups compared to HIV- controls on DTI measures. HIV+ and HIV+/HCV+ groups had significantly lower FA values and higher MD and RD values compared to HIV- controls; however, no differences were present between the HIV+ and HIV+/HCV+ groups. Duration of HIV infection was significantly related to DTI metrics in total corpus callosum FA only, but not other markers of HIV disease burden or neurocognitive function. Both HIV+ and HIV+/HCV+ individuals had significant alterations in white matter integrity within the corpus callosum; however, there was no evidence for an additive effect of HCV coinfection. The association between DTI metrics and duration of HIV infection suggests that HIV may continue to negatively impact white matter integrity even in well-controlled disease.

Accelerated degradation of MOFs under flue gas conditions.

The zero length column (ZLC) technique is used to investigate the stability of Mg- and Ni-CPO-27 metal-organic framework (MOF) crystals in the presence of water and humid flue gas. The design of the ZLC enables the stability test to be conducted over a considerably shorter time period and with lower gas consumption than other conventional techniques. A key advantage over other experimental methods for testing the stability of adsorbents is the fact that the ZLC allows us to quantify the amount adsorbed of every component present in the gas mixture. The developed protocol is based on a two-stage stability test. The samples were first exposed to a humid carbon dioxide and helium mixture in order to study the effect of water on the carbon dioxide adsorption capacity of the samples. In the second stage the samples were exposed to a flue gas mixture containing water. From the preliminary water stability test, the Ni-sample exhibited the highest tolerance to the presence of water, retaining approximately 85% of its pristine CO2 capacity. The Mg-MOFs deactivated rapidly in the presence of water. The Ni-CPO-27 was then selected for the second stage of the protocol in which the material was exposed to the wet flue gas. The sample showed an initial drop in CO2 capacity after the first exposure to the wet flue gas, followed by a stabilisation of the performance over several cycles.

Development and evaluation of a specifically designed website for haematopoietic stem cell transplant patients in Leeds.

The purpose of this project was to develop and evaluate a specifically designed website (ALLograft INformation EXchange - ALLINEX) for adult allogeneic haematopoietic stem cell transplant (allo-HSCT) patients in Leeds. Specifications included information on the transplant journey and supportive care services, discussion forum and patient-clinical team electronic messaging service. The method followed a participatory action research approach in a five-phase project involving stakeholders. Phase 1 involved information gathering; Phase 2 development of content; Phase 3 building of website and usability testing; Phase 4 preliminary evaluation; and Phase 5 clinical implementation. Results concluded that Phase 1 patients were unaware of all services and reported unmet needs; gaps in support services were identified from a service evaluation; Phase 2 content was collected from experts, collated and synthesised; Phase 3 patient and staff feedback was positive and constructive resulting in more than 50 changes; Phase 4 ALLINEX evaluation demonstrated acceptable usability with good layout, content and aesthetics reported; Phase 5, over 15 weeks, ALLINEX had 6630 page hits, 9 new forum topics posted and received 3 clinical messages. The clinical team embraced responsibility for reviewing and monitoring ALLINEX. Financial and indemnity cover was secured for 3 years. ALLINEX, adopted locally, is sustainable and has functionality to roll-out to other UK allo-HSCT centres.

Costs of cancer care for use in economic evaluation: a UK analysis of patient-level routine health system data.

BACKGROUND: The rising financial burden of cancer on health-care systems worldwide has led to the increased demand for evidence-based research on which to base reimbursement decisions. Economic evaluations are an integral component of this necessary research. Ascertainment of reliable health-care cost and quality-of-life estimates to inform such studies has historically been challenging, but recent advances in informatics in the United Kingdom provide new opportunities. METHODS: The costs of hospital care for breast, colorectal and prostate cancer disease-free survivors were calculated over 15 months from initial diagnosis of cancer using routinely collected data within a UK National Health Service (NHS) Hospital Trust. Costs were linked at patient level to patient-reported outcomes and registry-derived sociodemographic factors. Predictors of cost and the relationship between costs and patient-reported utility were examined. RESULTS: The study population included 223 breast cancer patients, 145 colorectal and 104 prostate cancer patients. The mean 15-month cumulative health-care costs were £12 595 (95% CI £11 517-£13 722), £12 643 (£11 282-£14 102) and £3722 (£3263-£4208), per-patient respectively. The majority of costs occurred within the first 6 months from diagnosis. Clinical stage was the most important predictor of costs for all cancer types. EQ-5D score was predictive of costs in colorectal cancer but not in breast or prostate cancer. CONCLUSION: It is now possible to evaluate health-care cost using routine NHS data sets. Such methods can be utilised in future retrospective and prospective studies to efficiently collect economic data.

Risk factors associated with an outbreak of dengue fever/dengue haemorrhagic fever in Hanoi, Vietnam.

Dengue fever/dengue haemorrhagic fever (DF/DHF) appears to be emerging in Hanoi in recent years. A case-control study was performed to investigate risk factors for the development of DF/DHF in Hanoi. A total of 73 patients with DF/DHF and 73 control patients were included in the study. The risk factor analysis indicated that living in rented housing, living near uncovered sewers, and living in a house discharging sewage directly into to ponds were all significantly associated with DF/DHF. People living in rented houses were 2·2 times more at risk of DF/DHF than those living in their own homes [adjusted odds ratio (aOR) 2·2, 95% confidence interval (CI) 1·1-4·6]. People living in an unhygienic house, or in a house discharging sewage directly to the ponds were 3·4 times and 4·3 times, respectively, more likely to be associated with DF/DHF (aOR 3·4, 95% CI 1-11·7; aOR 4·3, 95% CI 1·1-16·9). These results contribute to the understanding of the dynamics of dengue transmission in Hanoi, which is needed to implement dengue prevention and control programmes effectively and efficiently.

Evolution, ecology and physiology of amphibious killifishes (Cyprinodontiformes).

The order Cyprinodontiformes contains an exceptional diversity of amphibious taxa, including at least 34 species from six families. These cyprinodontiforms often inhabit intertidal or ephemeral habitats characterized by low dissolved oxygen or otherwise poor water quality, conditions that have been hypothesized to drive the evolution of terrestriality. Most of the amphibious species are found in the Rivulidae, Nothobranchiidae and Fundulidae. It is currently unclear whether the pattern of amphibiousness observed in the Cyprinodontiformes is the result of repeated, independent evolutions, or stems from an amphibious common ancestor. Amphibious cyprinodontiforms leave water for a variety of reasons: some species emerse only briefly, to escape predation or capture prey, while others occupy ephemeral habitats by living for months at a time out of water. Fishes able to tolerate months of emersion must maintain respiratory gas exchange, nitrogen excretion and water and salt balance, but to date knowledge of the mechanisms that facilitate homeostasis on land is largely restricted to model species. This review synthesizes the available literature describing amphibious lifestyles in cyprinodontiforms, compares the behavioural and physiological strategies used to exploit the terrestrial environment and suggests directions and ideas for future research.

Characterization of a weakly expressed KIR2DL1 variant reveals a novel upstream promoter that controls KIR expression.

Members of the human KIR (killer cell immunoglobulin-like receptor) class I major histocompatibility complex receptor gene family contain multiple promoters that determine the variegated expression of KIR on natural killer cells. In order to identify novel genetic alterations associated with decreased KIR expression, a group of donors was characterized for KIR gene content, transcripts and protein expression. An individual with a single copy of the KIR2DL1 gene but a very low level of gene expression was identified. The low expression phenotype was associated with a single-nucleotide polymorphism (SNP) that created a binding site for the inhibitory ZEB1 (Zinc finger E-box-binding homeobox 1) transcription factor adjacent to a c-Myc binding site previously implicated in distal promoter activity. Individuals possessing this SNP had a substantial decrease in distal KIR2DL1 transcripts initiating from a novel intermediate promoter located 230 bp upstream of the proximal promoter start site. Surprisingly, there was no decrease in transcription from the KIR2DL1 proximal promoter. Reduced intermediate promoter activity revealed the existence of alternatively spliced KIR2DL1 transcripts containing premature termination codons that initiated from the proximal KIR2DL1 promoter. Altogether, these results indicate that distal transcripts are necessary for KIR2DL1 protein expression and are required for proper processing of sense transcripts from the bidirectional proximal promoter.

Psychosocial supportive care services for haematopoietic stem cell transplant patients; a service evaluation of three UK transplant centres.

Following haematopoietic stem cell transplant (HSCT) some patients experience long-term physical and psychosocial problems which impact on everyday life. The aim of this service evaluation was to investigate the psychosocial supportive care available for HSCT patients in three UK centres, particularly related to five identified areas of concern: fatigue; psychological distress; vocational and financial issues; sexuality, and fertility. HSCT health professionals were invited to audio-recorded semi-structured interviews. Enquiry was made into supportive care provided routinely (proactive), provided in response to a need (reactive) and missing (gaps in service) from pre-transplant to 18 months post transplant. Information gathered was transcribed and subjected to framework analysis. Interviews were conducted with 84 staff including nurses, doctors, psychologists, social workers, physiotherapists, dieticians and occupational therapists. Support for the five main areas of concern was variable across centres particularly with limitation of services for psychology; sexual dysfunction and fertility. Pro-active interventions such as psychological screening were rare with support being more commonly provided in response to an identified need. Support provided reactively for the areas of concern was comprehensive across professional groups and centres. Further work explores patients' psychosocial issues and other ways of providing adjuvant support.

A new Monte Carlo program for simulating light transport through Port Wine Stain skin.

A new Monte Carlo program is presented for simulating light transport through clinically normal skin and skin containing Port Wine Stain (PWS) vessels. The program consists of an eight-layer mathematical skin model constructed from optical coefficients described previously. A simulation including diffuse illumination at the surface and subsequent light transport through the model is carried out using a radiative transfer theory ray-tracing technique. Total reflectance values over 39 wavelengths are scored by the addition of simulated light returning to the surface within a specified region and surface reflections (calculated using Fresnel's equations). These reflectance values are compared to measurements from individual participants, and characteristics of the model are adjusted until adequate agreement is produced between simulated and measured skin reflectance curves. The absorption and scattering coefficients of the epidermis are adjusted through changes in the simulated concentrations and mean diameters of epidermal melanosomes to reproduce non-lesional skin colour. Pseudo-cylindrical horizontal vessels are added to the skin model, and their simulated mean depths, diameters and number densities are adjusted to reproduce measured PWS skin colour. Accurate reproductions of colour measurement data are produced by the program, resulting in realistic predictions of melanin and PWS blood vessel parameters. Using a modest personal computer, the simulation currently requires an average of five and a half days to complete.

The effect of sustained hypoxia on the cardio-respiratory response of bowfin Amia calva: implications for changes in the oxygen transport system.

This study examined mechanisms underlying cardio-respiratory acclimation to moderate sustained hypoxia (6.0 kPa for 7 days at 22° C) in the bowfin Amia calva, a facultative air-breathing fish. This level of hypoxia is slightly below the critical oxygen tension (pcrit ) of A. calva denied access to air (mean ± s.e. = 9.3 ± 1.0 kPa). Before exposure to sustained hypoxia, A. calva with access to air increased air-breathing frequency on exposure to acute progressive hypoxia while A. calva without access to air increased gill-breathing frequency. Exposure to sustained hypoxia increased the gill ventilation response to acute progressive hypoxia in A. calva without access to air, regardless of whether they had access to air or not during the sustained hypoxia. Additionally, there was a decrease in Hb-O2 binding affinity in these fish. This suggests that, in A. calva, acclimation to hypoxia elicits changes that increase oxygen delivery to the gas exchange surface for oxygen uptake and reduce haemoglobin affinity to enhance oxygen delivery to the tissues.