Genomics of Secondarily Temperate Adaptation in the Only Non-Antarctic Icefish.

White-blooded Antarctic icefishes, a family within the adaptive radiation of Antarctic notothenioid fishes, are an example of extreme biological specialization to both the chronic cold of the Southern Ocean and life without hemoglobin. As a result, icefishes display derived physiology that limits them to the cold and highly oxygenated Antarctic waters. Against these constraints, remarkably one species, the pike icefish Champsocephalus esox, successfully colonized temperate South American waters. To study the genetic mechanisms underlying secondarily temperate adaptation in icefishes, we generated chromosome-level genome assemblies of both C. esox and its Antarctic sister species, Champsocephalus gunnari. The C. esox genome is similar in structure and organization to that of its Antarctic congener; however, we observe evidence of chromosomal rearrangements coinciding with regions of elevated genetic divergence in pike icefish populations. We also find several key biological pathways under selection, including genes related to mitochondria and vision, highlighting candidates behind temperate adaptation in C. esox. Substantial antifreeze glycoprotein (AFGP) pseudogenization has occurred in the pike icefish, likely due to relaxed selection following ancestral escape from Antarctica. The canonical AFGP locus organization is conserved in C. esox and C. gunnari, but both show a translocation of two AFGP copies to a separate locus, previously unobserved in cryonotothenioids. Altogether, the study of this secondarily temperate species provides an insight into the mechanisms underlying adaptation to ecologically disparate environments in this otherwise highly specialized group.

Mercury biomagnification in a Southern Ocean food web.

Biomagnification of mercury (Hg) in the Scotia Sea food web of the Southern Ocean was examined using the stable isotope ratios of nitrogen (δ15N) and carbon (δ13C) as proxies for trophic level and feeding habitat, respectively. Total Hg and stable isotopes were measured in samples of particulate organic matter (POM), zooplankton, squid, myctophid fish, notothenioid fish and seabird tissues collected in two years (austral summers 2007/08 and 2016/17). Overall, there was extensive overlap in δ13C values across taxonomic groups suggesting similarities in habitats, with the exception of the seabirds, which showed some differences, possibly due to the type of tissue analysed (feathers instead of muscle). δ15N showed increasing enrichment across groups in the order POM to zooplankton to squid to myctophid fish to notothenioid fish to seabirds. There were significant differences in δ15N and δ13C values among species within taxonomic groups, reflecting inter-specific variation in diet. Hg concentrations increased with trophic level, with the lowest values in POM (0.0005 ± 0.0002 µg g-1 dw) and highest values in seabirds (3.88 ± 2.41 µg g-1 in chicks of brown skuas Stercorarius antarcticus). Hg concentrations tended to be lower in 2016/17 than in 2007/08 for mid-trophic level species (squid and fish), but the opposite was found for top predators (i.e. seabirds), which had higher levels in the 2016/17 samples. This may reflect an interannual shift in the Scotia Sea marine food web, caused by the reduced availability of a key prey species, Antarctic krill Euphausia superba. In 2016/17, seabirds would have been forced to feed on higher trophic-level prey, such as myctophids, that have higher Hg burdens. These results suggest that changes in the food web are likely to affect the pathway of mercury to Southern Ocean top predators.

Antarctic octopod beaks as proxy for mercury concentrations in soft tissues.

As the role of mercury is poorly known in Southern Ocean biota, the total mercury (T-Hg) concentrations were evaluated in upper/lower beaks, digestive gland, gills and mantle muscle of Adelieledone polymorpha and Pareledone turqueti, two of the most abundant octopod species around South Georgia. Beaks had the lowest T-Hg concentrations (A. polymorpha: [T-Hg]Upper = 27.2 ± 12.9 ng∙g-1 and [T-Hg]Lower = 27.5 ± 20.0 ng∙g-1; P. turqueti: [T-Hg]Upper = 34.6 ± 13.9 ng∙g-1 and [T-Hg]Lower = 56.8 ± 42.0 ng∙g-1), followed by gills and muscle. The highest values were recorded in the digestive gland (A. polymorpha: 251.6 ± 69.7 ng∙g-1; P. turqueti: 347.0 ± 177.0 ng∙g-1). Significant relationships were found between the concentrations of T-Hg in the beaks and muscle of A. polymorpha (T-Hg in muscle is 10 times higher than in beaks). This study shows that beaks can be used as proxy for T-Hg in muscle for some octopod species, and a helpful tool for estimating total Hg body burden from beaks.

Mercury levels in Southern Ocean squid: Variability over the last decade.

The concentrations of total and proportions of organic mercury were measured in tissues of 355 individuals of 8 species of Southern Ocean squid (Alluroteuthis antarcticus, Bathyteuthis abyssicola, Filippovia knipovitchi, Galiteuthis glacialis, Gonatus antarcticus, Kondakovia longimana, Psychroteuthis glacialis and Slosarczykovia circumantarctica). Squid were caught around South Georgia (Scotia Sea) during 5 cruises, between the austral summers of 2006/07 to 2016/17 to evaluate temporal changes in bioaccumulation and tissue partitioning. Total mercury concentrations varied between 4 ng g-1 and 804 ng g-1 among all tissues. Net accumulation of mercury in muscle with size was observed in A. antarcticus, B. abyssicola and P. glacialis, but no relationship was found for S. circumantarctica and lower concentrations were observed in larger individuals of G. glacialis. Muscle tissues had the highest mercury concentrations in the majority of species, except for F. knipovitchi for which the digestive gland contained highest concentrations. In terms of the percentage of organic mercury in the tissues, muscle always contained the highest values (67%-97%), followed by the digestive gland (22%-38%). Lowest organic mercury percentages were found consistently in the gills (9%-19%), suggesting only low levels of incorporation through the dissolved pathway and/or a limited redistribution of dietary organic mercury towards this tissue. Overall, results are indicative of a decreasing trend of mercury concentrations in the majority of analysed species over the last decade. As cephalopods are an important Southern Ocean trophic link between primary consumers and top predators, these changes suggest decreasing mercury levels in lower trophic levels and an alleviation of the mercury burden on higher predators that consume squid.

Show your beaks and we tell you what you eat: Different ecology in sympatric Antarctic benthic octopods under a climate change context.

Sympatry can lead to higher competition under climate change and other environmental pressures, including in South Georgia, Antarctica, where the two most common octopod species, Adelieledone polymorpha and Pareledone turqueti, occur side by side. Since cephalopods are typically elusive animals, the ecology of both species is poorly known. As beaks of cephalopods are recurrently found in top predator's stomachs, we studied the feeding ecology of both octopods through the evaluation of niche overlapping and specific beak adaptations that both species present. A multidisciplinary approach combining carbon (δ13C) and nitrogen (δ15N) stable isotope signatures, mercury (Hg) analysis and biomaterials' engineering techniques was applied to investigate the beaks. An isotopic niche overlap of 95.6% was recorded for the juvenile stages of both octopod species, dropping to 19.2% for the adult stages. Both A. polymorpha and P. turqueti inhabit benthic ecosystems around South Georgia throughout their lifecycles (δ13C: -19.21 ±â€¯1.87‰, mean ±â€¯SD for both species) but explore trophic niches partially different during adult life stages (δ15N: 7.01 ±â€¯0.40‰, in A. polymorpha, and 7.84 ±â€¯0.65‰, in P. turqueti). The beaks of A. polymorpha are less dense and significantly less stiff than in P. turqueti. Beaks showed lower mercury concentration relative to muscle (A. polymorpha - beaks: 0.052 ±â€¯0.009  µg g-1, muscle: 0.322 ±â€¯0.088  µg g-1; P. turqueti - beaks: 0.038 ±â€¯0.009  µg g-1; muscle: 0.434 ±â€¯0.128  µg g-1). Overall, both octopods exhibit similar habitats but different trophic niches, related to morphology/function of beaks. The high Hg concentrations in both octopods can have negative consequences on their top predators and may increase under the present climate change context.

Evaluation of a dental model for training veterinary students.

Periodontal disease has deleterious effects on an animal's health and potentially serious implications for its welfare. Consequently, veterinarians frequently perform routine periodontal treatment in small-animal practice. One would therefore assume that small-animal dentistry would constitute a core component of a veterinary curriculum. However, most practitioners received little or no formal training in dentistry during their veterinary degrees, and the amount of instruction students currently receive is variable, often with limited opportunities to practice. At the Royal Veterinary College, a prototype dental model was developed to address the lack of practical training; it was made using ceramic tiles, silicone sealant, and grout to emulate teeth, gingiva, and calculus, respectively. A study was conducted with third-year veterinary students to compare the outcomes of learning to perform a professional dental cleaning using a model (group A) or a video (group B). Performance was assessed using an objective structured clinical examination. Students in group A scored significantly better than those in group B (p<.001). All students also completed a questionnaire evaluating attitudes toward the use of a dental model in learning dentistry-related skills. All students identified a model as a potentially valuable learning tool to supplement existing teaching methods and facilitate the acquisition of small-animal dentistry skills. The dental model has the potential to equip students with useful, practical skills in a safe and risk-free environment.

A qualitative study exploring why people do not participate in cardiac rehabilitation and coronary heart disease self-help groups, and their rehabilitation experience without these resources.

BACKGROUND: Secondary prevention and self-management of coronary heart disease (CHD) are of major importance to people who survive myocardial infarction (MI). This can be facilitated by cardiac rehabilitation (CR; the formal health service programme) and informal CHD self-help groups. Non-participation is an important issue, yet it is poorly understood. Rehabilitation difficulties and prevention challenges have been identified among people following MI, but the particular experience and perspective of CR and CHD group non-participants are largely unknown. AIM: The study aimed to understand non-participation in CR and CHD self-help groups from the perspectives of the non-participants and to provide insight into their experience and that of their 'significant others' in rehabilitating in the absence of these resources. METHODS: In-depth interviews were conducted with 27 people who had not participated in either hospital-based CR or a CHD group, 6-14 months post-MI, and 17 'significant others' in Lothian, Scotland. FINDINGS: Factors influencing non-participation fell into three broad themes 'No need/no point', 'Not worth it', and 'Not possible'. In the latter two categories, non-participation in these resources was often considered a 'missed opportunity' and needs had remained unmet. Shifts between categories could occur over time. Non-participation was linked to rehabilitation difficulties for some people and family members. Recommendations to enhance post-MI support are made.

Association between hepatic histopathologic lesions and clinical findings in dogs undergoing surgical attenuation of a congenital portosystemic shunt: 38 cases (2000-2004).

OBJECTIVE: To review hepatic histopathologic lesions in dogs undergoing surgical attenuation of a congenital portosystemic shunt (CPSS) in relation to clinical findings and tolerance of complete surgical attenuation. DESIGN: Retrospective case series. ANIMALS: 38 dogs that underwent surgical attenuation of a CPSS. PROCEDURES: Hepatic histologic examination findings and medical records of dogs undergoing surgical attenuation of a single CPSS between August 2000 and July 2004 were reviewed. Liver biopsy specimens were obtained from 38 dogs during surgery prior to complete (n = 16) or partial (22) attenuation of a CPSS and from 13 of the same dogs a median of 3 months following surgical attenuation. RESULTS: Portal tracts were inadequate for interpretation in 2 liver biopsy specimens. Liver biopsy specimens obtained prior to surgical attenuation of a CPSS had a lack of identifiable portal veins (13/36 dogs), hepatic arteriolar proliferation (25/36), ductular reaction (5/36), steatosis (16/38), and iron accumulation (32/38). Lack of identifiable portal veins on histologic examination was associated with increased hepatic arteriolar proliferation, decreased tolerance to complete surgical CPSS attenuation, and decreased opacification of intrahepatic portal vessels on portovenography. Ductular reaction was always associated with failure to tolerate complete surgical attenuation of a CPSS. Surgical CPSS attenuation resulted in significant clinical, serum biochemical, and portovenographic changes indicative of improved liver function, but only subtle changes in hepatic histologic examination findings. CONCLUSIONS AND CLINICAL RELEVANCE: Dogs without identifiable intrahepatic portal veins that had a ductular reaction on hepatic histologic examination were less likely to tolerate complete attenuation of a CPSS.

Comparison between two different measures of self-rated health: a single-question measure and a visual analogue scale.

INTRODUCTION: Self-rated health (SRH) is a useful concept for research and health planning, and an important indicator of population health. AIM: The present study aims to evaluate the appropriateness of two different measures used to assess SRH, a single question with a five-response Likert-type scale and a visual analogue scale (VAS), by studying the correlation between the two measures and the factors influencing response rates according to respondent characteristics. MATERIAL AND METHODS: A population-based postal survey was carried out within the framework of a World Health Organisation (WHO) project, with a national sample of randomly selected geographically stratified individuals. The factors influencing SRH using each measure were determined. The comparison of the two measures was also studied with respect to response frequencies and differences in association with potential determinants (age, sex, income, education). Answering to each measure depending upon answering to the other measure was also tested. RESULTS: The maximum correlation between the two measures was p = -0.78 (p < 0.001). Age, sex, income and education had an effect on SRH as measured using both measures. More people replies to the single question measure irrespective of any particular socio-economic characteristic. Generally, those completing the VAS were women of higher income. CONCLUSIONS: The two measures are moderately correlated, the structure of the questionnaire and sequence of questions seems to affect correlation, and the single question yields higher response rate than VAS does. Still, other factors may also play a significant explanatory role in SRH among the Greek population and in relation to which measure is used.

Self-help groups for patients with coronary heart disease as a resource for rehabilitation and secondary prevention-what is the evidence?

Cardiovascular heart disease (CHD) is a major health care concern worldwide. Maintaining regular cardiac rehabilitation attendance and secondary-prevention strategies are significant health care challenges. Although self-help groups provide benefit for many chronic health conditions, it is not clear if they address the challenges of CHD rehabilitation and self-management. This literature review was guided by the following question: Can self-help groups address the challenges of CHD rehabilitation and self-management? This article reviews the traditional published and "grey" literature on CHD-related self-help groups identified from a database search (Cochrane Library, PubMed, PsychINFO, Medline, Cumulative Index to Nursing and Allied Health Literature, Applied Social Sciences Index and Abstracts, and Social Sciences Citation Index). Identified articles were screened based on the type of initiative: Community-based non-health service-organized groups were included, but hospital-based group treatment and therapy interventions or programs were excluded. Published research and analysis of CHD-related self-help groups is scarce. Sixteen articles focusing on self-help groups were identified. The review results indicate that the limited quantity, limited range, and variable quality of studies prevents reliable conclusions being made regarding effects and outcomes as well as the extent and profile of participation. Strengthening the evidence base regarding the impact of CHD-related self-help groups, the reasons for participation versus nonparticipation in such groups, and determining nonparticipants support needs must be done to establish if and for which patients such groups constitute an effective resource for rehabilitation and secondary prevention.

Persistent vaginal hemorrhage caused by vaginal vascular ectasia in a dog.

CASE DESCRIPTION: A 6-year-old 36.5-kg (80.3-lb) spayed female Labrador Retriever was evaluated because of an 11-month history of vaginal bleeding. Previous radiographic, endoscopic, and surgical interventions had failed to detect an underlying cause for the bleeding. The dog was examined on an emergency basis because of severe anemia after the bleeding increased in severity. CLINICAL FINDINGS: Bleeding was severe, and results of vaginoscopy and radiography (after administration of a contrast agent) did not confirm the cause of the hemorrhage. An exploratory episiotomy revealed multiple bleeding vascular abnormalities within the vaginal mucosa cranial to the external urethral orifice, which were suggestive of vascular ectasia. TREATMENT AND OUTCOME: A total vaginectomy was performed via a ventral midline incision and a pubic symphysiotomy. Macroscopic and microscopic examination of excised vaginal tissues confirmed changes compatible with vascular ectasia. The dog made an uneventful recovery with no further vulval bleeding until 19 months after surgery, at which time vulval bleeding recurred. Further investigation and treatment were declined by the owner. CLINICAL RELEVANCE: Vascular ectasia may be a cause of chronic vaginal hemorrhage and life-threatening anemia in dogs. In the dog of this report, the diagnosis was made on the basis of direct observation during exploratory episiotomy and histopathologic findings. To manage the condition, total vaginectomy was performed; however, despite radical surgery, bleeding recurred.

Interleukin-2 and interferon-gamma mRNA expression in canine anal furunculosis lesions and the effect of ciclosporin therapy.

German Shepherd Dogs have an increased incidence of anal furunculosis (AF), which is a disease characterised by inflammation and ulceration of the perianal tissues. Ciclosporin, an immunosuppressive drug, has been successfully used to treat AF, suggesting that the pathogenesis of disease is likely to have an immune-mediated component. Previous research has shown that the cytokine mRNA profile in AF lesions is consistent with T cell-mediated inflammation. The aims of the current study were to quantify IL-2 and IFNgamma mRNA expression in AF biopsies taken before and after treatment with ciclosporin and to compare cytokine expression with lesion severity. Twenty-two dogs with AF were recruited into the study and lesional biopsies were taken prior to ciclosporin therapy. Lesion severity was graded using a visual analogue scale. All dogs were evaluated after 4 weeks of ciclosporin therapy and, in 10 dogs with persistent disease, residual lesions were resected. RNA was extracted from AF-lesional tissue and control perianal tissue samples (n=10), which was used as the template for RT-PCR. Analysis of IL-2 and IFNgamma mRNA expression was performed using real-time PCR. IL-2 and IFNgamma mRNA was consistently detected in pre-treatment AF biopsies and, when quantified, this was significantly increased compared to control tissue (P<0.05). However, no correlation was seen between lesion severity and pre-treatment cytokine mRNA expression. In the ten paired pre- and post-treatment samples, IL-2 mRNA expression was significantly reduced in residual disease tissue following ciclosporin therapy (P=0.013). Treatment with ciclosporin seemed to result in decreased expression of IFNgamma mRNA in AF lesions but this was not statistically significant. In six of the 10 dogs with persistent disease, T cell cytokine mRNA could still be detected in the tissues, suggesting that there was inadequate immunosuppression. The absence of a correlation between T cell cytokine expression and the severity of disease suggests that tissue destruction observed in AF might be a consequence of other inflammatory mediators or downstream effects of T cell activation.

A composite element that binds basic helix loop helix and basic leucine zipper transcription factors is important for gonadotropin-releasing hormone regulation of the follicle-stimulating hormone beta gene.

Although FSH plays an essential role in controlling gametogenesis, the biology of FSHbeta transcription remains poorly understood, but is known to involve the complex interplay of multiple endocrine factors including GnRH. We have identified a GnRH-responsive element within the rat FSHbeta promoter containing an E-box and partial cAMP response element site that are bound by the basic helix loop helix transcription factor family members, upstream stimulating factor (USF)-1/USF-2, and the basic leucine zipper member, cAMP response element-binding protein (CREB), respectively. Expression studies with CREB, USF-1/USF-2, and activating protein-1 demonstrated that the USF transcription factors increased basal transcription, an effect not observed if the cognate binding site was mutated. Conversely, expression of a dominant negative CREB mutant or CREB knockdown attenuated induction by GnRH, whereas dominant negative Fos or USF had no effect on the GnRH response. GnRH stimulation specifically induced an increase in phosphorylated CREB occupation of the FSHbeta promoter, leading to the recruitment of CREB-binding protein to enhance gene transcription. In conclusion, a composite element bound by both USF and CREB serves to integrate signals for basal and GnRH-stimulated transcription of the rat FSHbeta gene.

Pattern-recognition receptor mRNA expression and function in canine monocyte/macrophages and relevance to canine anal furunuclosis.

Pattern-recognition receptors (PRRs) are important components of the innate immune system, enabling early detection of infection. Defective PRR function has been implicated in several infectious and immune-mediated diseases of human beings, including Crohn's disease (CD). Anal furunculosis (AF) is an immune-mediated disease which primarily occurs in German shepherd dogs (GSD) and could result from a similar type of PRR dysfunction. The aim of the current study was to investigate canine PRR responses in vitro and to test the hypothesis that these were altered in AF-affected GSD. The pattern-recognition receptors TLR1, TLR2, TLR4, TLR6, TLR9, NOD1 (nucleotide-binding oligomerisation domain) and NOD2 were evaluated in the DH82 canine monocyte/macrophage cell line. These cells were found to express mRNA for all the selected PRRs with TLR2 mRNA the most and TLR5 mRNA the least abundant. A similar pattern of expression was found in canine blood-derived monocyte/macrophages. Stimulation of DH82 cells and blood-derived monocyte/macrophages using specific PRR-ligands, resulted in expression of pro-inflammatory cytokine mRNA. Quantification of TNFalpha mRNA and protein secretion from stimulated cells demonstrated variable responses with lipopolysaccharide (TLR4 ligand) and PAM(3)CSK4 (TLR1/2 ligand) proving to be the most potent and CpG DNA (TLR9 ligand) the least potent. Comparing PRR responses in blood-derived monocyte/macrophages from healthy blood-donor dogs with those from AF-affected GSD showed a deficiency in the latter in response to LD-MDP (NOD2 ligand) at the mRNA level but not at the protein level. It is possible that dysfunctional NOD2 responses by cells of the monocyte/macrophage lineage are involved in the pathogenesis of AF.

Gonadotropin-releasing hormone stimulates prolactin release from lactotrophs in photoperiodic species through a gonadotropin-independent mechanism.

Previous studies have provided evidence for a paracrine interaction between pituitary gonadotrophs and lactotrophs. Here, we show that GnRH is able to stimulate prolactin (PRL) release in ovine primary pituitary cultures. This effect was observed during the breeding season (BS), but not during the nonbreeding season (NBS), and was abolished by the application of bromocriptine, a specific dopamine agonist. Interestingly, GnRH gained the ability to stimulate PRL release in NBS cultures following treatment with bromocriptine. In contrast, thyrotropin-releasing hormone, a potent secretagogue of PRL, stimulated PRL release during both the BS and NBS and significantly enhanced the PRL response to GnRH during the BS. These results provide evidence for a photoperiodically modulated functional interaction between the GnRH/gonadotropic and prolactin axes in the pituitary gland of a short day breeder. Moreover, the stimulation of PRL release by GnRH was shown not to be mediated by the gonadotropins, since immunocytochemical, Western blotting, and PCR studies failed to detect pituitary LH or FSH receptor protein and mRNA expressions. Similarly, no gonadotropin receptor expression was observed in the pituitary gland of the horse, a long day breeder. In contrast, S100 protein, a marker of folliculostellate cells, which are known to participate in paracrine mechanisms within this tissue, was detected throughout the pituitaries of both these seasonal breeders. Therefore, an alternative gonadotroph secretory product, a direct effect of GnRH on the lactotroph, or another cell type, such as the folliculostellate cell, may be involved in the PRL response to GnRH in these species.

Cochlear implants: the young people's perspective.

Cochlear implantation is a relatively new procedure, which has already had significant impact on the lives of many profoundly deaf children and adults, in providing useful hearing to those unable to benefit significantly from hearing aids. After 16 years of cochlear implantation in the United Kingdom, there is now a body of evidence covering a range of outcomes, much of which covers perceptual and linguistic outcomes. This study looks at the impact of cochlear implantation on a group of 29 young people aged 13-16 years, using a semistructured questionnaire. It examines issues from the perspective of the young people themselves, including their understanding of and degree of satisfaction with the way their implant works for them, their social and communication abilities and choices, their educational challenges, and their identity. It concludes that the young people in this group feel positive toward their cochlear implants and the decisions made on their behalf by parents. Many have a flexible attitude to communication modes and an identity which is not fixed in terms of conventional descriptors.

Inhaled CD86 antisense oligonucleotide suppresses pulmonary inflammation and airway hyper-responsiveness in allergic mice.

The B7-family molecule CD86, expressed on the surface of pulmonary and thoracic lymph node antigen-presenting cells, delivers essential costimulatory signals for T-cell activation in response to inhaled allergens. CD86-CD28 signaling is involved in priming allergen-specific T cells, but it is unclear whether these interactions play a role in coordinating memory T-helper 2 cell responses. In the ovalbumin (OVA)-induced mouse model of asthma, administration of CD86-specific antibody before systemic sensitization suppresses inhaled OVA-induced pulmonary inflammation and airway hyper-responsiveness (AHR). In previously OVA-sensitized mice, systemic and intranasal coadministration of CD86 antibody is required to produce these effects. To directly assess the importance of pulmonary CD86 expression in secondary immune responses to inhaled allergens, mice were sensitized and locally challenged with nebulized OVA before treatment with an inhaled aerosolized CD86 antisense oligonucleotide (ASO). CD86 ASO treatment suppressed OVA-induced up-regulation of CD86 protein expression on pulmonary dendritic cells and macrophages as well as on recruited eosinophils. Suppression of CD86 protein expression correlated with decreased methacholine-induced AHR, airway inflammation, and mucus production following rechallenge with inhaled OVA. CD86 ASO treatment reduced BAL eotaxin levels, but it did not reduce CD86 protein on cells in the draining lymph nodes of the lung, and it had no effect on serum IgE levels, suggesting a local and not a systemic effect. These results demonstrate that CD86 expression on pulmonary antigen-presenting cells plays a vital role in regulating pulmonary secondary immune responses and suggest that treatment with an inhaled CD86 ASO may have utility in asthma and other chronic inflammatory lung conditions.

Evaluation and management of respiratory muscle dysfunction in ALS.

Neuromuscular respiratory failure is the cause of death in the majority of patients with ALS. Respiratory muscle dysfunction impacts on quality of life and survival. Attentive management of respiratory muscle weakness is an important aspect of the management of the ALS patient. The respiratory muscles may be thought of as four functional groups: the inspiratory muscles, the expiratory muscles, the accessory muscles of respiration, and the upper airway muscles. This paper will review the structure and function of the neuromuscular respiratory system, and the evaluation and management of respiratory muscle dysfunction in ALS patients.

Anti-inflammatory activity of inhaled IL-4 receptor-alpha antisense oligonucleotide in mice.

The Th2 cytokines IL-4 and IL-13 mediate allergic pulmonary inflammation and airways hyperreactivity (AHR) in asthma models through signaling dependent upon the IL-4 receptor-alpha chain (IL-4Ralpha). IL-13 has been further implicated in the overproduction of mucus by the airway epithelium and in lung remodeling that commonly accompanies chronic inflammation. IL-4Ralpha-deficient mice are resistant to allergen-induced asthma, highlighting the therapeutic promise of selective molecular inhibitors of IL-4Ralpha. We designed a chemically modified IL-4Ralpha antisense oligonucleotide (IL-4Ralpha ASO) that specifically inhibits IL-4Ralpha protein expression in lung eosinophils, macrophages, dendritic cells, and airway epithelium after inhalation in allergen-challenged mice. Inhalation of IL-4Ralpha ASO attenuated allergen-induced AHR, suppressed airway eosinophilia and neutrophilia, and inhibited production of airway Th2 cytokines and chemokines in previously allergen-primed and -challenged mice. Histologic analysis of lungs from these animals demonstrated reduced goblet cell metaplasia and mucus staining that correlated with inhibition of Muc5AC gene expression in lung tissue. Therapeutic administration of inhaled IL-4Ralpha ASO in chronically allergen-challenged mice produced a spectrum of anti-inflammatory activity similar to that of systemically administered Dexamethasone with the added benefit of reduced airway neutrophilia. These data support the potential utility of a dual IL-4 and IL-13 oligonucleotide inhibitor in allergy/asthma, and suggest that local inhibition of IL-4Ralpha in the lung is sufficient to suppress allergen-induced pulmonary inflammation and AHR.

Association of portovenographic findings with outcome in dogs receiving surgical treatment for single congenital portosystemic shunts: 45 cases (2000-2004).

OBJECTIVE: To determine whether hepatic portal vascularity, as assessed by intraoperative mesenteric portovenography (IMP), is related to outcome in dogs undergoing attenuation of single congenital portosystemic shunts (CPSSs). DESIGN: Retrospective case series. ANIMALS: 45 dogs, each with a single CPSS, in which IMP was performed before and after temporary complete occlusion of the shunting vessel and that underwent complete (17 dogs) or partial (28 dogs) CPSS attenuation (surgery 1). PROCEDURES: Medical records were reviewed for signalment, clinical history, and bile acids stimulation test results. Intrahepatic portal vessel (IPV) opacification in pre- and postocclusion portovenograms was graded to determine whether the degree of opacification was correlated with the degree of shunt attenuation, clinical or biochemical factors, or long-term clinical outcome. In 17 of 28 dogs that had partial CPSS attenuation, these procedures were subsequently repeated (surgery 2) to achieve complete (14 dogs) or further partial (3 dogs) CPSS attenuation. RESULTS: Compared with preattenuation findings, IPV opacification increased significantly after partial or complete CPSS attenuation. The degree of IPV opacification before and after CPSS occlusion (surgery 1) was greater in dogs that tolerated complete versus partial CPSS attenuation and was correlated positively with age. The degree of IPV opacification following CPSS occlusion (surgery 1) was maximal in all dogs without encephalopathy and was correlated negatively with follow-up preprandial serum bile acids concentrations and positively with clinical improvement. CONCLUSIONS AND CLINICAL RELEVANCE: Data suggest that IMP can be used to assess changes in IPV blood flow and help predict outcome following attenuation of single CPSSs in dogs.