The genomic architecture of resistance to Campylobacter jejuni intestinal colonisation in chickens.

BACKGROUND: Campylobacter is the leading cause of foodborne diarrhoeal illness in humans and is mostly acquired from consumption or handling of contaminated poultry meat. In the absence of effective licensed vaccines and inhibitors, selection for chickens with increased resistance to Campylobacter could potentially reduce its subsequent entry into the food chain. Campylobacter intestinal colonisation levels are influenced by the host genetics of the chicken. In the present study, two chicken populations were used to investigate the genetic architecture of avian resistance to colonisation: (i) a back-cross of two White Leghorn derived inbred lines [(61 x N) x N] known to differ in resistance to Campylobacter colonisation and (ii) a 9(th) generation advanced intercross (61 x N) line. RESULTS: The level of colonisation with Campylobacter jejuni following experimental infection was found to be a quantitative trait. A back-cross experiment using 1,243 fully informative single nucleotide polymorphism (SNP) markers revealed quantitative trait loci (QTL) on chromosomes 7, 11 and 14. In the advanced intercross line study, the location of the QTL on chromosome 14 was confirmed and refined and two new QTLs were identified located on chromosomes 4 and 16. Pathway and re-sequencing data analysis of the genes located in the QTL candidate regions identified potential pathways, networks and candidate resistance genes. Finally, gene expression analyses were performed for some of the candidate resistance genes to support the results. CONCLUSION: Campylobacter resistance in chickens is a complex trait, possibly involving the Major Histocompatibility Complex, innate and adaptive immune responses, cadherins and other factors. Two of the QTLs for Campylobacter resistance are co-located with Salmonella resistance loci, indicating that it may be possible to breed simultaneously for enhanced resistance to both zoonoses.

Phenytoin loading doses in adult critical care patients: does current practice achieve adequate drug levels?

Phenytoin is regularly employed in the critically ill for prophylaxis against or treatment of seizure disorders. No prior studies have examined current dosing practices in an Australasian intensive care unit (ICU) setting. The aims of this study were to: a) describe the adequacy of contemporary dosing in respect to free and total serum phenytoin concentrations; b) identify factors associated with therapeutic drug concentrations; and c) examine the accuracy of predictive equations that estimate free concentrations in this setting. All patients receiving a loading dose of phenytoin in a tertiary-level ICU were eligible for enrolment; 53 patients were enrolled in the study. Serum samples to determine free and total phenytoin concentrations (measured by high performance liquid chromatography) were then drawn prior to the following dose. Free concentrations below the recommended target (<1 mg/l) were considered as suboptimal. The most common indication for phenytoin loading was traumatic brain injury (49%) and the mean administered dose was 14.5 (3.66) mg/kg. Twenty-six patients (49%) had suboptimal trough free concentrations, although this subgroup was significantly heavier and therefore received a lower per kilogram dose (12.8 [3.1] vs 16.3 [3.4] mg/kg, P=0.001). In multivariate analysis, larger weight adjusted doses (P=0.018), higher albumin concentration (P=0.034) and receiving phenytoin for an indication other than seizure (P=0.035), were associated with a greater likelihood of adequate concentrations. In conclusion, phenytoin dosing remains complex in critically ill patients, although lower per kilogram loading doses are strongly associated with free concentrations below the desired target.

Intoxicaciones en menores de 7 años en España. Aspectos de mejora en la prevención y tratamiento / Poisoning in children under age 7 in Spain. Areas of improvement in the prevention and treatment

Introducción: La prevención de las intoxicaciones agudas pediátricas requiere conocer las circunstancias en que suceden. Objetivos: Analizar las circunstancias de las intoxicaciones en<7 años de edad y su manejo en los Servicios de Urgencias Pediátricos hospitalarios en España (SUPE). Material y métodos: Estudio prospectivo incluyendo episodios de intoxicaciones en <7 años de edad registrados en 44 hospitales entre los años 2008 y 2011. Resultados: Se registraron 400 intoxicaciones, 308 (77%) en <7 años; 23 (7,5%) referían episodios similares previos familiares. Sucedieron en domicilio familiar 230, principalmente por ingesta no intencionada (89,6%) de medicamentos (182; 59%), productos del hogar (75; 24,4%) y cosméticos (18; 5,8%). El 36,6% contactó previamente con otros servicios. En el hospital recibieron tratamiento 160 (51,9%) y el 45,4% ingresó. Ninguno falleció. En las intoxicaciones por fármacos se practicaron más frecuentemente exploraciones complementarias (48,9% vs. 32% por productos del hogar y 11,1% por cosméticos; p<0,05), tratamientos (64,8% vs. 36% y 16,6%; p<0,0001) e ingreso (54,9% vs. 37,3% y 5,5%; p=0,015) y el 12,1% no fue por ingesta accidental (vs. 2,6% y 0%; p<0,05), sobre todo errores de dosificación. Las intoxicaciones por productos del hogar se asociaron más frecuentemente a conservación en envases no originales y al alcance de los niños. Conclusiones: La mayoría de las intoxicaciones atendidas en SUPE suceden en <7 años, tras ingesta no intencionada de fármacos y productos del hogar en el domicilio. Las intoxicaciones por fármacos fueron potencialmente más peligrosas. La prevención debiera considerar la educación sobre almacenaje de medicamentos/productos del hogar, administración de medicamentos y consejos para evitar nuevos episodios (AU)

Introduction: To prevent acute poisoning in children we need to know in which circumstances they occur. Objective: To analyse the circumstances of poisoning in children under 7 years-old and the management of these children in Spanish Paediatric Emergency Departments (SPED). Material and methods: We perform a prospective study of charts of poisoned children less than 7 years admitted to 44 hospitals between 2008 and 2011. Results: A total of 400 poisoned children were recorded: 308 (77%) in children under 7 years, of whom 23 (7.5%) of them had previous episodes of poisoning in the family. More than half (230) occurred at home, mainly due to accidental ingestion (89.6%), of drugs (182, 59%), household products (75, 24.4%), and cosmetics (18, 5.8%). More than one-third (36.6%) contacted other departments before the patient reached SPED. A total of 160 (51.9%) were treated in the hospital, and 45.4% were admitted in the hospital. None of them died. Drug poisoning required complementary tests more often (48.9% vs. 32% household products, and 11.1% cosmetics, P<.05), more treatments (64.8% vs. 36% and 16.6%, P<.0001) and more admissions (54.9% vs. 37.3% and 5.5%, P=.015), and 12.1% were not due to accidental ingestion but dosage errors (vs. 2.6% and 0%, P<.05).Household product poisonings were more often related with storage in non-original packaging and being reachable by children. Conclusions: The most frequent poisonings seen in SPED were caused by the accidental ingestion of drugs and household products by children less than 7 years-old at home. Drug poisoning was potentially more risky. Drug and household product storage education, proper drug dosage and administration, and good advice are the main issues to prevent these poisonings (AU)

'We just stick together': how disabled teens negotiate stigma to create lasting friendship.

BACKGROUND: Friendship is a crucial relationship offering practical support, enjoyment and improved health. When disability is added into the mix, the permutations of friendship shift. Despite the presence of inclusive social policies many disabled teens continue to experience stigma and social isolation, yet some teens are able to establish long-term friendships. METHODS: A nuanced understanding about how disabled teens navigate stigma to create lasting friendships was constructed through this qualitative study. Seven boys and seven girls between the ages 15 to 20 years who experienced disability engaged in research interviews and participant observation sessions. Nine adults were also interviewed. A critical approach to data analysis was complimented by coding in Atlas.ti. RESULTS: This article describes the strategies used by these disabled teens to make and keep friends: disrupting norms about friendship, coming out as disabled, connecting through stigma and choosing self-exclusion. CONCLUSION: Disabled teens in this study felt a greater sense of belonging when with peers who shared the disability experience, thus self-exclusion was a viable strategy for creating sustainable friendships in the context of oppression. Social policy informed by the experiences of disabled youth in the current study will more effectively promote social inclusion by first acknowledging and then disrupting ableism.

[Poisoning in children under age 7 in Spain. Areas of improvement in the prevention and treatment]. / Intoxicaciones en menores de 7 años en España. Aspectos de mejora en la prevención y tratamiento.

INTRODUCTION: To prevent acute poisoning in children we need to know in which circumstances they occur. OBJECTIVE: To analyse the circumstances of poisoning in children under 7 years-old and the management of these children in Spanish Paediatric Emergency Departments (SPED). MATERIAL AND METHODS: We perform a prospective study of charts of poisoned children less than 7 years admitted to 44 hospitals between 2008 and 2011. RESULTS: A total of 400 poisoned children were recorded: 308 (77%) in children under 7 years, of whom 23 (7.5%) of them had previous episodes of poisoning in the family. More than half (230) occurred at home, mainly due to accidental ingestion (89.6%), of drugs (182, 59%), household products (75, 24.4%), and cosmetics (18, 5.8%). More than one-third (36.6%) contacted other departments before the patient reached SPED. A total of 160 (51.9%) were treated in the hospital, and 45.4% were admitted in the hospital. None of them died. Drug poisoning required complementary tests more often (48.9% vs. 32% household products, and 11.1% cosmetics, P<.05), more treatments (64.8% vs. 36% and 16.6%, P<.0001) and more admissions (54.9% vs. 37.3% and 5.5%, P=.015), and 12.1% were not due to accidental ingestion but dosage errors (vs. 2.6% and 0%, P<.05). Household product poisonings were more often related with storage in non-original packaging and being reachable by children. CONCLUSIONS: The most frequent poisonings seen in SPED were caused by the accidental ingestion of drugs and household products by children less than 7 years-old at home. Drug poisoning was potentially more risky. Drug and household product storage education, proper drug dosage and administration, and good advice are the main issues to prevent these poisonings.

Identification, cloning and characterisation of interleukin-1F5 (IL-36RN) in the chicken.

The human IL-1 family contains eleven genes encoded at three separate loci. Nine, including IL-36 receptor antagonist (IL-36RN), also known as IL-1F5, are present at a single locus on chromosome 2, whereas IL-18 and IL-33 lie on chromosomes 11 and 9 respectively. There are currently only three known orthologues in the chicken - IL-1ß, IL-18 and IL-1RN - which are encoded on chromosomes 22, 24 and unplaced, respectively. A novel chicken IL-1 family sequence representing IL-36RN (IL-1F5) was initially identified from an expressed sequence tag (EST) library by its similarity to both chicken IL-1RN and chicken IL-1ß. Following isolation of the cDNA from the liver of an uninfected bird, a number of unique sequence features were identified. The predicted protein has a longer NH(2)-terminus than the human protein; however, as in mammals, this region contains neither a prodomain nor a signal peptide. A putative nuclear export sequence is also apparent, yet a similar motif is absent in mammalian IL-36RN. Although chIL-36RN exhibits low homology with its mammalian orthologues, it encodes a predicted ß-trefoil structure whose ß-strands are conserved with those of the mouse sequence. Unlike in mammals, chIL-36RN expression was constitutive in all tissues and cell subsets examined. In response to viral infection, expression was significantly downregulated in a line of birds which are susceptible to the virus. Chicken IL-36RN, like chIL-1RN, is not encoded at the chIL-1ß locus, further emphasising the genomic fragmentation of the large IL-1 gene cluster found in mammals. This suggests differential evolution of this cytokine family since the divergence of birds and mammals from a common ancestor, and underlines the difficulty of determining the full repertoire of chIL-1 family members.

Genome-wide SNP analysis identifies major QTL for Salmonella colonization in the chicken.

Salmonella-infected poultry products are a major source of human Salmonella infection. The prophylactic use of antimicrobials in poultry production was recently banned in the EU, increasing the need for alternative methods to control Salmonella infections in poultry flocks. Genetic selection of chickens more resistant to Salmonella colonization provides an attractive means of sustainably controlling the pathogen in commercial poultry flocks and its subsequent entry into the food chain. Analysis of different inbred chickens has shown that individual lines are consistently either susceptible or resistant to the many serovars of Salmonella that have been tested. In this study, two inbred chicken lines with differential susceptibility to Salmonella colonization (61 ((R)) and N((S)) ) were used in a backcross experimental design. Unlike previous studies that used a candidate gene approach or low-density genome-wide screens, we have exploited a high-density marker set of 1255 SNPs covering the whole genome to identify quantitative trait loci (QTL). Analysis of log-transformed caecal bacterial levels between the parental lines revealed a significant difference at 1, 2, 3 and 4 days post-infection (P < 0.05). Analysis of the genotypes of the backcross (F1 × N) population (n = 288) revealed four QTL on chromosomes 2, 3, 12 and 25 for the two traits examined in this study: log-transformed bacterial counts in the caeca and presence of a hardened caseous caecal core. These included one genome-wide significant QTL on chromosome 2 at 20 Mb and three additional QTL, on chromosomes 3, 12 and 25 at 96, 15 and 1 Mb, respectively, which were significant at the chromosome-wide level (P < 0.05). The results generated in this study will inform future breeding strategies to control these pathogens in commercial poultry flocks.

[What perspectives for cognitive remediation in schizophrenia?]. / Quelles perspectives pour la remédiation cognitive dans la schizophrénie?

Cognitive deficits are routinely evident in schizophrenia, and are of sufficient magnitude to influence functional outcomes in work, social functioning and illness management. Cognitive remediation is an evidenced-based non-pharmacological treatment for the neurocognitive deficits seen in schizophrenia. Narrowly defined, cognitive remediation is a set of cognitive drills or compensatory interventions designed to enhance cognitive functioning, but from the vantage of the psychiatric rehabilitation field, cognitive remediation is a therapy which engages the patient in learning activities that enhance the neurocognitive skills relevant to their chosen recovery goals. Cognitive remediation programs vary in the extent to which they reflect these narrow or broader perspectives but a metaanalytic study reports moderate range effect sizes on cognitive test performance, and daily functioning. Reciprocal interactions between baseline ability level, the type of instructional techniques used, and motivation provide some explanatory power for the heterogeneity in patient response to cognitive remediation. Recent studies indicate that intrinsic motivation mediates the relationship between neurocognition and functional outcomes. Results of these studies suggest that intrinsic motivation should be a viable treatment target in cognitive remediation intervention. In this perspective, NEAR (Neuropsychological Educational Approach to Remediation) program was created to enhance intrinsic motivation by employing more engaging and interesting software packages for cognitive practice, involving consumers in choosing the focus of training and having the NEAR leader serve as a coach to engage the consumers in active guidance of their own treatment program.

Towards the selection of chickens resistant to Salmonella and Campylobacter infections.

Resistance to infection with enteric pathogens such as Salmonella and Campylobacter can be at many levels and include both non-immune and immune mechanisms. Immune resistance mechanisms can be specific, at the level of the adaptive immune response, or non-specific, at the level of the innate immune response. Whilst we can extrapolate to some degree in birds from what is known about immune responses to these pathogens in mammals, chickens are not "feathered mice", but have a different repertoire of genes, molecules, cells and organs involved in their immune response compared to mammals. Fundamental work on the chicken's immune response to enteric pathogens is therefore still required. Our studies focus particularly on the innate immune response, as responses of heterophils (the avian neutrophil equivalent) from commercial birds, and macrophages from inbred lines of chickens, correlate with resistance or susceptibility to Salmonella infection with a variety of Salmonella serovars and infection models. We work on two basic resistance mechanisms - resistance to colonization with Salmonella or Campylobacter, and resistance to systemic salmonellosis (or fowl typhoid). To map genes involved in resistance to colonization with Salmonella and Campylobacter, we are using a combination of expression quantitative trait loci (eQTLs) from microarray studies, allied with whole genome SNP arrays (WGA), a candidate gene approach and analysis of copy number variation across the genome. For resistance to systemic salmonellosis, we have refined the location ofa novel resistance locus on Chromosome 5, designated SAL1, using high density SNP panels, combined with advanced back-crossing of resistant and susceptible lines. Using a 6th generation backcross mapping population we have confirmed and refined the SAL1 locus to 8-00 kb of Chromosome 5. This region spans 14 genes, including two very striking functional candidates; CD27-binding protein (Siva) and the RAC-alpha serine/threonine protein kinase homologue, AKT1.

Polyelectrolyte multilayer films promote human cord blood stem cells differentiation into mature endothelial cells exhibiting a stable phenotype.

BACKGROUND: recent studies in bio-engineering have showed the influence of Polyelectrolyte Multilayer (PEM) films on endothelial cells (ECs), especially poly(sodium-4-styrene-sulfonate) (PSS) and poly(allylamine hydrochloride) (PAH). They were tested either with human mature ECs or rabbit immature endothelial progenitor cells (EPCs), but never on human EPCs. In view to obtain an EC covered surface, human cord blood (HCB) EPCs were cultivated on PSS/PAH films. MATERIAL AND METHODS: PEMs were obtained by 7 alternate depositions of cationic PAH and anionic PSS layers. HCB mononuclear cells were isolated by centrifugation through density gradient. 7 days after seeding on PEM, unattached cells were removed and adherent EPCs were cultivated in endothelial specific medium until P6. Appearance of CD31 and vWF was evaluated by confocal microscopy. RESULTS: EPCs not only successfully adhered on PEM, but also spread and proliferated. Moreover, cells differentiated into a typical endothelial cobblestone monolayer within 2 weeks. Immunostaining of CD31 and vWF confirmed the formation of an EC-like confluent monolayer. Furthermore, these cells showed after 6 passages a good phenotypic stability while reseeded on the PEM film. CONCLUSION: these results show an easy way to obtain mature ECs from human stem cells, which may open new applications for a scaffold cellularization in tissue bio-engineering.

Fine mapping of the chicken salmonellosis resistance locus (SAL1).

Salmonella enterica serovar Typhimurium is a Gram-negative bacterium that has a significant impact on both human and animal health. It is one of the most common food-borne pathogens responsible for a self-limiting gastroenteritis in humans and a similar disease in pigs, cattle and chickens. In contrast, intravenous challenge with S. Typhimurium provides a valuable model for systemic infection, often causing a typhoid-like infection, with bacterial replication resulting in the destruction of the spleen and liver of infected animals. Resistance to systemic salmonellosis in chickens is partly genetically determined, with bacterial numbers at systemic sites in resistant lines being up to 1000-fold fewer than in susceptible lines. Identification of genes contributing to disease resistance will enable genetic selection of resistant lines that will reduce Salmonella levels in poultry flocks. We previously identified a novel resistance locus on Chromosome 5, designated SAL1. Through the availability of high-density SNP panels in the chicken, combined with advanced back-crossing of the resistant and susceptible lines, we sought to refine the SAL1 locus and identify potential positional candidate genes. Using a 6(th) generation backcross mapping population, we have confirmed and refined the SAL1 locus as lying between 54.0 and 54.8 Mb on the long arm of Chromosome 5 (F = 8.72, P = 0.00475). This region spans 14 genes, including two very striking functional candidates; CD27-binding protein (Siva) and the RAC-alpha serine/threonine protein kinase homolog, AKT1 (protein kinase B, PKB).

Integrated immunogenomics in the chicken: deciphering the immune response to identify disease resistance genes.

Resistance to infection takes place at many levels, and involves both non-specific and specific immune mechanisms. The chicken has a different repertoire of immune genes, molecules, cells and organs compared to mammals. To understand the role of any disease resistance gene(s), it is therefore important to understand these different repertoires, and the bird's response to a particular pathogen. Our studies focus on the innate immune response, as responses of macrophages from inbred lines of chickens, and heterophils from commercial birds, correlate with resistance or susceptibility to Salmonella infection with a variety of Salmonella serovars and infection models. To map disease resistance genes, we are using a combination of expression quantitative trait loci (eQTLs) from microarray studies, allied with whole genome SNP arrays (WGA) and a candidate gene approach. There are over 500 human genes with the Gene Ontology term "innate immunity". We have identified over 400 of these genes in the chicken genome, and are actively identifying informative SNPs in them. The segregation of 6000 WGA SNPs across all of our inbred lines was also assessed, which should yield approximately 900 informative SNPs for a cross between any two lines. The initial focus of these studies is on mapping resistance genes in our inbred lines, but the studies will be extended to commercial flocks.

Anaesthetic management of an obstetric patient with Pompe disease.

Pompe disease (Glycogen storage disease type II) leads to abnormal glycogen deposition in various vital organs resulting in multiple systemic sequelae. We present the anaesthetic management for caesarean section of a 31-year-old parturient with known Pompe disease. The parturient had symptoms and signs of respiratory dysfunction and the pregnancy was complicated by preeclampsia. She underwent urgent caesarean section under regional anaesthesia resulting in the birth of a healthy baby girl. To our knowledge, this is the first reported case of both spinal anaesthesia for caesarean section and successful live birth in a patient with Pompe disease.

The genes encoding E-selectin (SELE) and lymphotactin (SCYC1) lie on separate chicken chromosomes although they are closely linked in human and mouse.

Three differentially expressed selectin genes (SELE, SELP, and SELL), important in the initial stages of leukocyte extravasation, have been reported in mammals. All three genes map close to the chemokine SCYC1 (small inducible cytokine subfamily C, member 1) in a large conserved chromosomal segment that extends from RXRG (retinoic acid receptor, gamma) to TNNT2 (troponin T2) on Chromosome (Chr) 1 in both human and mouse. In the mouse, we demonstrate that Sele is flanked by Prrx1 (paired-related homeobox gene 1) and Scyc1 and define the order of, and distances between, loci as centromere-Prrx1-(0.7+/-0.7 cM)-Sele-(1.2+/-0.9 cM)-Scyc1-telomere. In the chicken, we isolated BAC clones containing PRRX1, SELE, and SCYC1 and positioned them by fluorescent in situ hybridization. SELE and PRRX1 mapped to the short arm of chicken Chr 8 and SCYC1 mapped to the region equivalent to 1q11-1q13 on the long arm of chicken Chr 1. The location of SELE on chicken Chr 8 was independently established by linkage analysis of COM0185, an (AT)16 microsatellite locus identified in a BAC clone that contained SELE. COM0185 was linked to several loci that mapped to one end of chicken Chr 8, with the order of loci, and genetic distances (in cM) between them defined as MSU0435, MSU0325-(7.8+/-3.7)-COM0185-(5.8+/-3.2)-ROS0338-(9.6+/-4.0)-ABR0322-(3.8+/-2.6)-GLUL. We have therefore positioned an evolutionary breakpoint in mammals and chickens between SELE and SCYC1. Furthermore, comparative mapping analysis of the RXRG-TNNT2 chromosomal segment that is conserved on human and mouse Chr 1 indicates that it is divided into four segments in the chicken, each of which maps to a different chromosome.

A comparison of alfentanil requirements in European and Asian patients during general anaesthesia.

Alfentanil requirements were compared in thirty-six Asian and forty-three European patients during general anaesthesia with muscle relaxants. Alfentanil infusion at 5 micrograms/kg/min was started immediately after induction with thiopentone and alcuronium. The infusion rate was reduced to 0.5 microgram/kg/min after ten minutes. An incremental dose of 5 micrograms/kg/min for five minutes was given on each occasion when anaesthesia was clinically judged to be inadequate. Recovery parameters were recorded. Pharmacokinetics were also studied in five Europeans, four Chinese and four Nepalese. The dosage of alfentanil required was comparable in both Asian and European patients, but recovery was slower in the Asian patients. The elimination half-life in the Chinese and the Nepalese were both significantly shorter than that of the Europeans (P less than 0.05), but at the time of recovery of spontaneous ventilation, the mean plasma concentrations were not significantly different.

Extradural block. Confirmation of the injection site by X-ray monitoring.

X-ray monitoring was used to confirm the accuracy of extradural block in 100 patients who attended the Pain Relief Clinic for treatment of a variety of different conditions. A Tuohy needle was introduced by the central or paramedian approach and conventional physical signs, notably loss of resistance, used to identify entry into the extradural space. A radio-opaque dye was introduced prior to the analgesic solution, to display the injection site. X-ray screening confirmed the accuracy of the block in 83 patients, but unexpectedly in 17 the point of the needle was either just outside the spinal canal or only partly in the extradural space. There was no difficulty in correcting the needle position with the X-ray facilities available. Imprecise needle siting is only partially explained by technical problems. Imprecise siting of the needle may be responsible for at least some cases of inadequate analgesia or unexpected complications. In our view X-ray confirmation of site is essential for difficult extradural blocks, or when neurolytic solutions are introduced into the spinal canal. It may also be useful in teaching and research.

[Catecholamines and their derivatives in the study of pheochromocytoma]. / Les catécholamines et leurs dérivés dans l'exploration du phéochromocytome.

The biochemical diagnosis of pheochromocytoma is essentially based on the plasma and urinary levels of catecholamines and their derivatives, the metanephrines and vanyl-mandelic acid. The advantages and disadvantages of these investigations are reviewed, especially as regards the specificity and sensitivity of each test. The measurement of urinary metanephrine is the best test as its excretion is relatively higher, and it is rarely normal. The measurement of plasma catecholamines is more difficult but gives satisfactory results, but experience so far is limited.