Psychological Stress Is Associated with Increased Cancer Risk in Dogs.

Although there is evidence that psychological stress may be associated with increased cancer risk, the effect of stress on cancer risk is difficult to study, both in humans, due to socioeconomic factors, and in animal models, due to questionable biological relevance. Here, we test whether heritable canine temperament that increases psychological stress is associated with cancer risk. The study data are breed-specific averages of incidences of multiple cancer types and of temperament classes. The latter are derived from a latent class analysis of behavioral questionnaires completed by owners (C-BARQ). We thus classified the dogs according to whether they are calm vs. reactive within and across breeds. Using meta-analysis approaches, we modeled the risk of multiple cancer types in calm vs. reactive dogs. We adjusted for breed averages of body mass and lifespan, which are common confounders that impact cancer. Our study confirms that body size has a significant effect of on risk of multiple types of cancers in dogs and shows for the first time that temperament also has a moderate effect. These findings suggest dog models of heritable psychological stress are suitable for molecular epidemiological and translational studies on its effects on cancer risk.

Machine learning prediction and classification of behavioral selection in a canine olfactory detection program.

There is growing interest in canine behavioral research specifically for working dogs. Here we take advantage of a dataset of a Transportation Safety Administration olfactory detection cohort of 628 Labrador Retrievers to perform Machine Learning (ML) prediction and classification studies of behavioral traits and environmental effects. Data were available for four time points over a 12 month foster period after which dogs were accepted into a training program or eliminated. Three supervised ML algorithms had robust performance in correctly predicting which dogs would be accepted into the training program, but poor performance in distinguishing those that were eliminated (~ 25% of the cohort). The 12 month testing time point yielded the best ability to distinguish accepted and eliminated dogs (AUC = 0.68). Classification studies using Principal Components Analysis and Recursive Feature Elimination using Cross-Validation revealed the importance of olfaction and possession-related traits for an airport terminal search and retrieve test, and possession, confidence, and initiative traits for an environmental test. Our findings suggest which tests, environments, behavioral traits, and time course are most important for olfactory detection dog selection. We discuss how this approach can guide further research that encompasses cognitive and emotional, and social and environmental effects.

Latent class analysis of behavior across dog breeds reveal underlying temperament profiles.

Latent class analysis (LCA) is a type of modeling analysis approach that has been used to identify unobserved groups or subgroups within multivariate categorical data. LCA has been used for a wide array of psychological evaluations in humans, including the identification of depression subtypes or PTSD comorbidity patterns. However, it has never been used for the assessment of animal behavior. Our objective here is to identify behavioral profile-types of dogs using LCA. The LCA was performed on a C-BARQ behavioral questionnaire dataset from 57,454 participants representing over 350 pure breeds and mixed breed dogs. Two, three, and four class LCA models were developed using C-BARQ trait scores and environmental covariates. In our study, LCA is shown as an effective and flexible tool to classify behavioral assessments. By evaluating the traits that carry the strongest relevance, it was possible to define the basis of these grouping differences. Groupings can be ranked and used as levels for simplified comparisons of complex constructs, such as temperament, that could be further exploited in downstream applications such as genomic association analyses. We propose this approach will facilitate dissection of physiological and environmental factors associated with psychopathology in dogs, humans, and mammals in general.

Genome scanning of behavioral selection in a canine olfactory detection breeding cohort.

Research on working dogs is growing rapidly due to increasing global demand. Here we report genome scanning of the risk of puppies being eliminated for behavioral reasons prior to entering the training phase of the US Transportation Security Administration's (TSA) canine olfactory detection breeding and training program through 2013. Elimination of dogs for behavioral rather than medical reasons was based on evaluations at three, six, nine and twelve months after birth. Throughout that period, the fostered dogs underwent standardized behavioral tests at TSA facilities, and, for a subset of tests, dogs were tested in four different environments. Using methods developed for family studies, we performed a case-control genome wide association study (GWAS) of elimination due to behavioral observation and testing results in a cohort of 528 Labrador Retrievers (2002-2013). We accounted for relatedness by including the pedigree as a covariate and maximized power by including individuals with phenotype, but not genotype, data (approximately half of this cohort). We determined genome wide significance based on Bonferroni adjustment of two quasi-likelihood score tests optimized for either small or nearly-fully penetrant effect sizes. Six loci were significant and five suggestive, with approximately equal numbers of loci for the two tests and frequencies of loci with single versus multiple mapped markers. Several loci implicate a single gene, including CHD2, NRG3 and PDE1A which have strong relevance to behavior in humans and other species. We briefly discuss how expanded studies of canine breeding programs could advance understanding of learning and performance in the mammalian life course. Although human interactions and other environmental conditions will remain critical, our findings suggest genomic breeding selection could help improve working dog populations.

One-particle engine with a porous piston.

We propose a variation of the classical Szilard engine that uses a porous piston. Such an engine requires neither information about the position of the particle, nor the removal and subsequent insertion of the piston when resetting the engine to continue doing work by lifting a mass against a gravitational field. Though the engine operates in contact with a single thermal reservoir, the reset mechanism acts as a second reservoir, dissipating energy when a mass that has been lifted by the engine is removed to initiate a new operation cycle.

Genetic testing of dogs predicts problem behaviors in clinical and nonclinical samples.

BACKGROUND: Very little is known about the etiology of personality and psychiatric disorders. Because the core neurobiology of many such traits is evolutionarily conserved, dogs present a powerful model. We previously reported genome scans of breed averages of ten traits related to fear, anxiety, aggression and social behavior in multiple cohorts of pedigree dogs. As a second phase of that discovery, here we tested the ability of markers at 13 of those loci to predict canine behavior in a community sample of 397 pedigree and mixed-breed dogs with individual-level genotype and phenotype data. RESULTS: We found support for all markers and loci. By including 122 dogs with veterinary behavioral diagnoses in our cohort, we were able to identify eight loci associated with those diagnoses. Logistic regression models showed subsets of those loci could predict behavioral diagnoses. We corroborated our previous findings that small body size is associated with many problem behaviors and large body size is associated with increased trainability. Children in the home were associated with anxiety traits; illness and other animals in the home with coprophagia; working-dog status with increased energy and separation-related problems; and competitive dogs with increased aggression directed at familiar dogs, but reduced fear directed at humans and unfamiliar dogs. Compared to other dogs, Pit Bull-type dogs were not defined by a set of our markers and were not more aggressive; but they were strongly associated with pulling on the leash. Using severity-threshold models, Pit Bull-type dogs showed reduced risk of owner-directed aggression (75th quantile) and increased risk of dog-directed fear (95th quantile). CONCLUSIONS: Our association analysis in a community sample of pedigree and mixed-breed dogs supports the interbreed mapping. The modeling shows some markers are predictive of behavioral diagnoses. Our findings have broad utility, including for clinical and breeding purposes, but we caution that thorough understanding is necessary for their interpretation and use.

Safety and Effectiveness of the Flexible Cervical Implant: Preliminary Short-Term Clinical Results.

OBJECTIVE: We sought to determine the safety and effectiveness of the Flexible Cervical Implant in 1- or 2-level cervical segments. METHODS: Retrospective data collection was carried out on consecutive patients who underwent the implantation of the Flexible Cervical Implant in a local private health institution. Demographics, clinical pictures, magnetic resonance images, x-ray images, technical considerations, and postoperative clinical results were reviewed. RESULTS: Twelve patients were treated with 15 implants. The mean age was 57.5 years (range 28-81), and 6 patients were males. The most common level was C5/C6 (7 cases). Radicular pain was the main symptom in all patients. Short-term postoperative clinical outcomes showed improvement in the visual analog scale (VAS) and the Neck Disability Index (NDI). The median VAS score for radicular pain improved from 6 to 2 (P < 0.001), whereas the median NDI showed a significant improvement from 25 to 5 (P < 0.001). No implant-related complications were reported. The mean follow-up was 7.3 months. CONCLUSIONS: The newly developed Flexible Cervical Implant was safe and effective in terms of morbidity and improvement in clinical outcomes. This new cervical artificial disk is promising, and further long-term clinical and radiologic follow-up is needed to determine its benefits.

Work done on a single-particle gas during an adiabatic compression and expansion process.

We compute the average work done by an external agent, driving a piston at constant speed, over a single-particle gas going through an adiabatic compression and expansion process. To do so, we get the analytical expression relating the number of collisions between the piston and the particle with the position of the piston during the process. The ergodicity breaking of the system during the process is identified as the source of its irreversibility. In addition, we observe that by using particular initial distributions for the state of the particle, it is possible to preclude the possibility of a net energy transfer from the agent to the particle during the process.

Risk-modeling of dog osteosarcoma genome scans shows individuals with Mendelian-level polygenic risk are common.

BACKGROUND: Despite the tremendous therapeutic advances that have stemmed from somatic oncogenetics, survival of some cancers has not improved in 50 years. Osteosarcoma still has a 5-year survival rate of 66%. We propose the natural canine osteosarcoma model can change that: it is extremely similar to the human condition, except for being highly heritable and having a dramatically higher incidence. Here we reanalyze published genome scans of osteosarcoma in three frequently-affected dog breeds and report entirely new understandings with immediate translational indications. RESULTS: First, meta-analysis revealed association near FGF9, which has strong biological and therapeutic relevance. Secondly, risk-modeling by multiple logistic regression shows 22 of the 34 associated loci contribute to risk and eight have large effect sizes. We validated the Greyhound stepwise model in our own, independent, case-control cohort. Lastly, we updated the gene annotation from approximately 50 genes to 175, and prioritized those using cross-species genomics data. Mostly positional evidence suggests 13 genes are likely to be associated with mapped risk (including MTMR9, EWSR1 retrogene, TANGO2 and FGF9). Previous annotation included seven of those 13 and prioritized four by pathway enrichment. Ten of our 13 priority genes are in loci that contribute to risk modeling and thus can be studied epidemiologically and translationally in pet dogs. Other new candidates include MYCN, SVIL and MIR100HG. CONCLUSIONS: Polygenic osteosarcoma-risk commonly rises to Mendelian-levels in some dog breeds. This justifies caninized animal models and targeted clinical trials in pet dogs (e.g., using CDK4/6 and FGFR1/2 inhibitors).

Cefalea post punción dural en embarazadas sometidas a cesárea con anestesia raquidea ¿problema actual o pasado? / Cefalea post dural puncture in pregnant submissions to caesárea with raquidea anesthesia problem current or past?

Objetivos: Conocer la incidencia de cefaleas postpunción dural (CPPD) en raquianestesia para cesárea y factores de riesgo reconocidos. Efectividad del tratamiento médico y necesidad de parche hemático peridural. Metodología: Estudio prospectivo, descriptivo, con seguimiento postoperatorio por 72 horas de 914 embarazadas que recibieron raquianestesia para cesárea en el Hospital de la Mujer durante 1 año. Datos registrados por anestesiólogo actuante, seguimiento por un residente. Al diagnosticar una CPPD, se instaló tratamiento según protocolo. Resultados: la incidencia de CPPD fue 2,6 casos/ 100 pacientes, 24 en la población estudiada. 66.7%, aparecieron a las 24 horas; 16,7% a las 48 horas. 54,2% mejoraron a las 24 horas, ninguna requirió parche hemático. 86,3% de las punciones fueron con agujan 25 punta de lápiz, 11,2% con 27 punta de lápiz 23 casos de CPPD para la primera y 1 caso para la segunda, no encontrando asociación estadística (p= 0,759). 76,6% fueron punción única, 15,2% 2 punciones, 7% más de 2. 80,7 % cesáreas urgencia, 65,2% en horario diurno. 42% realizadas por anestesiólogos, 54% por residentes. 8,6% tenían antecedente de cefalea y 2,7% antecedente de CPPD; encontrándose asociación estadística entre la primera y CPPD actual (p=0,001) y entre la segunda y la presencia de CPPD (p=0,004). Conclusiones: obtuvimos una incidencia de CPPD de 2,6%, concordante con datos de la literatura; la mayoría apareció a las 24 horas y todas mejoraron con tratamiento médico. Las pacientes con cefalea y CPPD previa presentaron un RR 5,8 y 5,4 respectivamente (IC 95%), no encontrando asociación con otros factores de riesgo.

Objectives: To know the incidence of post-dural puncture headaches (CPPD) in spinal anesthesia for caesarean section and recognized risk factors. Effectiveness of medical treatment and need for an epidural blood patch Methodology: Prospective, descriptive, postoperative follow-up for 72 hours of 914 pregnant women who received spinal anesthesia for cesarean section, Women 's Hospital during one year study. Data recorded by acting anesthesiologist monitoring by a resident. CPPD to diagnose, treatment was installed according to protocol. Results: CPPD incidence was 2.6 cases / 100 patients, 24 in the study population. 66.7% appeared at 24 hours; 16.7% at 48 hours. 54.2% improved within 24 hours, none required blood patch. 86.3% of punctures were 25G tip pen, 11.2% with 27G tip pen, 23 cases of CPPD for the first and 1 case for the second, finding no statistical association (p = 0.759). 76.6% were single puncture, 15.2% two punctures, 7% more than two. 80.7% cesarean urgency, 65.2% in daytime. 42% made by anesthesiologists, 54% by residents. 8.6% had a history of headache and 2.7% history of CPPD; statistical association was found between the first and current CPPD (p = 0.001) and between the second and the presence of CPPD (p = 0.004). Conclusions: We obtained a CPPD incidence of 2.6%, consistent with data from the literature; Most appeared within 24 hours and all improved with medical treatment. Patients with headache and previous PDCH presented RR 5.8 and 5.4 respectively (95% CI), and found no association with other risk factors.

Survey of vaccination practices in patients with diabetes: A report examining patient and provider perceptions and barriers.

In a cross-sectional study involving 279 patients with diabetes attending a primary care center the proportion of patients vaccinated for seasonal influenza, pneumococcus and hepatitis B was 40%, 2% and 2%, respectively. We found significant barriers for vaccination in 24% of patients and in 42% of providers.

Comparative genomics of canine hemoglobin genes reveals primacy of beta subunit delta in adult carnivores.

BACKGROUND: The main function of hemoglobin (Hb) is to transport oxygen in the circulation. It is among the most highly studied proteins due to its roles in physiology and disease, and most of our understanding derives from comparative research. There is great diversity in Hb gene evolution in placental mammals, mostly in the repertoire and regulation of the ß-globin subunits. Dogs are an ideal model in which to study Hb genes because: 1) they are members of Laurasiatheria, our closest relatives outside of Euarchontoglires (including primates, rodents and rabbits), 2) dog breeds are isolated populations with their own Hb-associated genetics and diseases, and 3) their high level of health care allows for development of biomedical investigation and translation. RESULTS: We established that dogs have a complement of five α and five ß-globin genes, all of which can be detected as spliced mRNA in adults. Strikingly, HBD, the allegedly-unnecessary adult ß-globin protein in humans, is the primary adult ß-globin in dogs and other carnivores; moreover, dogs have two active copies of the HBD gene. In contrast, the dominant adult ß-globin of humans, HBB, has high sequence divergence and is expressed at markedly lower levels in dogs. We also showed that canine HBD and HBB genes are complex chimeras that resulted from multiple gene conversion events between them. Lastly, we showed that the strongest signal of evolutionary selection in a high-altitude breed, the Bernese Mountain Dog, lies in a haplotype block that spans the ß-globin locus. CONCLUSIONS: We report the first molecular genetic characterization of Hb genes in dogs. We found important distinctions between adult ß-globin expression in carnivores compared to other members of Laurasiatheria. Our findings are also likely to raise new questions about the significance of human HBD. The comparative genomics of dog hemoglobin genes sets the stage for diverse research and translation.

Renormalized jellium model for colloidal mixtures.

In an attempt to quantify the role of polydispersity in colloidal suspensions, we present an efficient implementation of the renormalized jellium model for a mixture of spherical charged colloids. The different species may have different size, charge, and density. Advantage is taken from the fact that the electric potential pertaining to a given species obeys a Poisson's equation that is species independent; only boundary conditions do change from one species to the next. All species are coupled through the renormalized background (jellium) density, that is determined self-consistently. The corresponding predictions are compared to the results of Monte Carlo simulations of binary mixtures, where Coulombic interactions are accounted for exactly, at the primitive model level (structureless solvent with fixed dielectric permittivity). An excellent agreement is found.

Genetic mapping of canine fear and aggression.

BACKGROUND: Fear/anxiety and anger/aggression greatly influence health, quality of life and social interactions. They are a huge burden to wellbeing, and personal and public economics. However, while much is known about the physiology and neuroanatomy of such emotions, little is known about their genetics - most importantly, why some individuals are more susceptible to pathology under stress. RESULTS: We conducted genomewide association (GWA) mapping of breed stereotypes for many fear and aggression traits across several hundred dogs from diverse breeds. We confirmed those findings using GWA in a second cohort of partially overlapping breeds. Lastly, we used the validated loci to create a model that effectively predicted fear and aggression stereotypes in a third group of dog breeds that were not involved in the mapping studies. We found that i) known IGF1 and HMGA2 loci variants for small body size are associated with separation anxiety, touch-sensitivity, owner directed aggression and dog rivalry; and ii) two loci, between GNAT3 and CD36 on chr18, and near IGSF1 on chrX, are associated with several traits, including touch-sensitivity, non-social fear, and fear and aggression that are directed toward unfamiliar dogs and humans. All four genome loci are among the most highly evolutionarily-selected in dogs, and each of those was previously shown to be associated with morphological traits. We propose that the IGF1 and HMGA2 loci are candidates for identical variation being associated with both behavior and morphology. In contrast, we show that the GNAT3-CD36 locus has distinct variants for behavior and morphology. The chrX region is a special case due to its extensive linkage disequilibrium (LD). Our evidence strongly suggests that sociability (which we propose is associated with HS6ST2) and fear/aggression are two distinct GWA loci within this LD block on chrX, but there is almost perfect LD between the peaks for fear/aggression and animal size. CONCLUSIONS: We have mapped many canine fear and aggression traits to single haplotypes at the GNAT3-CD36 and IGSF1 loci. CD36 is widely expressed, but areas of the amygdala and hypothalamus are among the brain regions with highest enrichment; and CD36-knockout mice are known to have significantly increased anxiety and aggression. Both of the other genes have very high tissue-specificity and are very abundantly expressed in brain regions that comprise the core anatomy of fear and aggression - the amygdala to hypothalamic-pituitary-adrenal (HPA) axis. We propose that reduced-fear variants at these loci may have been involved in the domestication process.

Human Genetic Relevance and Potent Antitumor Activity of Heat Shock Protein 90 Inhibition in Canine Lung Adenocarcinoma Cell Lines.

BACKGROUND: It has been an open question how similar human and canine lung cancers are. This has major implications in availability of human treatments for dogs and in establishing translational models to test new therapies in pet dogs. The prognosis for canine advanced lung cancer is poor and new treatments are needed. Heat shock protein 90 (HSP90) is an ATPase-dependent molecular chaperone ubiquitously expressed in eukaryotic cells. HSP90 is essential for posttranslational conformational maturation and stability of client proteins including protein kinases and transcription factors, many of which are important for the proliferation and survival of cancer cells. We investigated the activity of STA-1474, a HSP90 inhibitor, in two canine lung cancer cell lines, BACA and CLAC. RESULTS: Comparative genomic hybridization analysis of both cell lines revealed genetic relevance to human non-small cell lung cancer. STA-1474 inhibited growth and induced apoptosis of both cell lines in a dose- and time-dependent manner. The ICs50 after 72 h treatment with STA-1474 were 0.08 and 0.11 µM for BACA and CLAC, respectively. When grown as spheroids, the IC50 of STA-1474 for BACA cells was approximately two-fold higher than when grown as a monolayer (0.348 µM vs. 0.168 µM), whereas CLAC spheroids were relatively drug resistant. Treatment of tumor-stromal fibroblasts with STA-1474 resulted in a dose-dependent decrease in their relative cell viability with a low IC50 of 0.28 µM. CONCLUSIONS: Here we first established that lung adenocarcinoma in people and dogs are genetically and biochemically similar. STA1474 demonstrated biological activity in both canine lung cancer cell lines and tumor-stromal fibroblasts. As significant decreases in relative cell viability can be achieved with nanomolar concentrations of STA-1474, investigation into the clinical efficacy of this drug in canine lung cancer patients is warranted.

Canine Mammary Carcinomas: A Comparative Analysis of Altered Gene Expression.

Breast cancer represents the second most frequent neoplasm in humans and sexually intact female dogs after lung and skin cancers, respectively. Many similar features in human and dog cancers including, spontaneous development, clinical presentation, tumor heterogeneity, disease progression and response to conventional therapies have supported development of this comparative model as an alternative to mice. The highly conserved similarities between canine and human genomes are also key to this comparative analysis, especially when compared to the murine genome. Studies with canine mammary tumor (CMT) models have shown a strong genetic correlation with their human counterparts, particularly in terms of altered expression profiles of cell cycle regulatory genes, tumor suppressor and oncogenes and also a large group of non-coding RNAs or microRNAs (miRNAs). Because CMTs are considered predictive intermediate models for human breast cancer, similarities in genetic alterations and cancer predisposition between humans and dogs have raised further interest. Many cancer-associated genetic defects critical to mammary tumor development and oncogenic determinants of metastasis have been reported and appear to be similar in both species. Comparative analysis of deregulated gene sets or cancer signaling pathways has shown that a significant proportion of orthologous genes are comparably up- or down-regulated in both human and dog breast tumors. Particularly, a group of cell cycle regulators called cyclin-dependent kinase inhibitors (CKIs) acting as potent tumor suppressors are frequently defective in CMTs. Interestingly, comparative analysis of coding sequences has also shown that these genes are highly conserved in mammals in terms of their evolutionary divergence from a common ancestor. Moreover, co-deletion and/or homozygous loss of the INK4A/ARF/INK4B (CDKN2A/B) locus, encoding three members of the CKI tumor suppressor gene families (p16/INK4A, p14ARF and p15/INK4B), in many human and dog cancers including mammary carcinomas, suggested their important conserved genetic order and localization in orthologous chromosomal regions. miRNAs, as powerful post-transcriptional regulators of most of the cancer-associated genes, have not been well evaluated to date in animal cancer models. Comprehensive expression profiles of miRNAs in CMTs have revealed their altered regulation showing a strong correlation with those found in human breast cancers. These genetic correlations between human and dog mammary cancers will greatly advance our understanding of regulatory mechanisms involving many critical cancer-associated genes that promote neoplasia and contribute to the promising development of future therapeutics.

Naturally occurring cancers in dogs: insights for translational genetics and medicine.

Here, we briefly review the state of knowledge of human cancer genetics to elaborate on the need for different types of mammalian models, highlighting the strengths of the dog. Mouse models are unparalleled for their experimental tractability and rapid genetic manipulation but have some key limitations in the area of human relevance. Companion dog models are attractive, because they are genetically more similar to humans, share environmental exposures with their owners, suffer from the same diseases as humans, and receive a high level of health care. They are ideal for the study of chronic diseases, because they age five to eight times faster than humans and generally live to old age. In addition, each dog breed is on the order of 100-fold genetically simpler than the whole human or dog population. These traits make the dog ideal for the study of complex genetics of naturally occurring cancers. Here, we contrast the relative strengths of cancer genetics in humans and dogs. We propose that humans are most ideal for the study of somatic cancer genetics, whereas dogs are most ideal for germline genetics. That proposition is supported by comparison of genome-wide association studies (GWASs) in human and canine cancer. One of the advantages of dog cancer GWASs is the ability to rapidly map complex traits, conduct fine mapping and identification of causative variation, and thus be in a position to move on to functional studies. We mention how these strengths of dog models will lead to rapid advances in translational medicine.

[Use of pulse oximetry as screening method for peripheral arterial disease in patients admitted to a general medicine service]. / Utilidad de la pulsioximetría en el cribado de enfermedad arterial periférica en pacientes ingresados en servicios de medicina interna.

INTRODUCTION: Ankle-brachial index measured by a continuous wave Doppler device remains as the reference method for office diagnosis of peripheral arterial disease. This method is time consuming, requires an appropriate device and training of the examiner. We evaluated the usefulness of pulse oximetry as an easier method to screen for peripheral arterial disease. METHODS: A total of 110 subjects were selected by opportunistic sampling among patients admitted to a general medicine service. Entry criteria were age older than 50 years and having an additional cardiovascular risk factor. Patients with known cardiovascular disease were excluded. We measured oxygen saturation (SaO2) by means of a pocket finger tip pulse oximeter at 4 limbs. SaO2 was measured at right and left index fingers and great toes with patient lying and after elevating the foot 30 cm above the bed. We considered as abnormal a difference in SaO2 greater than 2% between fingers and toes. Brachial index was estimated by means of a handheld Doppler device. RESULTS: The prevalence of peripheral arterial disease was 10% (95% confidence interval [CI], 6%-14%). Pulse oximetry has sensitivity 12% (95%CI, 4%-37%), specificity 67% (95%CI, 60%-74%), positive likelihood ratio 0.43 (95%CI, 0.11-1.19), negative likelihood ratio 1.27 (95%CI, 0.91-1.45) and area under the receiving operating characteristics curve 0.75 (95%CI, 0.67-0.82). CONCLUSIONS: Pulse oximetry showed low accuracy as screening method for peripheral arterial disease. Simpler and more accurate devices than ankle-brachial index measured by Doppler are necessary to ease the screening of peripheral arterial disease.

Mammalian α arrestins link activated seven transmembrane receptors to Nedd4 family e3 ubiquitin ligases and interact with ß arrestins.

The complement of fungal cell surface proteins is widely regulated by ubiquitination of membrane proteins, which results in their endocytosis and vacuolar degradation. For diverse fungal transporters, the specificity of ubiquitination is conferred by alpha arrestin adaptors, which recruit the Nedd4 family E3 ubiquitin ligase Rsp5. A recent study showed that one mammalian alpha arrestin also mediates ubiquitination and lysosomal trafficking of an activated plasma membrane receptor. Here we first screen all five widely-expressed human alpha arrestins for subcellular localization in ligand-stimulated and -unstimulated cells overexpressing the seven transmembrane receptor vasopressin 2. We then characterize the effects of alpha arrestins ARRDC3 and ARRDC4 upon activation of the seven transmembrane receptors vasopressin 2 and beta adrenergic 2. Using biochemical and imaging approaches, we show that ligand-activated receptors interact with alpha arrestins, and this results in recruitment of Nedd4 family E3 ubiquitin ligases and receptor ubiquitination - which are known to result in lysosomal trafficking. Our time course studies show these effects occur in the first 1-5 minutes after ligand activation, the same time that beta arrestins are known to have roles in receptor endocytic trafficking and kinase signaling. We tested the possibility that alpha and beta arrestins function coordinately and found co-immunoprecipitation and colocalization evidence to support this. Others recently reported that Arrdc3 knockout mice are lean and resistant to obesity. In the course of breeding our own Arrdc3-deficient mice, we observed two novel phenotypes in homozygotes: skin abnormalities, and embryonic lethality on normal chow diet, but not on high fat diet. Our findings suggest that alpha and beta arrestins function coordinately to maintain the optimal complement and function of cell surface proteins according to cellular physiological context and external signals. We discuss the implications of the alpha arrestin functions in fungi having evolved into coordinated alpha/beta arrestin functions in animals.