RESUMEN
Introduction: Current high demand for effective odor detection dogs calls for the development of reliable methods for measuring performance-related behavioral phenotypes in these highly specialized working animals. The Canine Behavioral Assessment & Research Questionnaire (C-BARQ) is a widely used behavioral assessment tool among working dog organizations with a demonstrated ability to predict success/failure of dogs in training. However, this instrument was developed originally to study the prevalence of behavior problems in the pet dog population, and it therefore lacks the capacity to measure specific behavioral propensities that may also be important predictors of working dog success. The current paper examines the factor structure, internal reliability, and content validity of a modified version of the C-BARQ designed to evaluate four new domains of canine behavior in addition to those encompassed by the original C-BARQ. These domains, labeled Playfulness, Impulsivity, Distractibility, and Basophobia (fear of falling), respectively, describe aspects of canine behavior or temperament which are believed to contribute substantially to working dog performance. Methods: Exploratory factor analysis (EFA) of owner/handler questionnaire responses based on a sample of 1,117 working odor detection dogs. Results: A total of 15 factors were extracted by EFA, 10 of which correspond to original C-BARQ factors. The remaining 5 comprise the four new domains- Playfulness, Impulsivity, Distractibility, and Basophobia- as well as a fifth new factor labeled Food focus. Discussion: The resulting Working Dog Canine Behavioral Assessment & Research Questionnaire (WDC-BARQ) successfully expands the measurement capacities of the original C-BARQ to include dimensions of behavior/temperament of particular relevance to many working dog populations.
RESUMEN
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.
Asunto(s)
Aprendizaje Automático , Olfato , Perros , Animales , Aprendizaje Automático Supervisado , Algoritmos , Procesos MentalesRESUMEN
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.
Asunto(s)
Cruzamiento , Estudio de Asociación del Genoma Completo , Animales , Perros , Genoma , Genotipo , Humanos , Mamíferos , LinajeRESUMEN
PURPOSE: Anhydramnios secondary to anuria before 22 weeks of gestational age and congenital bilateral renal agenesis before 26 weeks of gestational age are collectively referred to as early-pregnancy renal anhydramnios. Early-pregnancy renal anhydramnios occurs in at least 1 in 2000 pregnancies and is considered universally fatal when left untreated because of severe pulmonary hypoplasia precluding ex utero survival The Renal Anhydramnios Fetal Therapy (RAFT) trial is a nonrandomized, nonblinded, multicenter clinical trial designed to assess the efficacy, safety, and feasibility of amnioinfusions for patients with pregnancies complicated by early-pregnancy renal anhydramnios. The primary objective of this study is to determine the proportion of neonates surviving to successful dialysis, defined as use of a dialysis catheter for ≥14 days. METHODS: A consortium of 9 North American Fetal Therapy Network (NAFTNet) centers was formed, and the RAFT protocol was refined in collaboration with the NAFTNet Scientific Committee. Enrollment in the trial began in April 2020. Participants may elect to receive amnioinfusions or to join the nonintervention observational expectant management group. Eligible pregnant women must be at least 18 years of age with a fetal diagnosis of isolated early-pregnancy renal anhydramnios. FINDINGS: In addition to the primary study objective stated above, secondary objectives include (1) to assess maternal safety and feasibility of the serial amnioinfusion intervention (2) to perform an exploratory study of the natural history of untreated early pregnancy renal anhydramnios (3) to examine correlations between prenatal imaging and lung specific factors in amniotic fluid as predictive of the efficacy of serial percutaneous amnioinfusions and (4) to determine short- and long-term outcomes and quality of life in surviving neonates and families enrolled in RAFT IMPLICATIONS: The RAFT trial is the first clinical trial to investigate the efficacy, safety, and feasibility of amnioinfusions to treat the survival-limiting pulmonary hypoplasia associated with anhydramnios. Although the intervention offers an opportunity to treat a condition known to be almost universally fatal in affected neonates, the potential burdens associated with end-stage kidney disease from birth must be acknowledged. CLINICALTRIALS: gov identifier: NCT03101891.
Asunto(s)
Terapias Fetales , Oligohidramnios , Líquido Amniótico , Femenino , Edad Gestacional , Humanos , Recién Nacido , Estudios Multicéntricos como Asunto , Oligohidramnios/terapia , Embarazo , Calidad de VidaRESUMEN
Conferences are spaces to meet and network within and across academic and technical fields, learn about new advances, and share our work. They can help define career paths and create long-lasting collaborations and opportunities. However, these opportunities are not equal for all. This article introduces 10 simple rules to host an inclusive conference based on the authors' recent experience organizing the 2021 edition of the useR! statistical computing conference, which attracted a broad range of participants from academia, industry, government, and the nonprofit sector. Coming from different backgrounds, career stages, and even continents, we embraced the challenge of organizing a high-quality virtual conference in the context of the Coronavirus Disease 2019 (COVID-19) pandemic and making it a kind, inclusive, and accessible experience for as many people as possible. The rules result from our lessons learned before, during, and after the organization of the conference. They have been written mainly for potential organizers and selection committees of conferences and contain multiple practical tips to help a variety of events become more accessible and inclusive. We see this as a starting point for conversations and efforts towards building more inclusive conferences across the world. * Translated versions of the English abstract and the list of rules are available in 10 languages in S1 Text: Arabic, French, German, Italian, Japanese, Korean, Portuguese, Spanish, Tamil, and Thai.
Asunto(s)
COVID-19 , COVID-19/epidemiología , Humanos , India , Italia , Pandemias , EscrituraRESUMEN
Congenital abnormalities of the kidney and urinary tract (CAKUT) represent 20% of prenatally diagnosed congenital abnormalities. Although the majority of these abnormalities do not require intervention either pre or postnatally, there is a subset of patients whose disease is so severe that it may warrant intervention prior to delivery to prevent morbidity and mortality. These cases consist of patients with moderate lower urinary tract obstruction (LUTO) in which vesicocentesis, shunting or cystoscopy are options and patients with early pregnancy renal anhydramnios (EPRA) in whom amnioinfusion therapy may be an option. The main causes of EPRA are congenital bilateral renal agenesis (CoBRA), cystic kidney disease (CKD) and severe LUTO. Untreated, EPRA is universally fatal secondary to anhydramnios induced pulmonary hypoplasia. The evidence regarding therapy for LUTO is limited and the stopped early PLUTO (Percutaneous Shunting in Lower Urinary Tract Obstruction) trial was unable to provide definitive answers about patient selection. Evidence for EPRA therapy is also scant. Serial amnioinfusions have shown promise in cases of EPRA due to CoBRA or renal failure and this treatment modality forms the basis of the ongoing NIH funded RAFT (Renal Anhydramnios Fetal Therapy) trial. At present, there is consensus that treatment for EPRA should only occur in the setting of a clinical trial.
RESUMEN
OBJECTIVE: To compare the cause of death (COD; whether by natural death or euthanasia for poor quality of life caused by a primary pathological condition) between search-and-rescue (SAR) dogs deployed to the World Trade Center, Pentagon, or Fresh Kills Landfill on Staten Island following the 9/11 terrorist attacks and SAR dogs that were not deployed to these sites. ANIMALS: 95 deployed SAR dogs (exposed dogs) and 55 nondeployed SAR dogs (unexposed dogs). PROCEDURES: Following natural death or euthanasia, 63 dogs (44 exposed and 19 unexposed) underwent a necropsy examination. For the remaining 87 dogs, the COD was categorized on the basis of information obtained from medical records or personal communications. RESULTS: The median age of death was 12.8 years for exposed dogs and 12.7 years for unexposed dogs. The COD was not impacted by deployment status. In the 150 exposed and unexposed dogs, degenerative conditions were the most common COD followed by neoplasia. Respiratory disease was infrequent (overall, 7 [4.7%] dogs); 4 of 5 cases of pulmonary neoplasia occurred in unexposed dogs. However, in dogs that underwent necropsy, pulmonary particulates were reported significantly more often in exposed dogs (42/44 [95%]), compared with unexposed dogs (12/19 [63.2%]). CONCLUSIONS AND CLINICAL RELEVANCE: No difference was found in the COD on the basis of disease category and organ system involved between exposed and unexposed SAR dogs. The long life spans and frequency of death attributed to degenerative causes (ie, age-related causes) suggested that the risk of long-term adverse health effects in this population of SAR dogs was low.
Asunto(s)
Enfermedades de los Perros , Enfermedades Respiratorias , Terrorismo , Perros de Trabajo , Animales , Enfermedades de los Perros/epidemiología , Perros , Polvo , Eutanasia Animal , Calidad de Vida , Enfermedades Respiratorias/veterinariaRESUMEN
The objective of this study was to evaluate 4 pre-exercise hydration strategies (oral water, chicken-flavored water, chicken-flavored oral electrolyte solution, and subcutaneous electrolyte solution) in working dogs conducting rigorous tracking operations in hot and arid conditions. In a randomized cross-over field study, 7 Border Patrol Search, Trauma, and Rescue (BORSTAR) Unit dogs working/training out of Fort Bliss in El Paso, Texas were randomly assigned to one of 4 different hydration strategy treatments each day for 4 days of study participation. Dogs were provided hydration treatment prior to running 2 separate one-mile tracks and were offered water while tracking. Body weight, blood, and urine were collected at the beginning of the study day and at the completion of each track. Core body temperatures were recorded using internal temperature sensing capsules. The impact of hydration strategy on change in weight, peak temperature, and serum chemical, hematological, and urinary parameters were analyzed using the COIN procedure in Ra. Compared to the other 3 hydration strategies, dogs receiving chicken-flavored water had higher blood creatine kinase values at the end of the second track (p = 0.0361). Otherwise, hydration strategy had minimal effects on blood or urine parameters. Total fluid intake was lower with water only compared to the other three hydration strategies. Dogs developed elevated core body temperatures (median 41°C; 106°F) without signs of heat exhaustion or heat stroke. Alternate hydration strategies increased total fluid intake compared to water alone; however, chicken-flavored water resulted in increased markers of muscle injury suggesting electrolyte-enriched strategies may have an advantage as a hydration strategy. Additionally, electrolyte-enriched fluids before exercise may help these dogs maintain lower peak temperatures.
RESUMEN
BACKGROUND & AIMS: In short-bowel syndrome (SBS), inadequate intestinal adaptation is responsible for the majority of complications, including sepsis, liver failure, and death. In this study, we sought to further delineate the adaptive response to identify potential therapeutic targets. METHODS: We performed a 75% small-bowel resection (SBR) or sham operation on C57Bl/6J wild-type (WT), lipocalin-2 (LCN2)-/-, and interleukin 22 (IL22)-/- mice. Exogenous IL22 was administered to SBR WT mice. Cecal fecal matter from SBR WT and SBR LCN2-/- mice were transplanted into germ-free mice. Intestinal permeability, inflammation, proliferation, and the microbiome were evaluated 1 week after surgery. CD4+IL22+ laminal propria lymphocytes were sorted by flow cytometry. Naïve T cells were polarized to T-helper cells with or without LCN2. RESULTS: A 75% SBR in a mouse re-creates the increased intestinal permeability, enterocyte proliferation, and intestinal dysbiosis seen in SBS. LCN2 expression increases after 75% SBR, and this increase can be abrogated with broad-spectrum antibiotic treatment. LCN2-/- mice have less intestinal inflammation, increased IL22 expression, and greater adaptation as evidenced by less intestinal permeability, increased carbohydrate enzyme expression, less weight loss, and less dysbiosis after 75% SBR than WT mice. The proinflammatory and anti-adaptive effects of LCN2 can be transferred to germ-free mice via a fecal transplant. Administration of exogenous IL22 improves adaptation and restores the normal microbiome after 75% SBR in WT mice. CONCLUSIONS: LCN2 promotes inflammation and slows intestinal adaptation through changes in the microbiome and IL22 inhibition in a mouse SBS model. Strategies to reduce LCN2 may offer novel therapeutic approaches to enhance adaptation in SBS.
Asunto(s)
Adaptación Fisiológica/inmunología , Interleucinas/metabolismo , Lipocalina 2/metabolismo , Síndrome del Intestino Corto/fisiopatología , Animales , Modelos Animales de Enfermedad , Regulación hacia Abajo/inmunología , Humanos , Interleucinas/genética , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Intestino Delgado/inmunología , Intestino Delgado/patología , Lipocalina 2/genética , Masculino , Ratones , Ratones Noqueados , Permeabilidad , Síndrome del Intestino Corto/inmunología , Síndrome del Intestino Corto/patología , Interleucina-22RESUMEN
Anhydramnios caused by early anuria is thought to be universally fatal due to pulmonary hypoplasia. Bilateral renal agenesis and early fetal renal failure leading to anhydramnios constitute early pregnancy renal anhydramnios (EPRA). There have been successful reports of amnioinfusions to promote lung growth in the setting of EPRA. Some of these successfully treated EPRA fetuses have survived the neonatal period, undergone successful dialysis, and subsequently received a kidney transplant. Conversely, there are no reports of untreated EPRA survivors. This early success of amnioinfusions to treat EPRA justifies a rigorous prospective trial. The objective of this study is to provide a review of what is known about fetal therapy for EPRA and describe the Renal Anhydramnios Fetal Therapy trial. We review the epidemiology, pathophysiology, and genetics of EPRA. Furthermore, we have performed systematic review of case reports of treated EPRA. We describe the ethical framework, logistical challenges, and rationale for the current single center (NCT03101891) and planned multicenter trial.
Asunto(s)
Anuria/complicaciones , Terapias Fetales/métodos , Enfermedades Renales/terapia , Riñón/anomalías , Anuria/epidemiología , Anuria/terapia , Femenino , Enfermedades Fetales/terapia , Terapias Fetales/ética , Humanos , Riñón/embriología , Enfermedades Renales/epidemiología , Enfermedades Renales/genética , Pulmón/embriología , EmbarazoRESUMEN
Next-generation sequencing (NGS) and expression technologies were utilized to investigate the genes and sequence elements in a 586 kb region of chicken chromosome 1 associated with the autosomal recessive diplopodia-1 (dp-1) mutation. This mutation shows a syndromic phenotype similar to known human developmental abnormalities (e.g., cleft palate, polydactyly, omphalocele [exposed viscera]). Toward our goal to ascertain the variant responsible, the entire 586 kb region was sequenced following utilization of a specifically designed capture array and to confirm/validate fine-mapping results. Bioinformatic analyses identified a total of 6142 sequence variants, which included SNPs, indels, and gaps. Of these, 778 SNPs, 146 micro-indels, and 581 gaps were unique to the UCD-Dp-1.003 inbred congenic line; those found within exons and splice sites were studied for contribution to the mutant phenotype. Upon further validation with additional mutant samples, a smaller subset (of variants [51]) remains linked to the mutation. Additionally, utilization of specific samples in the NGS technology was advantageous in that fine-mapping methodologies eliminated an additional 326 kb of sequence information on chromosome 1. Predicted and confirmed protein-coding genes within the smaller 260 kb region were assessed for their developmental expression patterns over several stages of early embryogenesis in regions/tissues of interest (e.g., digits, craniofacial region). Based on these results and known function in other vertebrates, 2 genes within 5 kb of each other, MRE11 and GPR83, are proposed as high-priority candidates for the dp-1 mutation.
Asunto(s)
Pollos/genética , Anomalías Craneofaciales/genética , Deformidades Congénitas de las Extremidades/genética , Proteína Homóloga de MRE11/genética , Receptores Acoplados a Proteínas G/genética , Animales , Mapeo Cromosómico , Anomalías Craneofaciales/diagnóstico , Análisis Mutacional de ADN , Secuenciación de Nucleótidos de Alto Rendimiento , Deformidades Congénitas de las Extremidades/diagnóstico , Mutación , SíndromeRESUMEN
Currently, demand for US-bred and born detector dogs exceeds available supply, while reliance on foreign-bred sources introduces many unnecessary and unwanted risks. With proper management of a domestic supply line, U.S. breeders can improve both health and behavior by applying scientific principles to breeding and raising of detector dogs. A cooperative national detector dog breeding and development program will mitigate the current shortage of domestic-bred dogs that meet the health and behavior standards required by government, military, and law enforcement agencies. To coordinate such a cooperative, we propose a Detector Dog Center of Excellence (DDCoE) led by representatives of academic canine science programs guided by an advisory board of stakeholders. As a non-governmental organization, the DDCoE will oversee selective breeding of dogs owned by breeders, purchase the resulting puppies, and its members will supervise puppy raising until dogs are of a suitable age to be purchased by government agencies or other working dog organizations. The DDCoE will serve as an approved vendor to facilitate the procurement process. Breeding decisions will be based on proven quantitative genetic methods implemented by a specialized database. A national working dog semen bank will ensure conservation of diverse genetic material and enhance selection response by providing numerous potential sires. As a data collection and genetic evaluation center, the DDCoE will lead research to define quantitative traits involved in odor detection, to understand how these traits develop, and methods to optimize training of dogs endowed with enhanced odor detection ability.
RESUMEN
Behavioral traits such as trainability, fearlessness, and energy are required for dogs to succeed as search-and-rescue (SAR) dogs. Certification by the Federal Emergency Management Agency (FEMA) ensures that dogs and handlers have extensive training and have demonstrated specific skills in the field. To determine whether behavioral differences exist between SAR and pet dogs, and between FEMA-certified USAR and non-FEMA-certified SAR dogs, the Canine Behavioral Assessment and Research Questionnaire (C-BARQ) was administered to 129 SAR dogs participating in the post-9/11 medical surveillance study and a breed-matched sample of 2,131 pet dogs. Non-parametric mixed models were fit for each C-BARQ subscale with explanatory variables SAR/non-SAR status, FEMA certification status, breed, sex, neuter status, and age. SAR dogs had higher scores for trainability (P < 0.001) and energy (P < 0.001), and lower scores for aggression toward strangers (P < 0.01), aggression and fear toward dogs (P < 0.01), fear of dogs (P < 0.001), chasing (P < 0.001), fear of strangers (P < 0.001), and non-social fear (P < 0.001) than pet dogs. FEMA-certification was associated with lower fear of dogs (P < 0.05) and separation-related issues (P < 0.01) than non-FEMA certified SAR dogs. The traits identified in this study could provide guidance for more efficient selection of candidate SAR dogs and breeding stock.
RESUMEN
PURPOSE: We sought to determine optimal timing for CPAM resection within the first year of life. METHODS: We queried the National Surgical Quality Improvement Program pediatric database from 2012 to 2015 for elective CPAM resections on patients less than 1year of age. Patients were divided by age in months: 1-3 (n=57), 4-6 (n=135), and 6-12 (n=214). Patient operative variables and 30-day postoperative outcomes were compared. RESULTS: A total of 406 patients were included with no differences in demographics or comorbidities. Median operative time increased with each older age category (115min, 152min, 163min, respectively; p<0.01). Thoracoscopic approach was less utilized in 1-3months (40.4%) compared to the older two age categories (65.9% and 69.6%, respectively; p<0.01). There were no differences by age in major complications, conversion to open, or readmissions. On multivariate analysis, ASA class≥3 (p<0.01) and prolonged operative time (p<0.01) were associated with a major complication. Furthermore, operations on patients aged 6-12months were associated with increased operative time (p<0.01) regardless of operative approach. CONCLUSION: Elective CPAM resections are equally safe in patients 1-12months of age. Earlier resection including both open and thoracoscopic resection is associated with decreased operative time. LEVEL OF EVIDENCE: IIc, Outcomes Research.
Asunto(s)
Procedimientos Quirúrgicos Electivos/métodos , Enfermedades Pulmonares/cirugía , Neumonectomía/métodos , Anomalías del Sistema Respiratorio/cirugía , Enfermedades Asintomáticas , Femenino , Humanos , Lactante , Pulmón/anomalías , Pulmón/cirugía , Enfermedades Pulmonares/congénito , Masculino , Análisis Multivariante , Tempo Operativo , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Toracoscopía , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Elevated levels of low-density lipoprotein cholesterol (LDL-C) are a major risk factor for cardiovascular disease via its contribution to the development and progression of atherosclerotic lesions. Although the genetic basis of LDL-C has been studied extensively, currently known genetic variants account for only ≈20% of the variation in LDL-C levels. METHODS: Through an array-based association analysis in 1102 Amish subjects, we identified a variant strongly associated with LDL-C levels. Using a combination of genetic analyses, zebrafish models, and in vitro experiments, we sought to identify the causal gene driving this association. RESULTS: We identified a founder haplotype associated with a 15 mg/dL increase in LDL-C on chromosome 5. After recombination mapping, the associated region contained 8 candidate genes. Using a zebrafish model to evaluate the relevance of these genes to cholesterol metabolism, we found that expression of the transcribed pseudogene, APOOP1, increased LDL-C and vascular plaque formation. CONCLUSIONS: Based on these data, we propose that APOOP1 regulates levels of LDL-C in humans, thus identifying a novel mechanism of lipid homeostasis.
Asunto(s)
Amish/genética , Aterosclerosis/genética , LDL-Colesterol/sangre , Cromosomas Humanos Par 5 , Dislipidemias/genética , Seudogenes , Animales , Animales Modificados Genéticamente , Aterosclerosis/sangre , Aterosclerosis/diagnóstico , Aterosclerosis/etnología , Dislipidemias/sangre , Dislipidemias/diagnóstico , Dislipidemias/etnología , Efecto Fundador , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Fenotipo , Recombinación Genética , Factores de Riesgo , Pez Cebra/genéticaRESUMEN
Physical activity in hot environments can increase the risk of heat stress or heat stroke in dogs. Heat tolerance is influenced by acclimatization to the environment, physical fitness, and hydration state. Three common strategies to promote hydration in working dogs are free access to water (W), oral electrolyte solutions (OESs), and administration of subcutaneous fluids (SQs). None of these methods have been compared for safety or efficacy in a working environment. In a cross-over design, seven vehicle-screening canines were randomly assigned to each of the three hydration strategies during working shifts at the Sarita, TX checkpoint. Physical, behavioral, and biochemical parameters were collected before, during, and after a work shift (mean 5.7 ± 0.8 h). Dogs were given 10 mL/kg oral W, 10 mL/kg chicken flavored OES, or 15 mL/kg of SQs initially followed by controlled access to W or OES. The dogs drank 15.61 ± 4.47 mL/kg/h of W and OES when in the OES group, compared to 7.04 ± 3.42 and 5.56 ± 4.40 mL of W, for the W and SQ groups, respectively. The median environmental temperature was 84.8°F (29.3°C). The median humidity was 70%. Based on mixed effects linear modeling, dogs in the OES and SQ groups had significantly higher total CO2, and lower packed cell volume and total plasma protein at the end of the day. Creatinine increased a small but significant amount in the SQ group and decreased in the OES group. Searching behaviors were independent of hydration strategy but highly related to the dog specific factors of sex, breed, and activity level. Under conditions of controlled activity in moderate heat and humidity, dogs accustomed to the work and the environment were more likely to increase fluid consumption and hydration when provided a flavored OES. Potential benefits of OES and SQ were indirect and no adverse effects were documented for any of the hydration strategies tested.
RESUMEN
Skeletal dysplasias represent a large and diverse group of rare conditions affecting collagen and bone. They can be clinically classified based on radiographic and physical features, and many can be further defined at a molecular level (Bonafe et al., 2015). Early diagnosis is critical to proper medical management including pharmacologic treatment when available. Patients with severe skeletal dysplasias often have small chests with respiratory insufficiency or airway obstruction and require immediate intubation after birth. Thereafter a variety of orthopedic, neurosurgical, pulmonary, otolaryngology interventions may be needed. In terms of definitive treatment for skeletal dysplasias, there are few pharmacotherapeutic options available for the majority of these conditions. We sought to describe therapies that are currently available or under investigation for skeletal dysplasias.
RESUMEN
The transmembrane 6 superfamily member 2 (TM6SF2) loss-of-function variant rs58542926 is a genetic risk factor for nonalcoholic fatty liver disease and progression to fibrosis but is paradoxically associated with lower levels of hepatically derived triglyceride-rich lipoproteins. TM6SF2 is expressed predominantly in liver and small intestine, sites for triglyceride-rich lipoprotein biogenesis and export. In light of this, we hypothesized that TM6SF2 may exhibit analogous effects on both liver and intestine lipid homeostasis. To test this, we genotyped rs58542926 in 983 bariatric surgery patients from the Geisinger Medical Center for Nutrition and Weight Management, Geisinger Health System, in Pennsylvania and from 3,556 study participants enrolled in the Amish Complex Disease Research Program. Although these two cohorts have different metabolic profiles, carriers in both cohorts had improved fasting lipid profiles. Importantly, following a high-fat challenge, carriers in the Amish Complex Disease Research Program cohort exhibited significantly lower postprandial serum triglycerides, suggestive of a role for TM6SF2 in the small intestine. To gain further insight into this putative role, effects of TM6SF2 deficiency were studied in a zebrafish model and in cultured human Caco-2 enterocytes. In both systems TM6SF2 deficiency resulted in defects in small intestine metabolism in response to dietary lipids, including significantly increased lipid accumulation, decreased lipid clearance, and increased endoplasmic reticulum stress. CONCLUSIONS: These data strongly support a role of TM6SF2 in the regulation of postprandial lipemia, potentially through a similar function for TM6SF2 in the lipidation and/or export of both hepatically and intestinally derived triglyceride-rich lipoproteins. (Hepatology 2017;65:1526-1542).
Asunto(s)
Estrés del Retículo Endoplásmico , Intestino Delgado/metabolismo , Metabolismo de los Lípidos/genética , Hígado/metabolismo , Proteínas de la Membrana/genética , Animales , Secuencia de Bases , Células CACO-2 , Enterocitos/metabolismo , Hígado Graso/genética , Femenino , Hepatocitos/metabolismo , Homeostasis , Humanos , Intestino Delgado/ultraestructura , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Persona de Mediana Edad , Datos de Secuencia Molecular , Polimorfismo de Nucleótido Simple , Periodo Posprandial , Triglicéridos/biosíntesis , Triglicéridos/sangre , Tunicamicina , Pez CebraRESUMEN
Type 2 diabetes (T2D) has been associated with a large number of genomic loci, many of which encompass multiple genes without a definitive causal gene. This complexity has hindered efforts to clearly identify functional candidate genes and interpret their role in mediating susceptibility to disease. Here we examined the relevance of individual genes found at T2D-associated loci by assessing their potential contribution to a phenotype relevant to the disease state: production and maintenance of ß-cell mass. Using transgenic zebrafish in which ß-cell mass could be rapidly visualized in vivo, we systematically suppressed the expression of orthologs of genes found at T2D-associated genomic loci. Overall, we tested 67 orthologs, many of which had no known relevance to ß-cell mass, at 62 human T2D-associated loci, including eight loci with multiple candidate genes. In total we identified 25 genes that were necessary for proper ß-cell mass, providing functional evidence for their role in a physiological phenotype directly related to T2D. Of these, 16 had not previously been implicated in the regulation of ß-cell mass. Strikingly, we identified single functional candidate genes at the majority of the loci for which multiple genes were analyzed. Further investigation into the contribution of the 25 genes to the adaptive capacity of ß-cells suggested that the majority of genes were not required for glucose-induced expansion of ß-cell mass but were significantly necessary for the regeneration of ß-cells. These findings suggest that genetically programmed deficiencies in ß-cell mass may be related to impaired maintenance. Finally, we investigated the relevance of our findings to human T2D onset in diabetic individuals from the Old Order Amish and found that risk alleles in ß-cell mass genes were associated with significantly younger age of onset and lower body mass index. Taken together, our study offers a functional approach to assign relevance to genes at T2D-associated loci and offers experimental evidence for the defining role of ß-cell mass maintenance in genetic susceptibility to T2D onset.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Células Secretoras de Insulina/fisiología , Adulto , Amish/genética , Animales , Tamaño de la Célula , Mapeo Cromosómico , Estudios de Asociación Genética , Sitios Genéticos , Predisposición Genética a la Enfermedad , Glucosa/metabolismo , Homeostasis , Humanos , Redes y Vías Metabólicas , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Pez CebraRESUMEN
Rare genetic syndromes characterized by early-onset type 2 diabetes have revealed the importance of pancreatic ß-cells in genetic susceptibility to diabetes. However, the role of genetic regulation of ß-cells in disorders that are also characterized by highly penetrant obesity, a major additional risk factor, is unclear. In this study, we investigated the contribution of genes associated with two obesity ciliopathies, Bardet-Biedl Syndrome and Alstrom Syndrome, to the production and maintenance of pancreatic ß-cells. Using zebrafish models of these syndromes, we identified opposing effects on production of ß-cells. Loss of the Alstrom gene, alms1, resulted in a significant decrease in ß-cell production whereas loss of BBS genes, bbs1 or bbs4, resulted in a significant increase. Examination of the regulatory program underlying ß-cell production suggested that these effects were specific to ß-cells. In addition to the initial production of ß-cells, we observed significant differences in their continued maintenance. Under prolonged exposure to high glucose conditions, alms1-deficient ß-cells were unable to continually expand as a result of decreased proliferation and increased cell death. Although bbs1-deficient ß-cells were similarly susceptible to apoptosis, the overall maintenance of ß-cell number in those animals was sustained likely due to increased proliferation. Taken together, these findings implicate discrepant production and maintenance of ß-cells in the differential susceptibility to diabetes found between these two genetic syndromes.