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1.  Breed-specific incidence rates of canine primary bone tumors — A population based survey of dogs in Norway 
This is one of few published population-based studies describing breed specific rates of canine primary bone tumors. Incidence rates related to dog breeds could help clarify the impact of etiological factors such as birth weight, growth rate, and adult body weight/height on development of these tumors. The study population consisted of dogs within 4 large/giant breeds; Irish wolfhound (IW), Leonberger (LB), Newfoundland (NF), and Labrador retriever (LR), born between January 1st 1989 and December 31st 1998. Questionnaires distributed to owners of randomly selected dogs — fulfilling the criteria of breed, year of birth, and registration in the Norwegian Kennel Club — constituted the basis for this retrospective, population-based survey. Of the 3748 questionnaires received by owners, 1915 were completed, giving a response rate of 51%. Forty-three dogs had been diagnosed with primary bone tumors, based upon clinical examination and x-rays. The breeds IW and LB, with 126 and 72 cases per 10 000 dog years at risk (DYAR), respectively, had significantly higher incidence rates of primary bone tumors than NF and LR (P < 0.0001). Incidence rates for the latter were 11 and 2 cases per 10 000 DYAR, respectively. Pursuing a search for risk factors other than body size/weight is supported by the significantly different risks of developing primary bone tumors between similarly statured dogs, like NF and LB, observed in this study. Defining these breed-specific incidence rates enables subsequent case control studies, ultimately aiming to identify specific etiological factors for developing primary bone tumors.
PMCID: PMC3122972  PMID: 22210997
2.  A Simple Genetic Architecture Underlies Morphological Variation in Dogs 
PLoS Biology  2010;8(8):e1000451.
The largest genetic study to date of morphology in domestic dogs identifies genes controlling nearly 100 morphological traits and identifies important trends in phenotypic variation within this species.
Domestic dogs exhibit tremendous phenotypic diversity, including a greater variation in body size than any other terrestrial mammal. Here, we generate a high density map of canine genetic variation by genotyping 915 dogs from 80 domestic dog breeds, 83 wild canids, and 10 outbred African shelter dogs across 60,968 single-nucleotide polymorphisms (SNPs). Coupling this genomic resource with external measurements from breed standards and individuals as well as skeletal measurements from museum specimens, we identify 51 regions of the dog genome associated with phenotypic variation among breeds in 57 traits. The complex traits include average breed body size and external body dimensions and cranial, dental, and long bone shape and size with and without allometric scaling. In contrast to the results from association mapping of quantitative traits in humans and domesticated plants, we find that across dog breeds, a small number of quantitative trait loci (≤3) explain the majority of phenotypic variation for most of the traits we studied. In addition, many genomic regions show signatures of recent selection, with most of the highly differentiated regions being associated with breed-defining traits such as body size, coat characteristics, and ear floppiness. Our results demonstrate the efficacy of mapping multiple traits in the domestic dog using a database of genotyped individuals and highlight the important role human-directed selection has played in altering the genetic architecture of key traits in this important species.
Author Summary
Dogs offer a unique system for the study of genes controlling morphology. DNA from 915 dogs from 80 domestic breeds, as well as a set of feral dogs, was tested at over 60,000 points of variation and the dataset analyzed using novel methods to find loci regulating body size, head shape, leg length, ear position, and a host of other traits. Because each dog breed has undergone strong selection by breeders to have a particular appearance, there is a strong footprint of selection in regions of the genome that are important for controlling traits that define each breed. These analyses identified new regions of the genome, or loci, that are important in controlling body size and shape. Our results, which feature the largest number of domestic dogs studied at such a high level of genetic detail, demonstrate the power of the dog as a model for finding genes that control the body plan of mammals. Further, we show that the remarkable diversity of form in the dog, in contrast to some other species studied to date, appears to have a simple genetic basis dominated by genes of major effect.
doi:10.1371/journal.pbio.1000451
PMCID: PMC2919785  PMID: 20711490
3.  Variation in Genes Related to Cochlear Biology Is Strongly Associated with Adult-Onset Deafness in Border Collies 
PLoS Genetics  2012;8(9):e1002898.
Domestic dogs can suffer from hearing losses that can have profound impacts on working ability and quality of life. We have identified a type of adult-onset hearing loss in Border Collies that appears to have a genetic cause, with an earlier age of onset (3–5 years) than typically expected for aging dogs (8–10 years). Studying this complex trait within pure breeds of dog may greatly increase our ability to identify genomic regions associated with risk of hearing impairment in dogs and in humans. We performed a genome-wide association study (GWAS) to detect loci underlying adult-onset deafness in a sample of 20 affected and 28 control Border Collies. We identified a region on canine chromosome 6 that demonstrates extended support for association surrounding SNP Chr6.25819273 (p-value = 1.09×10−13). To further localize disease-associated variants, targeted next-generation sequencing (NGS) of one affected and two unaffected dogs was performed. Through additional validation based on targeted genotyping of additional cases (n = 23 total) and controls (n = 101 total) and an independent replication cohort of 16 cases and 265 controls, we identified variants in USP31 that were strongly associated with adult-onset deafness in Border Collies, suggesting the involvement of the NF-κB pathway. We found additional support for involvement of RBBP6, which is critical for cochlear development. These findings highlight the utility of GWAS–guided fine-mapping of genetic loci using targeted NGS to study hereditary disorders of the domestic dog that may be analogous to human disorders.
Author Summary
The domestic dog offers a unique opportunity to study complex disorders similar to those seen in humans, but within the context of the much simpler genetic backgrounds of pure breeds, which represent closed populations. We performed a whole-genome search for genetic risk factors of adult-onset deafness in the Border Collie, a breed of herding dog that relies on acute hearing to perceive and respond to commands while working. Adult-onset deafness in Border Collies typically begins in early adulthood and is similar to age-related hearing loss in humans. This earlier onset has particular impact on the utility of working Border Collies and the livelihoods of their owners, and it appears to have a genetic cause. We identified three genetic variants that were strongly associated with adult-onset deafness in a sample of 405 Border Collies. These variants are located in two genes that have previously been linked to deafness, one involved in ear development and another that appears to mitigate tissue damage in the ear. These results provide new insight regarding genetic risk factors for age-related hearing loss in both dogs and humans.
doi:10.1371/journal.pgen.1002898
PMCID: PMC3441646  PMID: 23028339
4.  Random repeated cross sectional study on breeding site characterization of Anopheles sinensis larvae in distinct villages of Yongcheng City, People's Republic of China 
Parasites & Vectors  2012;5:58.
Background
Characterizing the breeding site of Anopheles sinensis is of major importance for the transition from malaria control to elimination in China. However, little information is available especially regarding the characteristics and influencing factors of breeding sites of An. sinensis in Yongcheng City, a representative region of unstable malaria transmission in the Huang-Huai River region of central China. The aims of this study were to determine the breeding site characteristics of An. sinensis and related environmental and physicochemical parameters, to find out which breeding site characteristics could best explain the presence of An. sinensis larvae, and to determine whether the breeding habit of An. sinensis has changed or not.
Methods
Random repeated cross sectional study was undertaken in six villages of the Yongcheng city characterized by different levels of the historical incidence of P. vivax malaria. The potential breeding sites of An. sinensis larvae in each village were examined twice per month both in the household courtyards and the village surroundings. The larval sampling was done by the standard dipping method. Some important breeding site characterizations were recorded and characterized. The anopheline mosquito larvae and emerged adults were identified to the species level morphologically and to sub-species by the ribosomal DNA PCR technique. Chi-square analysis and logistic regression analysis were applied to determine the importance of factors for explaining the presence or absence of An. sinensis larvae.
Results
According to the ribosomal DNA PCR assay, all sampled anopheline mosquito larvae and emerged adults belonged to An. sinensis. Only 3 containers that were sampled from the household courtyards were found to contain An. sinensis larvae. There were no differences in the species composition of mosquito larvae among containers that contained water in the household courtyards (P > 0.05). An. sinensis larvae were shown to be present in a total of 60 breeding sites in the village surroundings, this included 8 (13.3%) river fringes, 26 (43.3%) ponds, 23 (38.3%) puddles, and 3 (5.0%) irrigation/drainage ditches. Logistic regression analysis revealed that the breeding site type, water depth, chemical oxygen demand (COD), ammonia nitrogen, and sulphate were found to be the key factors determining the presence of An. sinensis larvae. Approximately 94.9% of An. sinensis larvae inhabited relatively large and medium-sized water bodies, with depths between 0.5 m and 1.0 m (73.3%), COD lower than 2 mg/L (75%), ammonia nitrogen lower than 0.4 mg/L (86.7%), and sulphate lower than 150 mg/L (58.3%), respectively.
Conclusion
These results indicate that the majority of An. sinensis larval breeding sites were relatively large and medium-sized water bodies with depths between 0.5 m and 1.0 m, and containing low levels of COD, ammonia nitrogen, and sulphate, respectively. For effective An. sinensis larval control, the type of breeding site, water depth, COD, ammonia nitrogen, and sulphate should be given higher priority over other factors in areas where it is the primary vector.
doi:10.1186/1756-3305-5-58
PMCID: PMC3323357  PMID: 22444032
Breeding site; Characterization; Mosquito; Anopheles vectors; Ecology, Malaria elimination
5.  Cigarette smoking, body mass index associated with the risks of age-related cataract in male patients in northeast China 
AIM
To determine the association between cigarettes smoking, body mass index (BMI) and the risk of age-related cataract (ARC) in middle-aged and elderly men in Northeast China.
METHODS
A hospital-based case control study was conducted. Cases (n =362) were men who had surgically treated ARC, 45-85 years old; controls frequency-matched (n =362) were men who had been admitted to the same hospital as cases for other diseases not related with eye diseases. Cases and controls were matched with 1:1. The cases and controls were interviewed during their hospital stay, using a structured interviewer-administrated questionnaire that included information on sociodemographic characteristics, socioeconomic, lifestyle habits (tobacco smoking and alcohol consumption, etc.), anthropometric measures, personal medical history, and family history of ARC in first-degree relatives, and simultaneously BMI was calculated. The odds ratios (OR) and 95% confidence intervals (CI) of ARC were estimated using multiple logistic regression models.
RESULTS
After adjusting for age and multiple potential confounders, higher BMI was associated with an increased risk of ARC. Cigarette smoking, years smoking or moderate cigarette smoking (1-29 cigarettes per day) had no relation with the risk of ARC (P>0.05), although patients smoking ≥30 cigarettes per day had an elevated risk of ARC as compared with the non-smokers (OR=1.55, 95% CI; 1.16-2.85, P=0.026). Higher BMI was associated with an increased risk of ARC. Both overweight and obesity was associated with an obviously increased risk for surgically ARC (OR=1.55, 95% CI: 1.02-1.98, P=0.015 and OR=1.71, 95% CI: 1.32-2.39, P=0.013 respectively) compared to normal BMI. Then participants were grouped into quartiles of BMI (Q1 to Q4), compared to controls in the lowest quartile, the OR for cases in the highest quartile of BMI was 1.54 (OR=1.54, 95% CI: 1.08-2.46, P=0.022). The results of univariate analysis showed cigarette smoking was not associated with ARC formation for men with lower or normal BMI (P>0.05). Compared to the non-smokers, for men of overweight or obesity, cigarette smoking was associated with a significantly increased risk for surgically ARC (OR=2.00, 95% CI: 1.49-6.65, P=0.003 and OR=1.66, 95% CI: 1.63-13.21, P=0.002 respectively). Similarly, smokers in the highest quartile of BMI had approximately 1.5 times the risk of ARC as non-smokers in the lowest quartile (OR=1.46, 95% CI: 1.06-5.29, P<0.001). Followed multivariate models revealed that the association had never changed.
CONCLUSION
Current cigarette smoking is positively related to ARC only among those who smoking 30 or more cigarettes per day. For men who are both overweight and obesity, cigarette smoking is associated with a significantly increased risk for ARC.
doi:10.3980/j.issn.2222-3959.2012.03.13
PMCID: PMC3388400  PMID: 22773980
age-related cataract; male; smoking; body mass index; risk
6.  Determination of Morphological, Biometric and Biochemical Susceptibilities in Healthy Eurasier Dogs with Suspected Inherited Glaucoma 
PLoS ONE  2014;9(11):e111873.
In both humans and dogs, the primary risk factor for glaucoma is high intraocular pressure (IOP), which may be caused by iridocorneal angle (ICA) abnormalities. Oxidative stress has also been implicated in retinal ganglion cell damage associated with glaucoma. A suspected inherited form of glaucoma was recently identified in Eurasier dogs (EDs), a breed for which pedigrees are readily available. Because of difficulties in assessing ICA morphology in dogs with advanced glaucoma, we selected a cohort of apparently healthy dogsfor the investigation of ICA morphological status, IOP and plasma concentrations of oxidative stress biomarkers. We aimed to establish correlations between these factors, to identify predictive markers of glaucoma in this dog breed. A cohort of 28 subjects, volunteered for inclusion by their owners, was selected by veterinary surgeons. These dogs were assigned to four groups: young males, young females (1–3 years old), adult males and adult females (4–8 years old). Ocular examination included ophthalmoscopy, tonometry, gonioscopy, biometry and ultrasound biomicroscopy (UBM), and the evaluation of oxidative stress biomarkers consisting of measurements of plasma glutathione peroxidase (GP) activity and taurine and metabolic precursor (methionine and cysteine) concentrations in plasma. The prevalence of pectinate ligament abnormalities was significantly higher in adult EDs than in young dogs. Moreover, in adult females, high IOP was significantly correlated with a short axial globe length, and a particularly large distance between Schwalbe's line and the anterior lens capsule. GP activity levels were significantly lower in EDs than in a randomized control group of dogs, and plasma taurine concentrations were higher. Hence, ICA abnormalities were associated with weaker antioxidant defenses in EDs, potentially counteracted by higher plasma taurine concentrations. This study suggests that EDs may constitute an appropriate canine model for the development of glaucoma. This cohort will be used as a sentinel for longitudinal monitoring.
doi:10.1371/journal.pone.0111873
PMCID: PMC4224419  PMID: 25380252
7.  Identification of Genomic Regions Associated with Phenotypic Variation between Dog Breeds using Selection Mapping 
PLoS Genetics  2011;7(10):e1002316.
The extraordinary phenotypic diversity of dog breeds has been sculpted by a unique population history accompanied by selection for novel and desirable traits. Here we perform a comprehensive analysis using multiple test statistics to identify regions under selection in 509 dogs from 46 diverse breeds using a newly developed high-density genotyping array consisting of >170,000 evenly spaced SNPs. We first identify 44 genomic regions exhibiting extreme differentiation across multiple breeds. Genetic variation in these regions correlates with variation in several phenotypic traits that vary between breeds, and we identify novel associations with both morphological and behavioral traits. We next scan the genome for signatures of selective sweeps in single breeds, characterized by long regions of reduced heterozygosity and fixation of extended haplotypes. These scans identify hundreds of regions, including 22 blocks of homozygosity longer than one megabase in certain breeds. Candidate selection loci are strongly enriched for developmental genes. We chose one highly differentiated region, associated with body size and ear morphology, and characterized it using high-throughput sequencing to provide a list of variants that may directly affect these traits. This study provides a catalogue of genomic regions showing extreme reduction in genetic variation or population differentiation in dogs, including many linked to phenotypic variation. The many blocks of reduced haplotype diversity observed across the genome in dog breeds are the result of both selection and genetic drift, but extended blocks of homozygosity on a megabase scale appear to be best explained by selection. Further elucidation of the variants under selection will help to uncover the genetic basis of complex traits and disease.
Author Summary
There are hundreds of dog breeds that exhibit massive differences in appearance and behavior sculpted by tightly controlled selective breeding. This large-scale natural experiment has provided an ideal resource that geneticists can use to search for genetic variants that control these differences. With this goal, we developed a high-density array that surveys variable sites at more than 170,000 positions in the dog genome and used it to analyze genetic variation in 46 breeds. We identify 44 chromosomal regions that are extremely variable between breeds and are likely to control many of the traits that vary between them, including curly tails and sociality. Many other regions also bear the signature of strong artificial selection. We characterize one such region, known to associate with body size and ear type, in detail using “next-generation” sequencing technology to identify candidate mutations that may control these traits. Our results suggest that artificial selection has targeted genes involved in development and metabolism and that it may have increased the incidence of disease in dog breeds. Knowledge of these regions will be of great importance for uncovering the genetic basis of variation between dog breeds and for finding mutations that cause disease.
doi:10.1371/journal.pgen.1002316
PMCID: PMC3192833  PMID: 22022279
8.  Signatures of Diversifying Selection in European Pig Breeds 
PLoS Genetics  2013;9(4):e1003453.
Following domestication, livestock breeds have experienced intense selection pressures for the development of desirable traits. This has resulted in a large diversity of breeds that display variation in many phenotypic traits, such as coat colour, muscle composition, early maturity, growth rate, body size, reproduction, and behaviour. To better understand the relationship between genomic composition and phenotypic diversity arising from breed development, the genomes of 13 traditional and commercial European pig breeds were scanned for signatures of diversifying selection using the Porcine60K SNP chip, applying a between-population (differentiation) approach. Signatures of diversifying selection between breeds were found in genomic regions associated with traits related to breed standard criteria, such as coat colour and ear morphology. Amino acid differences in the EDNRB gene appear to be associated with one of these signatures, and variation in the KITLG gene may be associated with another. Other selection signals were found in genomic regions including QTLs and genes associated with production traits such as reproduction, growth, and fat deposition. Some selection signatures were associated with regions showing evidence of introgression from Asian breeds. When the European breeds were compared with wild boar, genomic regions with high levels of differentiation harboured genes related to bone formation, growth, and fat deposition.
Author Summary
The domestic pig, an important source of protein worldwide, was domesticated from the ancestral wild boar in multiple locations throughout the world. In Europe, local types were developed following domestication, but phenotypically distinct breeds only arose in the eighteenth century with the advent of systematic breeding. Recently developed molecular tools for pigs (as well as other livestock species) now allow a genetic characterisation of breed histories, including identification of regions of the genome that have been under selection in the establishment of breeds. We have applied these tools to identify genomic regions associated with breed development in a set of commercial and traditional pig breeds. We found strong evidence of genetic differentiation between breeds near genes associated with traits that are used to define breed standards, such as ear morphology and coat colour, as well as in regions of the genome that are associated with pork production traits. It is well documented that crosses with Asian pigs have been used to modify European breeds. We have found evidence of genetic influence from Asian pigs in European breeds, again in regions of the genome associated with breed standard characteristics, including ear shape and coat colour, as well as production traits.
doi:10.1371/journal.pgen.1003453
PMCID: PMC3636142  PMID: 23637623
9.  Why breed every other year? The case of albatrosses. 
Albatrosses exhibit extremely low reproductive rates, each pair brooding only one egg and subsequent chick at a time. Furthermore, in several of the species, the majority of successful pairs breed only once every second year (termed 'biennial' breeding). Thus, on average, these latter species have an annual fecundity of about half an offspring per year, while other albatrosses produce an egg and chick every year. Using our 40-year bank of demographic data, we compared 12 species of albatrosses according to these two breeding strategies to examine potential causes of biennial breeding. Biennial breeding could be due to physiological constraints, larger animals breeding more slowly, or ecological constraints, more distant pelagic feeding trips being energetically costly, or both. We tested these hypotheses by looking for predicted associations between the duration of the rearing period, the distance to the oceanic feeding zone and breeding frequency. We also looked for associations of these variables with other life-history traits. Body size had a strong influence on the duration of the rearing period, but not on the distance that birds travelled to the feeding zone. Both the duration of the rearing period and distance to the feeding zone appeared to have direct influences on breeding frequency, as revealed by a path analysis, and thus both hypotheses to explain biennial breeding were supported. Finally, breeding frequency exhibited a strong trade-off with adult survival and age at maturity, indicating that slower breeders live through more breeding seasons, perhaps mitigating their lower annual reproductive output.
doi:10.1098/rspb.2002.2080
PMCID: PMC1691107  PMID: 12350259
10.  Genome-Wide Analysis of the World's Sheep Breeds Reveals High Levels of Historic Mixture and Strong Recent Selection 
PLoS Biology  2012;10(2):e1001258.
Genomic structure in a global collection of domesticated sheep reveals a history of artificial selection for horn loss and traits relating to pigmentation, reproduction, and body size.
Through their domestication and subsequent selection, sheep have been adapted to thrive in a diverse range of environments. To characterise the genetic consequence of both domestication and selection, we genotyped 49,034 SNP in 2,819 animals from a diverse collection of 74 sheep breeds. We find the majority of sheep populations contain high SNP diversity and have retained an effective population size much higher than most cattle or dog breeds, suggesting domestication occurred from a broad genetic base. Extensive haplotype sharing and generally low divergence time between breeds reveal frequent genetic exchange has occurred during the development of modern breeds. A scan of the genome for selection signals revealed 31 regions containing genes for coat pigmentation, skeletal morphology, body size, growth, and reproduction. We demonstrate the strongest selection signal has occurred in response to breeding for the absence of horns. The high density map of genetic variability provides an in-depth view of the genetic history for this important livestock species.
Author Summary
During the process of domestication, mankind recruited animals from the wild into a captive environment, changing their morphology, behaviour, and genetics. In the case of sheep, domestication and subsequent selection by their animal handlers over thousands of years has produced a spectrum of breeds specialised for the production of wool, milk, and meat. We sought to use this population history to search for the genes that directly underpin phenotypic variation. We collected DNA from 2,819 sheep, belonging to 74 breeds sampled from around the world, and assessed the genotype of each animal at nearly 50,000 locations across the genome. Our results show that sheep breeds have maintained high levels of genetic diversity, in contrast to other domestic animals such as dogs. We also show that particular regions of the genome contain strong evidence for accelerated change in response to artificial selection. The most prominent example was identified in response to breeding for the absence of horns, a trait now common across many modern breeds. Furthermore, we demonstrate that other genomic regions under selection in sheep contain genes controlling pigmentation, reproduction, and body size.
doi:10.1371/journal.pbio.1001258
PMCID: PMC3274507  PMID: 22346734
11.  Intrastromal Corneal Ring Implants for Corneal Thinning Disorders 
Executive Summary
Objective
The purpose of this project was to determine the role of corneal implants in the management of corneal thinning disease conditions. An evidence-based review was conducted to determine the safety, effectiveness and durability of corneal implants for the management of corneal thinning disorders. The evolving directions of research in this area were also reviewed.
Subject of the Evidence-Based Analysis
The primary treatment objectives for corneal implants are to normalize corneal surface topography, improve contact lens tolerability, and restore visual acuity in order to delay or defer the need for corneal transplant. Implant placement is a minimally invasive procedure that is purported to be safe and effective. The procedure is also claimed to be adjustable, reversible, and both eyes can be treated at the same time. Further, implants do not limit the performance of subsequent surgical approaches or interfere with corneal transplant. The evidence for these claims is the focus of this review.
The specific research questions for the evidence review were as follows:
Safety
Corneal Surface Topographic Effects:
Effects on corneal surface remodelling
Impact of these changes on subsequent interventions, particularly corneal transplantation (penetrating keratoplasty [PKP])
Visual Acuity
Refractive Outcomes
Visual Quality (Symptoms): such as contrast vision or decreased visual symptoms (halos, fluctuating vision)
Contact lens tolerance
Functional visual rehabilitation and quality of life
Patient satisfaction:
Disease Process:
Impact on corneal thinning process
Effect on delaying or deferring the need for corneal transplantation
Clinical Need: Target Population and Condition
Corneal ectasia (thinning) comprises a range of disorders involving either primary disease conditions such as keratoconus and pellucid marginal corneal degeneration or secondary iatrogenic conditions such as corneal thinning occurring after LASIK refractive surgery. The condition occurs when the normally round dome-shaped cornea progressively thins causing a cone-like bulge or forward protrusion in response to the normal pressure of the eye. Thinning occurs primarily in the stoma layers and is believed to be a breakdown in the collagen network. This bulging can lead to an irregular shape or astigmatism of the cornea and, because the anterior part of the cornea is largely responsible for the focusing of light on the retina, results in loss of visual acuity. This can make even simple daily tasks, such as driving, watching television or reading, difficult to perform.
Keratoconus (KC) is the most common form of corneal thinning disorder and is a noninflammatory chronic disease process. Although the specific causes of the biomechanical alterations that occur in KC are unknown, there is a growing body of evidence to suggest that genetic factors may play an important role. KC is a rare condition (<0.05% of the population) and is unique among chronic eye diseases as it has an early age of onset (median age of 25 years). Disease management for this condition follows a step-wise approach depending on disease severity. Contact lenses are the primary treatment of choice when there is irregular astigmatism associated with the disease. When patients can no longer tolerate contact lenses or when lenses no longer provide adequate vision, patients are referred for corneal transplant.
Keratoconus is one of the leading indications for corneal transplants and has been so for the last three decades. Yet, despite high graft survival rates of up to 20 years, there are reasons to defer receiving transplants for as long as possible. Patients with keratoconus are generally young and life-long term graft survival would be an important consideration. The surgery itself involves lengthy time off work and there are potential complications from long term steroid use following surgery, as well as the risk of developing secondary cataracts, glaucoma etc. After transplant, recurrent KC is possible with need for subsequent intervention. Residual refractive errors and astigmatism can remain challenging after transplantation and high refractive surgery rates and re-graft rates in KC patients have been reported. Visual rehabilitation or recovery of visual acuity after transplant may be slow and/or unsatisfactory to patients.
Description of Technology/Therapy
INTACS® (Addition Technology Inc. Sunnyvale, CA, formerly KeraVision, Inc.) are the only currently licensed corneal implants in Canada. The implants are micro-thin poly methyl methacrylate crescent shaped ring segments with a circumference arc length of 150 degrees, an external diameter of 8.10 mm, an inner diameter of 6.77 mm, and a range of different thicknesses. Implants act as passive spacers and, when placed in the cornea, cause local separation of the corneal lamellae resulting in a shortening of the arc length of the anterior corneal curvature and flattening the central cornea. Increasing segment thickness results in greater lamellar separation with increased flattening of the cornea correcting for myopia by decreasing the optical power of the eye. Corneal implants also improve corneal astigmatism but the mechanism of action for this is less well understood.
Treatment with corneal implants is considered for patients who are contact lens intolerant, having adequate corneal thickness particularly around the area of the implant incision site and without central corneal scarring. Those with central corneal scarring would not benefit from implants and those without an adequate corneal thickness, particularly in the region that the implants are being inserted, would be at increased risk for corneal perforation. Patients desiring to have visual rehabilitation that does not include glasses or contact lenses would not be candidates for corneal ring implants.
Placement of the implants is an outpatient procedure with topical anesthesia generally performed by either corneal specialists or refractive surgeons. It involves creating tunnels in the corneal stroma to secure the implants either by a diamond knife or laser calibrated to an approximate depth of 70% of the cornea. Variable approaches have been employed by surgeons in selecting ring segment size, number and position. Generally, two segments of equal thickness are placed superiorly and inferiorly to manage symmetrical patterns of corneal thinning whereas one segment may be placed to manage asymmetric thinning patterns.
Following implantation, the major safety concerns are for potential adverse events including corneal perforation, infection, corneal infiltrates, corneal neovascularization, ring migration and extrusion and corneal thinning. Technical results can be unsatisfactory for several reasons. Treatment may result in an over or under-correction of refraction and may induce astigmatism or asymmetry of the cornea.
Progression of the corneal cone with corneal opacities is also invariably an indication for progression to corneal transplant. Other reasons for treatment failure or patient dissatisfaction include foreign body sensation, unsatisfactory visual quality with symptoms such as double vision, fluctuating vision, poor night vision or visual side effects related to ring edge or induced or unresolved astigmatism.
Evidence-Based Analysis Methods
The literature search strategy employed keywords and subject headings to capture the concepts of 1) intrastromal corneal rings and 2) corneal diseases, with a focus on keratoconus, astigmatism, and corneal ectasia. The initial search was run on April 17, 2008, and a final search was run on March 6, 2009 in the following databases: Ovid MEDLINE (1996 to February Week 4 2009), OVID MEDLINE In-Process and Other Non-Indexed Citations, EMBASE (1980 to 2009 Week 10), OVID Cochrane Library, and the Centre for Reviews and Dissemination/International Agency for Health Technology Assessment. Parallel search strategies were developed for the remaining databases. Search results were limited to human and English-language published between January 2000 and April 17, 2008. The resulting citations were downloaded into Reference Manager, v.11 (ISI Researchsoft, Thomson Scientific, U.S.A), and duplicates were removed. The Web sites of several other health technology agencies were also reviewed including the Canadian Agency for Drugs and Technologies in Health (CADTH), ECRI, and the United Kingdom National Institute for Clinical Excellence (NICE). The bibliographies of relevant articles were scanned.
Inclusion Criteria
English language reports and human studies
Any corneal thinning disorder
Reports with corneal implants used alone or in conjunction with other interventions
Original reports with defined study methodology
Reports including standardized measurements on outcome events such as technical success, safety, effectiveness, durability, vision quality of life or patient satisfaction
Case reports or case series for complications and adverse events
Exclusion Criteria
Non-systematic reviews, letters, comments and editorials
Reports not involving outcome events such as safety, effectiveness, durability, vision quality or patient satisfaction following an intervention with corneal implants
Reports not involving corneal thinning disorders and an intervention with corneal implants
Summary of Findings
In the MAS evidence review on intrastromal corneal ring implants, 66 reports were identified on the use of implants for management of corneal thinning disorders. Reports varied according to their primary clinical indication, type of corneal implant, and whether or not secondary procedures were used in conjunction with the implants. Implants were reported to manage post LASIK thinning and/or uncorrected refractive error and were also reported as an adjunctive intervention both during and after corneal transplant to manage recurrent thinning and/or uncorrected refractive error.
Ten pre-post cohort longitudinal follow-up studies were identified examining the safety and effectiveness of INTAC corneal implants in patients with keratoconus. Five additional cohort studies were identified using the Ferrara implant for keratoconus management but because this corneal implant is not licensed in Canada these studies were not reviewed.
The cohorts implanted with INTACS involved 608 keratoconus patients (754 eyes) followed for 1, 2 or 3 years. Three of the reports involved ≥ 2 years of follow-up with the longest having 5-year follow-up data for a small number of patients. Four of the INTAC cohort studies involved 50 or more patients; the largest involved 255 patients. Inclusion criteria for the studies were consistent and included patients who were contact lens intolerant, had adequate corneal thickness, particularly around the area of the implant incision site, and without central corneal scarring. Disease severity, thinning pattern, and corneal cone protrusions all varied and generally required different treatment approaches involving defined segment sizes and locations.
A wide range of outcome measures were reported in the cohort studies. High levels of technical success or ability to place INTAC segments were reported. Technically related complications were often delayed and generally reported as segment migration attributable to early experience. Overall, complications were infrequently reported and largely involved minor reversible events without clinical sequelae.
The outcomes reported across studies involved statistically significant and clinically relevant improvements in corneal topography, refraction and visual acuity, for both uncorrected and best-corrected visual acuity. Patients’ vision was usually restored to within normal functioning levels and for those not achieving satisfactory correction, insertion of intraocular lenses was reported in case studies to result in additional gains in visual acuity. Vision loss (infrequently reported) was usually reversed by implant exchange or removal. The primary effects of INTACS on corneal surface remodelling were consistent with secondary improvements in refractive error and visual acuity. The improvements in visual acuity and refractive error noted at 6 months were maintained at 1 and 2-year follow-up
Improvements in visual acuity and refractive error following insertion of INTACS, however, were not noted for all patients. Although improvements were not found to vary across age groups there were differences across stages of disease. Several reports suggested that improvements in visual acuity and refractive outcomes may not be as large or predictable in more advanced stages of KC. Some studies have suggested that the effects of INTACs were much greater in flattening the corneal surface than in correcting astigmatism. However, these studies involved small numbers of high risk patients in advanced stages of KC and conclusions made from this group are limited.
INTACS were used for other indications other than primary KC. The results of implant insertion on corneal topography, refraction, and visual acuity in post-LASIK thinning cases were similar to those reported for KC. The evidence for this indication, however, only involved case reports and small case series. INTACS were also successfully used to treat recurrent KC after corneal transplant but this was based on only a single case report. Corneal implants were compared to corneal transplantation but these studies were not randomized and based on small numbers of selected patients.
The foremost limitation of the evidence base is the basic study design in the reports that involved longitudinal follow-up only for the treated group; there were no randomized trials. Follow-up in the trials (although at prescribed intervals) often had incomplete accounts of losses at follow-up and estimates of change were often not reported or based on group differences. Second, although standardized outcome measures were reported, contact lens tolerance (a key treatment objective) was infrequently specified. A third general limitation was the lack of reporting of patients’ satisfaction with their vision quality or functional vision. Outcome measures for vision quality and impact on patient quality of life were available but rarely reported and have been noted to be a limitation in ophthalmological literature in general. Fourth, the longitudinal cohort studies have not followed patients long enough to evaluate the impact of implants on the underlying disease process (follow-up beyond 3 years is limited). Additionally, only a few of these studies directly examined corneal thinning in follow-up. The overall quality of evidence determined using the GRADE hierarchy of evidence was moderate.
There is some evidence in these studies to support the claim that corneal implants do not interfere with, or increase the difficultly of, subsequent corneal transplant, at least for those performed shortly after INTAC placement. Although it’s uncertain for how long implants can delay the need for a corneal transplant, given that patients with KC are often young (in their twenties and thirties), delaying transplant for any number of years may still be a valuable consideration.
Conclusion
The clinical indications for corneal implants have evolved from management of myopia in normal eyes to the management of corneal thinning disorders such as KC and thinning occurring after refractive surgery. Despite the limited evidence base for corneal implants, which consists solely of longitudinal follow-up studies, they appear to be a valuable clinical tool for improving vision in patients with corneal thinning. For patients unable to achieve functional vision, corneal implants achieved statistically significant and clinically relevant improvements in corneal topography, refraction, and visual acuity, providing a useful alternative to corneal transplant. Implants may also have a rescue function, treating corneal thinning occurring after refractive surgery in normal eyes, or managing refractive errors following corneal transplant. The treatment offers several advantages in that it’s an outpatient based procedure, is associated with minimal risk, and has high technical success rates. Both eyes can be treated at once and the treatment is adjustable and reversible. The implants can be removed or exchanged to improve vision without limiting subsequent interventions, particularly corneal transplant.
Better reporting on vision quality, functional vision and patient satisfaction, however, would improve evaluation of the impact of these devices. Information on the durability of the implants’ treatment effects and their affects on underlying disease processes is limited. This information is becoming more important as alternative treatment strategies, such as collagen cross-linking aimed at strengthening the underlying corneal tissue, are emerging and which might prove to be more effective or increase the effectiveness of the implants, particularly in advances stages of corneal thinning.
Ontario Health System Considerations
At present there are approximately 70 ophthalmologists in Canada who’ve had training with corneal implants; 30 of these practice in Ontario. Industry currently sponsors the training, proctoring and support for the procedure. The cost of the implant device ranges from $950 to $1200 (CAD) and costs for instrumentation range from $20,000 to $30,000 (CAD) (a one time capital expenditure). There is no physician services fee code for corneal implants in Ontario but assuming that they are no higher than those for a corneal transplant, the estimated surgical costs would be $914.32(CAD) An estimated average cost per patient, based on device costs and surgical fees, for treatment is $1,964 (CAD) (range $1,814 to $2,114) per eye. There have also been no out of province treatment requests. In Ontario the treatment is currently being offered in private clinics and an increasing number of ophthalmologists are being certified in the technique by the manufacturer.
KC is a rare disease and not all of these patients would be eligible candidates for treatment with corneal implants. Based on published population rates of KC occurrence, it can be expected that there is a prevalent population of approximately 6,545 patients and an incident population of 240 newly diagnosed cases per year. Given this small number of potential cases, the use of corneal implants would not be expected to have much impact on the Ontario healthcare system. The potential impact on the provincial budget for managing the incident population, assuming the most conservative scenario (i.e., all are eligible and all receive bilateral implants) ranges from $923 thousand to $1.1 million (CAD). This estimate would vary based on a variety of criteria including eligibility, unilateral or bilateral interventions, re-interventions, capacity and uptake
Keywords
Keratoconus, corneal implants, corneal topography, corneal transplant, visual acuity, refractive error
PMCID: PMC3385416  PMID: 23074513
12.  MtDNA diversity among four Portuguese autochthonous dog breeds: a fine-scale characterisation 
BMC Genetics  2005;6:37.
Background
The picture of dog mtDNA diversity, as obtained from geographically wide samplings but from a small number of individuals per region or breed, has revealed weak geographic correlation and high degree of haplotype sharing between very distant breeds. We aimed at a more detailed picture through extensive sampling (n = 143) of four Portuguese autochthonous breeds – Castro Laboreiro Dog, Serra da Estrela Mountain Dog, Portuguese Sheepdog and Azores Cattle Dog-and comparatively reanalysing published worldwide data.
Results
Fifteen haplotypes belonging to four major haplogroups were found in these breeds, of which five are newly reported. The Castro Laboreiro Dog presented a 95% frequency of a new A haplotype, while all other breeds contained a diverse pool of existing lineages. The Serra da Estrela Mountain Dog, the most heterogeneous of the four Portuguese breeds, shared haplotypes with the other mainland breeds, while Azores Cattle Dog shared no haplotypes with the other Portuguese breeds.
A review of mtDNA haplotypes in dogs across the world revealed that: (a) breeds tend to display haplotypes belonging to different haplogroups; (b) haplogroup A is present in all breeds, and even uncommon haplogroups are highly dispersed among breeds and continental areas; (c) haplotype sharing between breeds of the same region is lower than between breeds of different regions and (d) genetic distances between breeds do not correlate with geography.
Conclusion
MtDNA haplotype sharing occurred between Serra da Estrela Mountain dogs (with putative origin in the centre of Portugal) and two breeds in the north and south of the country-with the Castro Laboreiro Dog (which behaves, at the mtDNA level, as a sub-sample of the Serra da Estrela Mountain Dog) and the southern Portuguese Sheepdog. In contrast, the Azores Cattle Dog did not share any haplotypes with the other Portuguese breeds, but with dogs sampled in Northern Europe. This suggested that the Azores Cattle Dog descended maternally from Northern European dogs rather than Portuguese mainland dogs. A review of published mtDNA haplotypes identified thirteen non-Portuguese breeds with sufficient data for comparison. Comparisons between these thirteen breeds, and the four Portuguese breeds, demonstrated widespread haplotype sharing, with the greatest diversity among Asian dogs, in accordance with the central role of Asia in canine domestication.
doi:10.1186/1471-2156-6-37
PMCID: PMC1180824  PMID: 15972107
13.  Connecting serum IGF-1, body size, and age in the domestic dog 
Age  2010;33(3):475-483.
Many investigations in recent years have targeted understanding the genetic and biochemical basis of aging. Collectively, genetic factors and biological mechanisms appear to influence longevity in general and specifically; reduction of the insulin/IGF-1 signaling cascade has extended life span in diverse species. Genetic alteration of mammals for life extension indicates correlation to serum IGF-1 levels in mice, and IGF-1 levels have been demonstrated as a physiological predictor of frailty with aging in man. Longevity and aging data in the dog offer a close measure of the natural multifactorial longevity interactions of genetic influence, IGF-1 signaling, and environmental factors such as exposure, exercise, and lifestyle. The absence of genetic alteration more closely represents the human longevity status, and the unique species structure of the canine facilitates analyses not possible in other species. These investigations aimed to measure serum IGF-1 in numerous purebred and mixed-breed dogs of variable size and longevity in comparison to age, gender, and spay/neuter differences. The primary objective of this investigation was to determine plasma IGF-1 levels in the adult dog, including a wide range of breeds and adult body weight. The sample set includes animals ranging from just a few months of age through 204 months and ranging in size from 5 to 160 lb. Four groups were evaluated for serum IGF-1 levels, including intact and neutered males, and intact and spayed females. IGF-1 loss over time, as a function of age, decreases in all groups with significant differences between males and females. The relationship between IGF-1 and weight differs depending upon spay/neuter status, but there is an overall increase in IGF-1 levels with increasing weight. The data, currently being interrogated further for delineation of IGF-1 receptor variants and sex differences, are being collected longitudinally and explored for longevity associations previously unavailable in non-genetically modified mammals.
doi:10.1007/s11357-010-9182-4
PMCID: PMC3168604  PMID: 20865338
Longevity; IGF-1; Canine; Aging; Insulin signaling
14.  Concentrations of cardiac Troponin I before and after ovariohysterectomy in 46 female dogs with pyometra 
Background
Canine pyometra is a common disease in countries where routine spaying of young dogs is not common practice. This disease is known to lead to systemic inflammation potentially affecting multiple organs in the body, including the heart. Cardiac-specific Troponin I (cTnI) is a sensitive marker of myocardial cell damage, which can result from ischemia, trauma, toxins or inflammation. Dogs with pyometra are also exposed to anaesthesia which can potentially result in myocardial cell damage. The aims of the study were 1) to evaluate the occurrence of myocardial cell damage as indicated by increased serum concentrations of cTnI in dogs with pyometra and relate these to presence of systemic inflammation and 2) to evaluate the change in cTnI-concentrations after anaesthesia and surgery.
Methods
Serum cTnI concentration was measured preoperatively and one day after surgery in 46 female dogs with pyometra and 15 female dogs that underwent surgery for other reasons (ovariohysterectomy and mammary tumours).
Results
Forty-six female dogs of different breeds diagnosed with pyometra were included. The dogs had a median age of 8.5 years (IQR 7.5–10) and a median weight of 29 kg (IQR 9–32). Of the 46 dogs, 37 (80%) fulfilled the chosen criteria for systemic inflammatory response syndrome (SIRS) at inclusion. Thirteen (28%) of the dogs had increased cTnI concentrations (> 0.2 μg/l) before surgery and 18 (39%) had increased cTnI-concentrations the day after surgery. The cTnI concentrations in the 13 dogs with increased preoperative cTnI concentrations decreased in 8 dogs, increased in 4 dogs, and was unchanged in one dog. Seven dogs with nondetectable preoperative cTnI concentrations had increased postoperative concentrations. The only significant association between the studied laboratory or clinical variables (including SIRS) and cTnI concentration was preoperative percentage band neutrophils (PBN) and postoperative cTnI concentration (P = 0.016). In total, 20 dogs (43%) had increased pre- or postoperative cTnI concentrations. Seven dogs (15%) had pre-or postoperative concentrations of cTnI of 1.0 μg/l or higher.
Conclusion
Mild to moderate increases in cTnI appears to be common in dogs with pyometra before and after surgery, but the clinical importance of this finding is uncertain. None of the studied clinical variables were found to reliably predict increased preoperative cTnI concentrations. Because of the pre- and postoperative variation in cTnI concentrations, it was not possible to identify a negative effect of anaesthesia and surgery on myocardial cell integrity.
doi:10.1186/1751-0147-50-35
PMCID: PMC2546406  PMID: 18786242
15.  A genetic dissection of breed composition and performance enhancement in the Alaskan sled dog 
BMC Genetics  2010;11:71.
Background
The Alaskan sled dog offers a rare opportunity to investigate the development of a dog breed based solely on performance, rather than appearance, thus setting the breed apart from most others. Several established breeds, many of which are recognized by the American Kennel Club (AKC), have been introduced into the sled dog population to enhance racing performance. We have used molecular methods to ascertain the constitutive breeds used to develop successful sled dog lines, and in doing so, determined the breed origins of specific performance-related behaviors.
One hundred and ninety-nine Alaskan sled dogs were genotyped using 96 microsatellite markers that span the canine genome. These data were compared to that from 141 similarly genotyped purebred dog breeds. Sled dogs were evaluated for breed composition based on a variety of performance phenotypes including speed, endurance and work ethic, and the data stratified based on population structure.
Results
We observe that the Alaskan sled dog has a unique molecular signature and that the genetic profile is sufficient for identifying dogs bred for sprint versus distance. When evaluating contributions of existing breeds we find that the Alaskan Malamute and Siberian Husky contributions are associated with enhanced endurance; Pointer and Saluki are associated with enhanced speed and the Anatolian Shepherd demonstrates a positive influence on work ethic.
Conclusion
We have established a genetic breed profile for the Alaskan sled dog, identified profile variance between sprint and distance dogs, and established breeds associated with enhanced performance attributes. These data set the stage for mapping studies aimed at finding genes that are associated with athletic attributes integral to the high performing Alaskan sled dog.
doi:10.1186/1471-2156-11-71
PMCID: PMC2920855  PMID: 20649949
16.  Selenium and Mercury in the Brazilian Amazon: Opposing Influences on Age-Related Cataracts 
Environmental Health Perspectives  2010;118(11):1584-1589.
Background
Age-related cataracts (ARCs) are an important cause of blindness in developing countries. Although antioxidants may be part of the body’s defense to prevent ARC, environmental contaminants may contribute to cataractogenesis. In fish-eating populations of the lower Tapajós region, elevated exposure to mercury (Hg) has been reported, and blood levels of selenium (Se) range from normal to very high (> 1,000 μg/L).
Objectives
We examined ARCs in relation to these elements among adults (≥ 40 years of age) from 12 riverside communities.
Methods
Participants (n = 211) provided blood samples and underwent an extensive ocular examination. Inductively coupled plasma mass spectrometry was used to assess Hg and Se in blood and plasma.
Results
One-third (n = 69; 32.7%) of the participants had ARC. Lower plasma Se (P-Se; < 25th percentile, 110 μg/L) and higher blood Hg (B-Hg; ≥ 25th percentile, 25 μg/L) were associated with a higher prevalence odds ratio (POR) of ARC [adjusted POR (95% confidence interval), 2.69 (1.11–6.56) and 4.45 (1.43–13.83), respectively]. Among participants with high P-Se, we observed a positive but nonsignificant association with high B-Hg exposure, whereas among those with low B-Hg, we observed no association for P-Se. However, compared with the optimum situation (high P-Se, low B-Hg), the POR for those with low P-Se and high B-Hg was 16.4 (3.0–87.9). This finding suggests a synergistic effect.
Conclusion
Our results suggest that persons in this population with elevated Hg, the cataractogenic effects of Hg may be offset by Se. Because of the relatively small sample size and possible confounding by other dietary nutrients, additional studies with sufficient power to assess multiple nutrient and toxic interactions are required to confirm these findings.
doi:10.1289/ehp.0901284
PMCID: PMC2974697  PMID: 20716509
age-related cataract; Brazilian Amazon; fish consumption; mercury; selenium
17.  Seasonal trade-offs in cell-mediated immunosenescence in ruffs (Philomachus pugnax). 
The immune system is an energetically expensive self-maintenance complex that, given the risks of parasitism, cannot be carelessly compromised. Life-history theory posits that trade-offs between fitness components, such as self-maintenance and reproduction, vary between genders and age classes depending on their expected residual lifetime reproductive success, and seasonally as energetic requirements change. Using ruff (Philomachus pugnax), a bird with two genetically distinct male morphs, we demonstrate here a decrease in male immunocompetence during the breeding season, greater variance in immune response among males than females, immunosenescence in both sexes and male morphs, and a seasonal shift in the age range required to detect senescence. Using a phytohaemagglutinin delayed hypersensitivity assay, we assessed cell-mediated immunity (CMI) of males of typical breeding age during the breeding and nonbreeding seasons, and of a larger sample that included females and birds of a greater age range during the non-breeding period. CMI was higher for breeding-aged males in May than in November, but the increase was not related to age or male morph. In November, mean CMI did not differ between the sexes, but the variance was higher for males than for females, and there were no differences in mean or variance between the two male morphs. For both sexes and male morphs, CMI was lower for young birds than for birds of typical breeding ages, and it declined again for older birds. In males, senescence was detected in the non-breeding season only when very old birds were included. These results, generally consistent with expectations from life-history theory, indicate that the immune system can be involved in multifarious trade-offs within a yearly cycle and along an individual's lifetime, and that specific predictions about means and variances in immune response should be considered in future immunoecological research.
doi:10.1098/rspb.2002.2309
PMCID: PMC1691355  PMID: 12816660
18.  A longitudinal study on diarrhoea and vomiting in young dogs of four large breeds 
Background
Prospective studies to document the occurrence of canine diarrhoea and vomiting are relatively scarce in dogs, and the majority of published studies are based on information from clinical records. This study investigates the incidence risk of diarrhoea and vomiting as well as potential risk factors.
Methods
A cohort study of 585 privately owned dogs of four breeds: Newfoundland, Labrador retriever, Leonberger, and Irish wolfhound. The owners maintained a continuous log regarding housing, exercise, nutrition, and health of their dogs. Episodes of diarrhoea and vomiting were recorded in a consecutive manner in a booklet. The owners completed the questionnaires and reported information at three, four, six, 12, 18, and 24/25 months of age, called observational ages.
Associations with potential risk factors for diarrhoea and vomiting were investigated in separate generalized estimating equation analyses.
Results
The incidence of both diarrhoea and vomiting was influenced by breed. Both diarrhoea and vomiting were relatively common in young dogs, occurring most frequently during the first months of life. After three months of age, the odds of diarrhoea were significantly lower when compared to the observational period seven weeks to three months (OR ranging from 0.31 to 0.70 depending on the period). More males than females suffered from diarrhoea (OR = 1.42). The occurrence of diarrhoea was more common in dogs that also experienced episode(s) of vomiting during the study period (OR = 5.43) and vice versa (OR = 5.50). In the majority of dogs episodes of diarrhoea and vomiting did not occur at the same time. Dogs in urban areas had higher odds (OR = 1.88) of getting diarrhoea compared to dogs living in rural areas. The occurrence of both diarrhoea and vomiting demonstrated a seasonal variation with higher incidence during the summer months.
Conclusion
Both diarrhoea and vomiting occurred most frequently during the first months of life. The incidence of diarrhoea and vomiting was significantly different between breeds. Diarrhoea occurred more frequently in males and in dogs living in urban areas. Also, a positive association between the occurrence of diarrhoea and vomiting in the same dog was found.
doi:10.1186/1751-0147-54-8
PMCID: PMC3293024  PMID: 22300688
longitudinal study; diarrhoea; vomiting; incidence; risk factors; dog
19.  Cooperative breeding in birds: a comparative test of the life history hypothesis 
In approximately 3.2% of bird species individuals regularly forgo the opportunity to breed independently and instead breed cooperatively with other conspecifics, either as non-reproductive 'helpers' or as co-breeders. The traditional explanation for cooperative breeding is that the opportunities for breeding independently are limited owing to peculiar features of the species' breeding ecology. However, it has proved remarkably difficult to find any common ecological correlates of cooperative breeding in birds. This difficulty has led to the 'life history hypothesis', which suggests that the common feature of cooperatively breeding birds is their great longevity, rather than any particular feature of their breeding ecology. Here, we use a comparative method to test the life history hypothesis by looking for correlations between life history variation and variation in the frequency of cooperative breeding. First, we find that cooperative breeding in birds is not randomly distributed, but concentrated in certain families, thus supporting the idea that there may be a common basis to cooperative breeding in birds. Second, increases in the level of cooperative breeding are strongly associated with decreases in annual adult mortality and modal clutch size. Third, the proportion of cooperatively breeding species per family is correlated with a low family-typical value of annual mortality, suggesting that low mortality predisposes cooperative breeding rather than vice versa. Finally, the low rate of mortality typically found in cooperatively breeding species is associated with increasing sedentariness, lower latitudes, and decreased environmental fluctuation. We suggest that low annual mortality is the key factor that predisposes avian lineages to cooperative breeding, then ecological changes, such as becoming sedentary, further slow population turnover and reduce opportunities for independent breeding. As the traditional explanation suggests, the breeding habitat of cooperatively breeding species is saturated, but this saturation is not owing to any peculiar feature of the breeding ecology of cooperative breeders. Rather, the saturation arises because the local population turnover in these species is unusually slow, as predicted by the life history hypothesis.
doi:10.1098/rspb.1998.0355
PMCID: PMC1689041
20.  A Single IGF1 Allele Is a Major Determinant of Small Size in Dogs 
Science (New York, N.Y.)  2007;316(5821):112-115.
The domestic dog exhibits greater diversity in body size than any other terrestrial vertebrate. We used a strategy that exploits the breed structure of dogs to investigate the genetic basis of size. First, through a genome-wide scan, we identified a major quantitative trait locus (QTL) on chromosome 15 influencing size variation within a single breed. Second, we examined genetic variation in the 15-megabase interval surrounding the QTL in small and giant breeds and found marked evidence for a selective sweep spanning a single gene (IGF1), encoding insulin-like growth factor 1. A single IGF1 single-nucleotide polymorphism haplotype is common to all small breeds and nearly absent from giant breeds, suggesting that the same causal sequence variant is a major contributor to body size in all small dogs.
doi:10.1126/science.1137045
PMCID: PMC2789551  PMID: 17412960
21.  Polymorphisms within the Telomerase Reverse Transcriptase gene (TERT) in four breeds of dogs selected for difference in lifespan and cancer susceptibility 
Background
Enzymatic activity of Telomerase Reverse Transcriptase (TERT) is important in maintaining the telomere length and has been implicated in cancer and aging related pathology. Since cancer susceptibility as well as longevity of dogs vary between breeds, this study involved sequencing the entire TERT gene of Canis familiaris from DNA samples obtained from forty dogs, with ten dogs each of four breeds: Shih Tzu, Dachshund, Irish Wolfhound, and Newfoundland, each with different life expectancies and susceptibility to cancer.
Results
We compared the sequences of all forty individuals amongst one another and with the published sequence of canine TERT, and analyzed relationships between members of the same or different breeds. Two separate phylogenetic trees were generated and analyzed from these individuals. Polymorphisms were found most frequently in intronic regions of the gene, although exonic polymorphisms also were observed. In many locations genotypes were observed that were either homozygous for the reference sequence or heterozygous, but the variant homozygous genotype was not observed.
Conclusions
We propose that these homozygous variants are likely to have adverse effects in dogs. It was also found that the polymorphisms did not segregate by breed. Because the four breeds chosen come from geographically and physiologically distinct backgrounds, it can be inferred that the polymorphic diversification of TERT preceded breed derivation.
doi:10.1186/1746-6148-10-20
PMCID: PMC3904191  PMID: 24423165
22.  Genetic diversity of canine olfactory receptors 
BMC Genomics  2009;10:21.
Background
Evolution has resulted in large repertoires of olfactory receptor (OR) genes, forming the largest gene families in mammalian genomes. Knowledge of the genetic diversity of olfactory receptors is essential if we are to understand the differences in olfactory sensory capability between individuals. Canine breeds constitute an attractive model system for such investigations.
Results
We sequenced 109 OR genes considered representative of the whole OR canine repertoire, which consists of more than 800 genes, in a cohort of 48 dogs of six different breeds. SNP frequency showed the overall level of polymorphism to be high. However, the distribution of SNP was highly heterogeneous among OR genes. More than 50% of OR genes were found to harbour a large number of SNP, whereas the rest were devoid of SNP or only slightly polymorphic. Heterogeneity was also observed across breeds, with 25% of the SNP breed-specific. Linkage disequilibrium within OR genes and OR clusters suggested a gene conversion process, consistent with a mean level of polymorphism higher than that observed for introns and intergenic sequences. A large proportion (47%) of SNP induced amino-acid changes and the Ka/Ks ratio calculated for all alleles with a complete ORF indicated a low selective constraint with respect to the high level of redundancy of the olfactory combinatory code and an ongoing pseudogenisation process, which affects dog breeds differently.
Conclusion
Our demonstration of a high overall level of polymorphism, likely to modify the ligand-binding capacity of receptors distributed differently within the six breeds tested, is the first step towards understanding why Labrador Retrievers and German Shepherd Dogs have a much greater potential for use as sniffer dogs than Pekingese dogs or Greyhounds. Furthermore, the heterogeneity in OR polymorphism observed raises questions as to why, in a context in which most OR genes are highly polymorphic, a subset of these genes is not? This phenomenon may be related to the nature of their ligands and their importance in everyday life.
doi:10.1186/1471-2164-10-21
PMCID: PMC2635374  PMID: 19144169
23.  Exploring mechanisms of sex differences in longevity: lifetime ovary exposure and exceptional longevity in dogs 
Aging Cell  2009;8(6):752-755.
To move closer to understanding the mechanistic underpinnings of sex differences in human longevity, we studied pet dogs to determine whether lifetime duration of ovary exposure was associated with exceptional longevity. This hypothesis was tested by collecting and analyzing lifetime medical histories, age at death, and cause of death for a cohort of canine ‘centenarians’– exceptionally long-lived Rottweiler dogs that lived more than 30% longer than average life expectancy for the breed. Sex and lifetime ovary exposure in the oldest-old Rottweilers (age at death, ≥ 13 years) were compared to a cohort of Rottweilers that had usual longevity (age at death, 8.0–10.8 years). Like women, female dogs were more likely than males to achieve exceptional longevity (OR, 95% CI = 2.0, 1.2–3.3; P= 0.006). However, removal of ovaries during the first 4 years of life erased the female survival advantage. In females, a strong positive association between ovaries and longevity persisted in multivariate analysis that considered other factors, such as height, body weight, and mother with exceptional longevity. A beneficial effect of ovaries on longevity in females could not be attributed to resistance against a particular disease or major cause of death. Our results document in dogs a female sex advantage for achieving exceptional longevity and show that lifetime ovary exposure, a factor not previously evaluated in women, is associated with exceptional longevity. This work introduces a conceptual framework for designing additional studies in pet dogs to define the ovary-sensitive biological processes that promote healthy human longevity.
doi:10.1111/j.1474-9726.2009.00513.x
PMCID: PMC2805875  PMID: 19732047
anti-aging; estrogen; ovarian conservation; ovariohysterectomy; sex difference in health
24.  Prospective Study on the Incidence and Progression of Clinical Signs in Naïve Dogs Naturally Infected by Leishmania infantum 
The incidence of clinical and clinicopathological signs associated with the progression of infection was evaluated prospectively in 329 naïve young dogs exposed to Leishmania infantum transmission and examined periodically during 22 months (M). The dogs were part of Leishmania vaccine investigations performed under natural conditions. Vaccinated groups were considered in the evaluation when the vaccine resulted non-protective and the appearance and progression of signs did not differ statistically from controls at each time point, otherwise only control groups were included. 115 beagles were part of 3 studies (A to C) performed in the same kennel; 214 owned dogs (29 breeds, 2.3% beagles) were included in a study (D) performed in 45 endemic sites. At M22 the prevalence of any Leishmania infection stage classified as subpatent, active asymptomatic, or symptomatic was 59.8% in studies A–C and 29.2% in study D. Despite different breed composition and infection incidence, the relative proportion of active infections and the progression and type of clinical and clinicopathological signs have been similar in both study sets. All asymptomatic active infections recorded have invariably progressed to full-blown disease, resulting in 56 sick dogs at M22. In these dogs, lymph nodes enlargement and weight loss — recorded from M12 — were the most common signs. Cutaneous signs were seen late (M18) and less frequently. Ocular signs appeared even later, being sporadically recorded at M22. Most clinicopathological alterations became evident from M12, although a few cases of thrombocytopenia or mild non-regenerative anemia were already observed at M6. Albumin/globulin inversions were recorded from M12 and urea/creatinine increase appeared mostly from M18. Altogether our findings indicate that any susceptible young dogs naturally infected by L. infantum present a common pattern of progression of signs during 2 years post infection, providing clues for medical and epidemiological applied aspects.
Author Summary
Despite dogs representing the main reservoir for the most widespread entity of human leishmaniasis (zoonotic visceral leishmaniasis caused by Leishmania infantum, endemic in five continents), many aspects of canine leishmaniasis (CanL) are still poorly understood. Dog responses to the infection are complex and broadly follow the two patterns of substantial resistance or clinical susceptibility. The latter is a progressive condition eventually leading to a dog's death, being associated with an increasing infectiousness to phlebotomine vectors. Because most information on CanL comes from cross-sectional investigations such as in-clinic pet diagnosis or mass population surveys, knowledge on the individual natural course of the infection/disease is limited. Prospective investigations are rarely performed because they are difficult and expensive. We took advantage of 4 prospective studies on experimental Leishmania vaccines to investigate the time-course of clinical signs in susceptible young dogs exposed to natural infection. We found that, whatever the dog breed and the local incidence of leishmaniasis, any asymptomatic active infections detected in naïve animals invariably progress to full-blown disease, showing a common pattern of early and late signs during 2 years post infection. These findings may provide clues for medical and epidemiological applied aspects.
doi:10.1371/journal.pntd.0002225
PMCID: PMC3649971  PMID: 23675551
25.  Molecular cytogenetic characterization of canine histiocytic sarcoma: A spontaneous model for human histiocytic cancer identifies deletion of tumor suppressor genes and highlights influence of genetic background on tumor behavior 
BMC Cancer  2011;11:201.
Background
Histiocytic malignancies in both humans and dogs are rare and poorly understood. While canine histiocytic sarcoma (HS) is uncommon in the general domestic dog population, there is a strikingly high incidence in a subset of breeds, suggesting heritable predisposition. Molecular cytogenetic profiling of canine HS in these breeds would serve to reveal recurrent DNA copy number aberrations (CNAs) that are breed and/or tumor associated, as well as defining those shared with human HS. This process would identify evolutionarily conserved cytogenetic changes to highlight regions of particular importance to HS biology.
Methods
Using genome wide array comparative genomic hybridization we assessed CNAs in 104 spontaneously occurring HS from two breeds of dog exhibiting a particularly elevated incidence of this tumor, the Bernese Mountain Dog and Flat-Coated Retriever. Recurrent CNAs were evaluated further by multicolor fluorescence in situ hybridization and loss of heterozygosity analyses. Statistical analyses were performed to identify CNAs associated with tumor location and breed.
Results
Almost all recurrent CNAs identified in this study were shared between the two breeds, suggesting that they are associated more with the cancer phenotype than with breed. A subset of recurrent genomic imbalances suggested involvement of known cancer associated genes in HS pathogenesis, including deletions of the tumor suppressor genes CDKN2A/B, RB1 and PTEN. A small number of aberrations were unique to each breed, implying that they may contribute to the major differences in tumor location evident in these two breeds. The most highly recurrent canine CNAs revealed in this study are evolutionarily conserved with those reported in human histiocytic proliferations, suggesting that human and dog HS share a conserved pathogenesis.
Conclusions
The breed associated clinical features and DNA copy number aberrations exhibited by canine HS offer a valuable model for the human counterpart, providing additional evidence towards elucidation of the pathophysiological and genetic mechanisms associated with histiocytic malignancies. Extrapolation of data derived from canine histiocytic disorders to human histiocytic proliferation may help to further our understanding of the propagation and cancerization of histiocytic cells, contributing to development of new and effective therapeutic modalities for both species.
doi:10.1186/1471-2407-11-201
PMCID: PMC3121728  PMID: 21615919

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