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Digital dermatitis (DD) is a polybacterial disease endemic to most UK dairy farms. It poses a major financial and welfare threat and is characterized by high incidence and recurrence rates. We aimed to investigate the association between the UK EBV for resistance to digital dermatitis, the digital dermatitis index (DDI), and the frequency of DD, heel horn erosion (HHE), and interdigital hyperplasia (IH) in a population of Holstein dairy cows. We enrolled and genotyped 2,352 cows from 4 farms in a prospective cohort study. Foot lesion records were recorded by veterinary surgeons for each animal at 4 time points during a production cycle, starting at approximately 2 mo before calving and ending in late lactation. Importantly, these records were not used in the calculation of the DDI. Lesion records were matched to the animal's own DDI (n = 2,101) and their sire's DDI (n = 1,812). Digital dermatitis index values in our study population ranged from -1.41 to +1.2 and were transformed to represent distance from the mean expressed in SD. The relationship between the DDI and the presence of DD was investigated using a logistic regression model, with farm, parity, and a farm-parity interaction fitted as covariates. A multivariable logistic regression model was fitted to evaluate the relationship between HHE and DDI with farm fitted as a covariate. Finally, a univariable logistic regression model with DDI as explanatory variable was used to investigate the relationship between IH and DDI. The odds ratio of an animal being affected by DD was 0.69 for 1 SD increase in the animal's DDI (95% CI = 0.63-0.76). The odds of HHE and IH were 0.69 (95% CI = 0.62-0.76) and 0.58 (95% CI = 0.49-0.68) respectively for 1 SD increase in DDI. The adjusted probability of DD was 32% (95% CI = 27-36%) for cows with mean DDI value of 0, while it was 24% (95% CI = 20-29%) in cows with a DDI value of +1. Sire DDI breeding values were standardized in the same way and then binned into terciles creating an ordinal variable representing bulls of high, medium, and low genetic merit for DD resistance. The daughters of low genetic merit bulls were at 2.05 (95% CI = 1.60-2.64), 1.96 (95% CI = 1.53-2.50), and 2.85 (95% CI = 1.64-5.16) times greater odds of being affected by DD, HHE, and IH, respectively, compared with the daughters of high genetic merit bulls. The results of this study highlight the potential of digital dermatitis genetic indexes to aid herd management of DD, and suggest that breeding for resistance to DD, alongside environmental and management control practices, could reduce the prevalence of the disease., (The Authors. Published by Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Hoof diseases are a major welfare and economic issue in the global dairy cattle production industry, which can be minimized through improved management and breeding practices. Optimal genetic improvement of hoof health could benefit from a deep understanding of the genetic background and biological underpinning of indicators of hoof health. Therefore, the primary objectives of this study were to perform genome-wide association studies, using imputed high-density genetic markers data from North American Holstein cattle, for 8 hoof-related traits: digital dermatitis, sole ulcer, sole hemorrhage, white line lesion, heel horn erosion, interdigital dermatitis, interdigital hyperplasia, and toe ulcer, and a hoof health index. De-regressed estimated breeding values from 25,580 Holstein animals were used as pseudo-phenotypes for the association analyses. The genomic quality control, genotype phasing, and genotype imputation were performed using the PLINK (version 1.9), Eagle (version 2.4.1), and Minimac4 software, respectively. The functional genomic analyses were performed using the GALLO R package and the DAVID platform. We identified 22, 34, 14, 22, 28, 33, 24, 43, and 15 significant markers for digital dermatitis, heel horn erosion, interdigital dermatitis, interdigital hyperplasia, sole hemorrhage, sole ulcer, toe ulcer, white line lesion disease, and the hoof health index, respectively. The significant markers were located across all autosomes, except BTA10, BTA12, BTA20, BTA26, BTA27, and BTA28. Moreover, the genomic regions identified overlap with various previously reported quantitative trait loci for exterior, health, meat and carcass, milk, production, and reproduction traits. The enrichment analyses identified 44 significant gene ontology terms. These enriched genomic regions harbor various candidate genes previously associated with bone development, metabolism, and infectious and immunological diseases. These findings indicate that hoof health traits are highly polygenic and influenced by a wide range of biological processes., (The Authors. Published by Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Background: This study aimed to determine the association between the lameness advantage genetic index and four outcomes: sole haemorrhage (SH), sole ulcers (SU), white line lesions (WL), and lameness during mobility scoring., Methods: We enrolled 2352 Holstein cows from four predominantly housed dairy herds in the UK. Cows were mobility scored and foot lesions recorded at four time points from before calving to late lactation. Cows were genotyped and genetic indexes were assigned to each cow following national genetic evaluations. Lameness records and genetic indexes were matched for 2107 cows. Four separate multivariable logistic regression models, which included farm and parity as covariables, were used to quantify the association between the lameness advantage index and whether animals were affected by SH, SU, WL, or lameness., Results: The odds ratios (95% confidence intervals) for one-point increases in the lameness advantage index were 0.79 (0.72-0.86), 0.68 (0.59-0.78), 0.94 (0.84-1.04), and 0.82 (0.74-0.91) for SH, SU, WL, and lameness, respectively. The same trends were present when the sire's lameness advantage index was evaluated in place of the animal's own, although the strength of this association was generally weaker., Conclusion: The lameness advantage index is associated with SH, SU, and lameness, therefore selection on the lameness advantage index could be considered in herds aiming to reduce lameness. Where genomic testing of heifers is not conducted, sire lameness advantage index may still be effective to reduce SH and SU incidence., (© 2022 British Veterinary Association.)

Laminitis results in impaired tissue integrity and Inflammation of the epidermal and dermal lamellae connecting the hoof capsule to the underlying distal phalanx and causes loss-of-use, poor quality of life and euthanasia in horses. Historically, studies to better understand the etiology of laminitis by documenting changes in gene expression were hampered by the paucity of gene annotation specific to hoof tissues. Next-generation sequencing enables improvements to annotation by incorporating equine- and hoof-specific transcripts. Here we characterize the hoof lamellar tissue transcriptome of naturally occurring supporting limb laminitis (SLL) using archived lamellar tissue from Thoroughbred racehorses consisting of 13 SLL hospital cases and seven age-matched control horses. This was achieved using: 1) Applied transcriptome annotation by long-read sequencing to document transcript diversity and 2) short-read RNA sequencing to document changes in gene expression correlating to the developmental and acute stages of naturally occurring SLL. 1.99Gbp of long-read transcriptome sequencing deeply documented 5067 unique loci, while short read RNA-seq under very stringent quality filters described 66 differentially expressed loci. Functional analysis of these loci revealed alterations in cell replication and growth, stress response and leukocyte recruitment and activation pathways. Differential expression of the Ezrin and TIMP3 genes suggests they may have utility as biomarkers for laminitis disease, while NR1D1 and genes relevant to the inflammasome are promising targets for novel pharmacological treatments., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Genome-wide association studies based on SNP have been completed for multiple traits in dairy cattle; however, copy number variants (CNV) could add genomic information that has yet to be harnessed. The objectives of this study were to identify CNV in genotyped Holstein animals and assess their association with hoof health traits using deregressed estimated breeding values as pseudophenotypes. A total of 23,256 CNV comprising 1,645 genomic regions were identified in 5,845 animals. Fourteen genomic regions harboring structural variations, including 9 deletions and 5 duplications, were associated with at least 1 of the studied hoof health traits. This group of traits included digital dermatitis, interdigital dermatitis, heel horn erosion, sole ulcer, white line lesion, sole hemorrhage, and interdigital hyperplasia; no regions were associated with toe ulcer. Twenty candidate genes overlapped with the regions associated with these traits including SCART1, NRXN2, KIF26A, GPHN, and OR7A17. In this study, an effect on infectious hoof lesions could be attributed to the PRAME (Preferentially Expressed Antigen in Melanoma) gene. Almost all genes detected in association with noninfectious hoof lesions could be linked to known metabolic disorders. The knowledge obtained considering information of associated CNV to the traits of interest in this study could improve the accuracy of estimated breeding values. This may further increase the genetic gain for these traits in the Canadian Holstein population, thus reducing the involuntary animal losses due to lameness., (The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).)

Context: Literature suggests that oncogenic osteomalacia is usually caused by a benign mesenchymal tumor secreting fibroblast growth factor subtype-23 (FGF-23), but the involvement of other phosphatonins has only been scarcely reported. We have previously published a seemingly typical case of oncogenic osteomalacia. Following curative neoplasm resection, we now report unique molecular characteristics and biology of this tumor., Case Description: A 25-year-old man had been diagnosed with severe oncogenic osteomalacia that gradually crippled him over 6 years. 68Ga-DOTA-TATE positron emission tomography/computed tomography scan localized the culprit tumor to his left sole, which on resection revealed a deep fibrous histiocytoma displaying a proliferation of spindle cells with storiform pattern associated with multinucleated giant cells resembling osteoclasts. Circulating FGF-23, which was elevated more than 2-fold, declined to undetectable levels 24 h after surgery. Microarray analysis revealed increased tumor gene expression of the phosphatonins FGF-23, matrix extracellular phosphoglycoprotein (MEPE) and secreted frizzled-related protein subtype 4, with elevated levels of all 3 proteins confirmed through immunoblot analysis. Differential expression of genes involved in bone formation and bone mineralization were further identified. The patient made an astonishing recovery from being wheelchair bound to fully self-ambulant 2 months postoperatively., Conclusion: This report describes oncogenic osteomalacia due to a deep fibrous histiocytoma, which coincidentally has been found to induce profound muscle weakness via the overexpression of 3 phosphatonins, which resolved fully upon radical resection of the tumor. Additionally, genes involved in bone formation and bone remodeling contribute to the molecular signature of oncogenic osteomalacia., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

The classification of undifferentiated soft tissue tumors continues to evolve with the expanded application of molecular analysis in clinical practice. We report three cases of a unique soft tissue tumor in young children (5 months to 2 years old) displaying a purely fibromyxoid histology, with positive staining for desmin and CD34. In two cases, RNA sequencing detected a YWHAZ-PLAG1 gene fusion, while in the third case, a previously unreported EEF1A1-PLAG1 fusion was identified. PLAG1 fusions have been reported in several pathologic entities including pleomorphic adenoma, myoepithelial tumors of skin and soft tissue, and lipoblastoma, the latter occurring preferentially in young children. In these tumors, expression of a full length PLAG1 protein comes under the control of the constitutively active promoter of the partner gene in the fusion, and the current cases conform to that model. Overexpression of PLAG1 was confirmed by diffusely positive immunostaining for PLAG1 in all three cases. Our findings raise the possibility of a novel fibromyxoid neoplasm in childhood associated with these rare PLAG1 fusion variants. The only other report of a PLAG1-YWHAZ fusion occurred in a pediatric tumor diagnosed as a "fibroblastic lipoblastoma." This finding raises the possibility of a relationship with our three cases, even though our cases lacked any fat component. Further studies with regard to a shared pathogenesis are required., (© 2020 Wiley Periodicals LLC.)

Laminitis is a devastating disease with diverse etiologies and few, if any, effective treatments. Gene expression and hypothesis-generating genomic studies have provided a fresh look at the key molecular players at crucial timepoints in diverse experimental and naturally affected tissues. We summarize findings to date, and propose a unifying model of the laminitis disease process that includes several pathogenesis concepts shared with other diseases of epidermal and epithelial tissues. The value of these new pathways as potential therapeutic targets is exciting but will require careful future work to validate new methods and launch systematic clinical trials., (Copyright © 2020 Elsevier Inc. All rights reserved.)

An 11G nucleotide repeat in the 3' UTR of FAM174A was recently postulated as a risk allele with a dominant mode of inheritance for equine metabolic syndrome (EMS) and laminitis status in Arabian horses. The objective of this project was to evaluate this hypothesis in a large and diverse across-breed population. A total of 301 ponies, 292 Morgans, 64 Arabians, 49 Tennessee Walking Horses and 59 Quarter Horses were genotyped for six observed G repeat alleles in the FAM174A 3' UTR. Phenotype data included laminitis status, baseline insulin, glucose, non-esterified fatty acids, triglycerides, adiponectin, leptin, ACTH, insulin and glucose post oral sugar test, and two proxies for insulin resistance. The 11G allele frequencies were 18.8, 6.9, 1.8, 0.2 and 0.0% in the Arabians, Tennessee Walkers, ponies, Morgans and Quarter Horses respectively. Association analyses between FAM174A genotype and EMS phenotypes, and between allele count and EMS phenotypes, identified no statistically significant associations. When a dominant effect for the 11G allele was evaluated, a statistically significant association with adiponectin levels was identified in the ponies, and pairwise comparisons revealed that the estimated marginal means were higher in ponies with the 11G allele vs. alternative alleles (i.e. the allele had a protective effect). In conclusion, our data do not support the FAM174A 11G allele as a risk allele for EMS in our studied breeds., (© 2020 Stichting International Foundation for Animal Genetics.)

Feet and legs disorders influence dairy cattle breeding by their effect on animal welfare, economic losses due to lower production and fertility, costs of treatment, and problems with herd management. In our study, we estimated heritabilities and performed a 2-step GWAS for 3 traits describing hoof health: hoof health status defined by a veterinarian (HSV), hoof health status defined by a claw trimmer (HSC), and the total number of hoof disorders (NHD), scored in 1,998 Fleckvieh and 979 Braunvieh cows. The individuals were genotyped with a high-density (HD) panel consisting of 76,934 SNP. For significant genomic regions, the SNP information was enhanced by SNP imputed from the whole-genome sequence of Fleckvieh and Braunvieh bulls from the 1000 Bulls Genome project. The heritabilities were estimated to be 0.035 for HSV, 0.249 for HSC, and 0.279 for NHD. Based on the first-stage GWAS with SNP from the HD panel, 7 significant genomic regions on 6 chromosomes were defined: (1) 120 SNP spanning 15,522 bp on BTA1, including the TOPBP1 gene; (2) 4,139 SNP spanning 1,426,046 bp on BTA7, including the RIOK2 and RGMB genes; (3) 167 SNP spanning 167,352 bp on BTA13, including the C13H20orf194 gene; (4) 2 regions on BTA14, one harboring 1,071 SNP spanning 380,024 bp, including RRM2B and NCALD, and the other comprising 632 SNP spanning 385,111 bp, including STK3; (5) 328 SNP on BTA15, spanning 235,567 bp between FAM168A and PLEKHB1; and (6) 1,549 SNP on BTA22, spanning 596,101 bp in the neighborhood of PTPRG. Then, we conducted a second-stage GWAS based on SNP from whole-genome sequences within the significant regions obtained in the first stage of the analysis. For HSV, the highest additive effect was estimated for 23 SNP located within a region on BTA15, close to FAM168A, corresponding to a predicted gene sequence. For HSC, the highest additive effect was attributed to 44 SNP located within a region of BTA22 corresponding to 4 predicted gene sequences, with rs135082893 within a sequence encoding a microRNA. Another potential causal mutation for HSC was rs134142607 on BTA13, within the exon of C13H20orf194. For NHD, 33 SNP with the highest estimated effect were located on BTA7 within a region of a predicted gene positioned between RIOK2 and RGMB. On BTA14, all significant SNP were located in introns of STK3, which is responsible for the "abnormal gait" phenotype in mice., (Copyright © 2020 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Spindle cell and sclerosing rhabdomyosarcoma (ssRMS) is a rare variant of rhabdomyosarcoma, which includes three distinct subtypes. In infants, these tumors are commonly associated with recurring fusions involving VGLL2 or NCOA2 and have a favorable prognosis. We present four cases of ssRMS and 16 additional cases from the literature, which show that these patients present with localized disease and have an excellent prognosis regardless of surgical margin or lack of radiation therapy. Molecularly defined spindle cell rhabdomyosarcoma in infants is likely a biologically distinct entity which may not require the aggressive multimodal treatment used for other subtypes of rhabdomyosarcoma., (© 2019 Wiley Periodicals, Inc.)

Claw lesions are the third most important health issue in dairy cattle, after mastitis and reproductive disorders, and genomic selection is a key component for long-term improvement of claw health. The objectives of this study were to assess the feasibility of a genomic evaluation for claw health in French Holstein cows, explore possibilities to increase evaluation accuracy, and gain a better understanding of the genetic determinism of claw health traits. The data set consisted of 48,685 trimmed Holstein cows, including 9,646 that were genotyped; 478 genotyped sires were also used. Seven claw lesion traits were evaluated using BLUP, genomic BLUP, BayesC, and single-step genomic BLUP, and the accuracies obtained using these approaches were measured through a validation study. The BayesC approach was used to detect quantitative trait locus (QTL) regions associated with the 7 individual traits (digital dermatitis, heel horn erosion, interdigital hyperplasia, sole hemorrhage circumscribed, sole hemorrhage diffused, sole ulcer, and white line fissure) based on their Bayes factor. Annotated genes on these regions were reported. Genomic evaluation approaches generally did not allow for greater accuracies than BLUP, except for single-step genomic BLUP. Accuracies were moderate, but best and worst validation animals were correctly discriminated and showed significant differences in lesion frequencies. A total of 192 QTL regions were identified, including 13 with major evidence or involved for 2 of the traits. A high number of genes were present on these regions, and several had functions associated with the immune system. In particular, the EPYC gene is located close to a major evidence QTL for resistance to digital dermatitis that is also a QTL for interdigital hyperplasia (on chromosome 5, around 20.9 MB) and has been associated with Ehlers-Danlos syndrome in cattle. Genomic selection can be used to improve resistance to individual claw lesions, and several possibilities exist to improve accuracies of genomic evaluations., (Copyright © 2019 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

The specific objective of this study was to evaluate the use of lameness scoring to genetically improve claw health in Austrian Fleckvieh, Brown Swiss, and Holstein cows based on data from the "Efficient Cow" project. In 2014, a 1-yr data collection was carried out. Data from 6,519 cows kept on 161 farms were recorded. At each time of milk recording, lameness scores were assessed by trained staff of the milk recording organizations. Hoof trimming on these farms was documented and recorded as well. Veterinarian diagnoses and culling due to foot and leg problems from these farms were available from the routine recording system. As repeated lameness records per cow and lactation were available, an overall lactation lameness score was calculated. Estimated heritabilities for lameness were 0.11, 0.05, and 0.09 for Fleckvieh, Brown Swiss, and Holstein, respectively; however, only heritability estimates for Fleckvieh were significantly different from zero. Breeding values for lameness were obtained, reversed in sign, and cows were ranked according to their breeding value. A low breeding value for lameness resistance (the bottom 10% of the cows) was associated with a significantly higher frequency of trimmed cows, which indicates that the cows selected by the farmer to be trimmed are not completely random. Additionally, a high breeding value for lameness resistance (the top 10% of the cows) was associated with lower frequencies of claw diseases recorded at trimming, claw and leg diagnoses, and culling due to foot and leg problems, which highlights the usefulness of lameness scoring for genetic improvement of claw health. Overall, selecting for a better lameness score has the potential to reduce claw diseases, especially the frequency of severe claw diseases that lead to culling., (Copyright © 2019 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Routine recording of claw health status at claw trimming of dairy cattle has been established in several countries, providing valuable data for genetic evaluation. In this review, we examine issues related to genetic evaluation of claw health; discuss data sources, trait definitions, and data validation procedures; and present a review of genetic parameters, possible indicator traits, and status of genetic and genomic evaluations for claw disorders. Different sources of data and traits can be used to describe claw health. Severe cases of claw disorders can be identified by veterinary diagnoses. Data from lameness and locomotion scoring, activity information from sensors, and feet and leg conformation traits are used as auxiliary traits. The most reliable and comprehensive information is data from regular hoof trimming. In genetic evaluation, claw disorders are usually defined as binary traits, based on whether or not the claw disorder was present (recorded) at least once during a defined time period. The traits can be specific disorders, composite traits, or overall claw health. Data validation and editing criteria are needed to ensure reliable data at the trimmer, herd, animal, and record levels. Different strategies have been chosen, reflecting differences in herd sizes, data structures, management practices, and recording systems among countries. Heritabilities of the most commonly analyzed claw disorders based on data from routine claw trimming were generally low, with ranges of linear model estimates from 0.01 to 0.14, and threshold model estimates from 0.06 to 0.39. Estimated genetic correlations among claw disorders varied from -0.40 to 0.98. The strongest genetic correlations were found among sole hemorrhage (SH), sole ulcer (SU), and white line disease (WL), and between digital/interdigital dermatitis (DD/ID) and heel horn erosion (HHE). Genetic correlations between DD/ID and HHE on the one hand and SH, SU, or WL on the other hand were, in most cases, low. Although some of the studies were based on relatively few records and the estimated genetic parameters had large standard errors, there was, with some exceptions, consistency among studies. Various studies evaluate the potential of various data soureces for use in breeding. The use of hoof trimming data is recommended for maximization of genetic gain, although auxiliary traits, such as locomotion score and some conformation traits, may be valuable for increasing the reliability of genetic evaluations. Routine genetic evaluation of direct claw health has been implemented in the Netherlands (2010); Denmark, Finland, and Sweden (joint Nordic evaluation; 2011); and Norway (2014), and other countries plan to implement evaluations in the near future., (The Authors. Published by FASS Inc. and Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).)

Acral melanoma (AM) is a rare subtype of cutaneous malignant melanoma (MM) found on acral skin, primarily on the soles of the feet. Although rare, it is the most common subtype of MM found in patients of African or East Asian ethnicity and has a poor prognosis, often because of the more advanced stage of presentation at diagnosis. The pathogenesis of AM is unclear, but genetic alterations, including mutations in BRAF, NRAS, and KIT have been implicated. Early diagnosis of AM is important for a better prognosis, but its identification is often challenging, leading to easy misdiagnosis. In the first of this two-part review, we review the history, epidemiology, aetiology and molecular pathology of AM; in part 2 we will review diagnosis and management., (© 2017 British Association of Dermatologists.)

Background: BRCA1-Associated-Protein 1 (BAP1) is a dynamic tumor suppressor which, when mutated, has been associated with an increased risk of uveal melanoma, cutaneous melanoma, mesothelioma, and several other cancers. Germline BAP1 mutations have been extensively studied, where they have been found to cause hereditary cancer susceptibility. However, their sporadic counterparts, tumors that display a loss of BAP1 expression due to somatically arising mutations in the BAP1 gene, remain a poorly described entity., Case Presentation: Here we present the case of a 49-year-old female who presented with an asymptomatic dome-shaped pink papule on the dorsal foot which was found on biopsy to be deficient in the BAP1 tumor suppressor. While the patient's family history did not suggest the presence of a familial cancer syndrome, germline genetic testing was performed and was negative. The patient underwent surgical excision of this sporadically appearing "BAPoma" by Mohs surgery., Conclusions: Given the relatively banal clinical appearance of these dome-shaped neoplasms, sporadic BAPomas may often be overlooked by clinicians and dermatologists. In addition to providing a representative case, here we also provide a synopsis of the current understanding of these neoplasms, both in terms of the histopathological features, as well as the molecular mechanisms underlying BAP1 function and its ability to prevent tumorigenesis.

The proportion of acral melanoma (AM) is much higher in Asian populations than in Caucasian populations. Although mutational profiles associated with AM have been discovered in Caucasian populations, knowledge of its genetic alterations in Asian populations is limited. To describe the molecular nature of AM in Korean patients, we performed mutational profiling of AM and matched normal tissues in patients. Fifty-one formalin-fixed paraffin-embedded AM samples and 32 matched pairs from patients' saliva DNA were analysed by next-generation sequencing. Only mutations confirmed via digital droplet PCR or in BRAF, KIT and NRAS, the most frequently altered cancer genes in cutaneous melanoma, were considered as positive. The relationship between mutational status and clinicopathological features were examined. Of the 47 AM patients screened, alteration of BRAF, NRAS and KIT genes was observed in 6.4%, 4.3% and 8.5%, respectively. We also tested matched normal tissues of patients to identify tumor-specific mutations. Examination of the mutational profile in a cohort of 28 primary melanomas and matched normal controls found BRAF mutations in two cases (7.1%), KIT mutations in three cases (10.7%) and CTNNB1 mutations in one case (3.6%). The BRAF, NRAS and KIT mutation status did not correlate with clinicopathological characteristics. Our results show that KIT, NRAS and BRAF hotspot mutations occur at a low frequency in Korean populations. We also observed a case with the CTNNB1 mutation, which raises the possibility that other pathways are associated with AM development., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

It has been more than 14 years since identification of the human genome. This phenomenon is creating a revolution in all components of the health-care world. To date, little has been included in the podiatric medical literature despite the fact that so many of the conditions affecting the pedal extremity have genomic implications. Genomics will have a major effect on prevention, diagnosis, and patient management and needs to be included in podiatric medical practice as well as in the curriculum of podiatric medical schools.

Corkscrew claw (CSC) is a conformational abnormality of the digit and affecting mostly but not exclusively the claws of the back leg, first reported during the 1950s in Dutch black and white cattle. The affected claws are longer and narrower than the claw and have an inward and upward spiral rotation of the toe. Similarly, the bearing surface of the wall is displaced inward. The animal starts to bear weight on the abaxial wall surface, particularly the caudal segment, and the sole may become completely non-weight bearing. The axial wall is displaced dorsomedially and a fold develops in the wall., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In most cases of cutaneous melanoma, ultraviolet (UV) radiation is recognized as a prominent risk factor. Less is known regarding the mechanisms of mutagenesis for melanoma arising in sun-protected sites, such as acral and mucosal melanoma. Acral and mucosal melanoma share many common features, including a late age of onset, a broad radial growth phase with prominent lentiginous growth, the presence of field cancerization cells, and, in most cases, lack of a precursor nevus. In addition to early chromosomal instability, many of the same genes are also involved in these two distinct melanoma subtypes. To better understand non-UV-mediated pathogenesis in melanoma, we conducted a joint literature review of clinical, histological, and molecular features in acral and mucosal melanoma. We also reviewed the current literature regarding aberrations in KIT, PDGFRA, TERT, and other commonly involved genes. By comparing common features of these two subtypes, we suggest potential mechanisms underlying acral and/or mucosal melanoma and offer direction for future investigations.

An accessory navicular bone (AN) is the most common accessory ossicle in the foot. The presence of an AN bone can trigger various foot problems, such as posterior tibial tendon pathology, flattening of the medial longitudinal arch, and medial foot pain. Despite the clinical influence of presence of an AN in foot disease, the research regarding its inheritance is still insufficient. A total of 135 pairs of monozygotic (MZ) twins, 25 pairs of dizygotic (DZ) twins, and 676 singletons from families were enrolled in order to estimate genetic influences on AN. After confirmation of zygosity and family relationship with a tandem repeat marker kit and questionnaires, the presence and type of the AN was classified through bilateral feet radiographic examination. The heritability of an AN was estimated using quantitative genetic analysis based on a variance decomposition model considering various types of family relationships: father-offspring pair, mother-offspring pair, and pooled DZ twin and sibling pairs. As a result, approximately 40.96% of the participants in this study had an AN in either foot, with type II being the most common type. The heritability for the presence of any type of an AN in any foot was estimated as 0.88 (95% CI [0.82, 0.94]) after adjusting for age and sex. Specifically, type II AN showed the highest heritability of 0.82 (95% CI [0.71-0.93]). The high heritability of an AN found in this large twin and family study suggests that an AN is determined by the substantial influence of genetic factor.

Reasons for Performing Study: There is a lack of evidence regarding genetic parameters of health traits in Swiss Warmblood horses., Objectives: To estimate heritabilities of equine sarcoid disease, horn quality of hooves, prognathism and increased filling of talocrural joints as a possible indicator for osteochondrosis in Swiss Warmblood horses examined at the field tests for 3-year-olds between 2005 and 2013., Study Design: Retrospective analysis of breed society database., Methods: Swiss Warmblood horses were examined clinically by 13 veterinarians at field tests in Switzerland between 2005 and 2013. The presence of sarcoids, horn quality of the hooves, incisor occlusion and increased joint filling were assessed and recorded. Records of 3715 horses were integrated in a pedigree comprising 217,282 horses. Variance components and heritabilities were estimated on the liability scale using multiple-trait Gibbs sampler for animal models (MTGSAM)., Results: The prevalences of the examined traits were rather low ranging from 2.4 to 13.0%. Heritabilities estimated were 0.21 ± 0.07 for the occurrence of sarcoids, 0.04 ± 0.02 for hooves with markedly brittle and friable horn quality, 0.03 ± 0.01 for hooves with marked growth ring formation, 0.06 ± 0.03 for prognathism and 0.08 ± 0.04 for increased filling of the talocrural joint (an indicator of possible osteochondrosis). The influence of the examiner on the variance of these observations was considerable., Conclusions: With the exception of equine sarcoid disease, estimates for the heritabilities for the traits examined here were low. A standardised examination protocol may reduce the variance due to the examiner., (© 2015 EVJ Ltd.)

Non-cage systems provide laying hens with considerable space allowance, perches and access to litter, thereby offering opportunities for natural species-specific behaviors. Conversely, these typical characteristics of non-cage systems also increase the risk of keel bone and foot pad disorders. The aim of this study was twofold: 1) to investigate if providing ramps between perches (housing factor) reduces keel bone and foot pad disorders and 2) to test for genetic predisposition by comparing 2 different layer hybrids. In a 2 × 2 design, 16 pens were equipped either with or without ramps between perches and nest boxes (8 pens/treatment), and housed with either 25 ISA Brown or Dekalb White birds per pen (in total 200 birds/hybrid). Keel bone injuries and foot health were repeatedly measured via palpation and visual assessment between 17 and 52 wk of age and daily egg production was recorded. The relationships between the dependent response variables (keel bone and footpad disorders, egg production) and independent factors (age, ramps, hybrid) were analyzed using generalized linear mixed models and corrected for repeated measures. Ramps reduced keel bone fractures (F 1,950  = 45.80, P < 0.001), foot pad hyperkeratosis (F 1,889  = 10.40, P = 0.001), foot pad dermatitis (F 1,792  = 20.48, P < 0.001) and bumble foot (F 1,395  = 8.52, P < 0.001) compared to pens without ramps. ISA Brown birds sustained more keel bone fractures (F 1,950  = 33.26, P < 0.001), had more foot pad hyperkeratosis (F 1,889  = 44.69, P < 0.001) and laid more floor eggs (F 1,1883  = 438.80, P < 0.001), but had fewer keel bone deviations (F 1,1473  = 6.73, P < 0.001), fewer cases of foot pad dermatitis (F 1,792  = 19.84, P < 0.001) and no bumble foot as compared to Dekalb White birds. Age, housing and hybrid showed several interaction effects. Providing ramps proved to be very effective in both reducing keel bone and foot pad problems in non-cage systems. Keel bone and foot pad disorders are related to genetic predisposition. These results indicate that adaptation of the housing systems and hybrid selection may be effective measures in improving laying hen welfare., (© 2016 Poultry Science Association Inc.)

Identification of genetic variants associated with feet and legs disorders (FLD) will aid in the genetic improvement of these traits by providing knowledge on genes that influence trait variations. In Denmark, FLD in cattle has been recorded since the 1990s. In this report, we used deregressed breeding values as response variables for a genome-wide association study. Bulls (5,334 Danish Holstein, 4,237 Nordic Red Dairy Cattle, and 1,180 Danish Jersey) with deregressed estimated breeding values were genotyped with the Illumina Bovine 54k single nucleotide polymorphism (SNP) genotyping array. Genotypes were imputed to whole-genome sequence variants, and then 22,751,039 SNP on 29 autosomes were used for an association analysis. A modified linear mixed-model approach (efficient mixed-model association eXpedited, EMMAX) and a linear mixed model were used for association analysis. We identified 5 (3,854 SNP), 3 (13,642 SNP), and 0 quantitative trait locus (QTL) regions associated with the FLD index in Danish Holstein, Nordic Red Dairy Cattle, and Danish Jersey populations, respectively. We did not identify any QTL that were common among the 3 breeds. In a meta-analysis of the 3 breeds, 4 QTL regions were significant, but no additional QTL region was identified compared with within-breed analyses. Comparison between top SNP locations within these QTL regions and known genes suggested that RASGRP1, LCORL, MOS, and MITF may be candidate genes for FLD in dairy cattle., (Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Claw disorders affect cow welfare and profitability of farms. Not only claw disorders but also the need for trimming, known as trimming status, has been shown to be heritable. Limited knowledge is available on whether claw health traits (claw disorders and trimming status) are genetically the same trait in different parities, lactation stages, or in herds with low or high frequency of claw disorders. The aim of the current study was to estimate frequencies, heritabilities, and genetic correlations of claw health traits measured in different parities (first vs. later parities), in different lactation stages (early vs. late lactation), and in herds with different frequencies of claw disorders (low vs. high frequency). Analyses revealed that heritabilities measured in different parities, lactation stages, or herds with different trait frequencies are similar for most claw health traits. Also, genetic correlations (rg) for most claw health traits were not found to be different from unity for traits in different parities, lactation stages, or herds with different trait frequencies. Sole hemorrhage and infectious lesions were genetically different traits in first or later parities (rg=0.29±0.31 and 0.66±0.15, respectively). White line separation and infectious lesions were genetically different in early and late lactation (rg=0.53±0.20 and 0.69±0.13, respectively), and sole ulcer was genetically different in herds with low or high frequency of sole ulcer (rg=0.75±0.14). In our analysis, we did not find convincing evidence to supports the use of multiple trait models for the analysis of claw health traits treating them as different traits in different parities, lactation stages, and herds with different claw disorder frequency., (Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

The aim of this study was to evaluate whether the predictive correlation of genomic breeding values (GEBV) for claw disorders increased by including genetically correlated traits as additional information in the analyses. Predictive correlations of GEBV for claw disorders were calculated based on claw disorders only and by analyzing claw disorders together with genetically correlated foot and leg conformation traits. The claw disorders analyzed were corkscrew claw (CSC); infectious claw disorder, including dermatitis, heel horn erosion, and interdigital phlegmon; and laminitis-related claw disorder, including sole ulcer, white line disorder, and hemorrhage of sole and white line. The foot and leg conformation traits included were hoof quality, foot angle, rear leg rear view new, and rear leg rear view old. The data consisted of 183,728 daughters with claw health records and 421,319 daughters with foot and leg conformation scores. A 25K/54K single nucleotide polymorphism (SNP) data set containing 48,249 SNP was available for the analyses. The number of genotyped sires with daughter information in the analyses was 1,093 including claw disorders and 3,111 including claw disorders and foot and leg conformation traits. Predictive correlations of GEBV for CSC, infectious claw disorder, and laminitis-related claw disorder were calculated from a 10-fold cross-validation and from an additional validation set including the youngest sires. Only sires having daughters with claw health records were in the validation sets, thus increasing the reference population when adding foot and leg conformation traits. The results showed marginal improvement in the predictive correlation of GEBV for CSC when including hoof quality and foot angle, both in 10-fold cross-validation (from 0.35 to 0.37) and in the validation including the youngest sires (from 0.38 to 0.49). For infectious claw disorder and laminitis-related claw disorder, including foot and leg conformation traits had no effect on the predictive correlation of GEBV. Claw disorders are novel traits with a limited amount of historical data and, therefore, a small reference population. Increasing the reference population by including sires with daughter information on foot and leg conformation traits had small effect on the predictive correlation of GEBV. However, the small increase in predictive correlation of GEBV for CSC shows a possible gain when including moderate to high genetically correlated traits., (Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Hoof lesions contributing to lameness are crucial economic factors that hinder the profitability of dairy enterprises. Producer-recorded hoof lesions data of US Holsteins were categorized into infectious (abscess, digital and interdigital dermatitis, heel erosion, and foot rot) and noninfectious (korn, corkscrew, sole and toe ulcer, sole hemorrhage, white line separation, fissures, thin soles, and upper leg lesions) categories of hoof lesions. Pedigree- and genomic-based univariate analyses were conducted to estimate the variance components and heritability of infectious and noninfectious hoof lesions. A threshold sire model was used with fixed effects of year-seasons and random effects of herd and sire. For genomic-based analysis, a single-step procedure was conducted, incorporating H matrix to estimate genomic variance components and heritability for hoof lesions. The pedigree-based analysis produced heritability estimates of 0.11 (±0.05) for infectious hoof lesions and 0.08 (±0.05) for noninfectious hoof lesions. The single-step genomic analysis produced heritability estimates of 0.14 (±0.06) for infectious hoof lesions and 0.12 (±0.08) for noninfectious hoof lesions. Approximated genetic correlations between hoof lesion traits and hoof type traits along with productive life and net merit were all low and ranged between -0.25 and 0.14. Sire reliabilities increased, on average, by 0.24 and 0.18 for infectious and noninfectious hoof lesions, respectively, with incorporation of genomic data., (Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Performing a genome-wide association study (GWAS) might add to a better understanding of the development of claw disorders and the need for trimming. Therefore, the aim of the current study was to perform a GWAS on claw disorders and trimming status and to validate the results for claw disorders based on an independent data set. Data consisted of 20,474 cows with phenotypes for claw disorders and 50,238 cows with phenotypes for trimming status. Recorded claw disorders used in the current study were double sole (DS), interdigital hyperplasia (IH), sole hemorrhage (SH), sole ulcer (SU), white line separation (WLS), a combination of infectious claw disorders consisting of (inter-)digital dermatitis and heel erosion, and a combination of laminitis-related claw disorders (DS, SH, SU, and WLS). Of the cows with phenotypes for claw disorders, 1,771 cows were genotyped and these cow data were used for the GWAS on claw disorders. A SNP was considered significant when the false discovery rate≤0.05 and suggestive when the false discovery rate≤0.20. An independent data set of 185 genotyped bulls having at least 5 daughters with phenotypes (6,824 daughters in total) for claw disorders was used to validate significant and suggestive SNP detected based on the cow data. To analyze the trait "trimming status" (i.e., the need for claw trimming), a data set with 327 genotyped bulls having at least 5 daughters with phenotypes (18,525 daughters in total) was used. Based on the cow data, in total 10 significant and 45 suggestive SNP were detected for claw disorders. The 10 significant SNP were associated with SU, and mainly located on BTA8. The suggestive SNP were associated with DS, IH, SU, and laminitis-related claw disorders. Three of the suggestive SNP were validated in the data set of 185 bulls, and were located on BTA13, BTA14, and BTA17. For infectious claw disorders, SH, and WLS, no significant or suggestive SNP associations were detected. For trimming status, 1 significant and 1 suggestive SNP were detected, both located close to each other on BTA15. Some significant and suggestive SNP were located close to SNP detected in studies on feet and leg conformation traits. Genes with major effects could not be detected and SNP associations were spread across the genome, indicating that many SNP, each explaining a small proportion of the genetic variance, influence claw disorders. Therefore, to reduce the incidence of claw disorders by breeding, genomic selection is a promising approach., (Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Background: Clear cell sarcoma (CCS) of soft tissue is a rare soft tissue sarcoma with melanocytic differentiation and shares morphologic, immunohistochemical, ultrastructural, and molecular features with malignant melanoma (MM). Because the prognosis of CCS is much different from MM, it is important to distinguish each other by selective method. CCS is well-recognized as having the t(12;22)(q13;q12) translocation, on the other hand MM is not. Therefore, detecting Ewing sarcoma region 1 (ESWR1) gene rearrangement can serve as a crucial diagnostic determinant., Methods: Biopsy was taken from a 52-year-old man who reported a 3-year history of a gradually enlarging nodule on the sole of his left foot. Routine and special stains for melanocytic markers and fluorescence in situ hybridization (FISH) evaluation using dual color break-apart rearrangement probes specific for ESWR1 was performed for formalin-fixed tissue., Results: Neoplastic cells expressed diffuse but strong positivity for HMB45 and S100 but not for Melan-A. Dual color, break-apart interphase FISH revealed EWS(22q12) gene rearrangements in CCS tumor cells., Conclusion: Fluorescence in situ hybridization evaluation using ESWR1 gene probe for CCS sharing clinical and histopathological characteristics with MM is a valuable tool to distinguish each other., (© 2014 The International Society of Dermatology.)

The aim of the present study was to infer daily genetic relationships between the selected claw disorders digital dermatitis, sole ulcer (SU), and interdigital hyperplasia (IH) and protein yield and the udder health indicator somatic cell score (SCS). Data were from 26,651 Holstein cows kept in 15 selected large-scale herds located in the region of Thuringia in the eastern part of Germany. Herds are characterized by organized data recording for novel health traits, and for the present study, claw disorders from the years 2008 to 2012 were used. A longitudinal and binary health data structure was created by assigning claw disorders to adjacent official test days. No entry of a claw disorder within a given interval of approximately 30 d implied a score of 0 (healthy), and otherwise, a score of 1 (diseased). Threshold random regression models (RRM) were applied to binary health data, and linear RRM to Gaussian-distributed protein yield and SCS. Genetic correlations between protein yield and SCS for identical days in milk (DIM) only revealed a tendency for genetic antagonisms between DIM 40 and DIM 180, with a maximal genetic correlation (rg) of 0.14 at DIM 100. With regard to protein yield and claw disorders, the largest and moderate values of rg (~0.30), indicating a genetic antagonism between productivity and claw health, were found when correlating protein yield from DIM 300 with SU from DIM 160. Especially for SU and protein yield, time-lagged relationships were more pronounced than genetic relationships from the same test days. Genetic correlations between IH and protein yield were favorable and negative from calving to DIM 300. Generally, on the genetic scale, we found heterogeneous associations between protein yield and claw disorders (i.e., different rg at identical test days for different claw disorders, and also an alteration of rg for identical traits at different DIM). The SCS measured at d 20, 160, and 300 was genetically positively correlated with SU over the whole trajectory of 365 d, indicating a common genetic background for claw and udder health. A maximal value of 0.36 was found for the rg between SCS from d 300 and SU early in lactation. Additionally, a recursive effect was observed (i.e., rg=0.26 between SCS from d 20 and SU from d 340). Genetic correlations between SCS and IH, and between SCS and digital dermatitis, were close to zero and partly negative during lactation. Results showed the feasibility of threshold RRM applications to binary claw health data, and a changing genetic background in the course of lactation. From a practical perspective, and with regard to the herds used in this study, continuation of breeding on productivity will have different effects on incidences of different claw disorders, with the highest susceptibility to SU., (Copyright © 2014 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

The aim of this study was to estimate genetic correlations between claw disorders and feet and leg conformation traits in Norwegian Red cows. A total of 188,928 cows with claw health status recorded at claw trimming from 2004 to September 2013 and 210,789 first-lactation cows with feet and leg conformation scores from 2001 to September 2013 were included in the analyses. Traits describing claw health were corkscrew claw, infectious claw disorders (dermatitis, heel horn erosion, and interdigital phlegmon), and laminitis-related claw disorders (sole ulcer, white line disorder, and hemorrhage of sole and white line). The feet and leg conformation traits were rear leg rear view (new and old definition), rear leg side view, foot angle, and hoof quality. Feet and leg conformation traits were scored linearly from 1 to 9, with optimum scores depending on the trait. Claw disorders were defined as binary (0/1) traits for each lactation. Threshold sire models were used to model claw disorders, whereas the feet and leg conformation traits were described by linear sire models. Three multivariate analyses were performed, each including the 5 feet and leg conformation traits and 1 of the 3 claw disorders at a time. Posterior means of heritability of liability of claw disorders ranged from 0.10 to 0.20 and heritabilities of feet and leg conformation traits ranged from 0.04 to 0.11. Posterior standard deviation of heritability was ≤0.01 for all traits. Genetic correlations between claw disorders and feet and leg conformation traits were all low or moderate, except between corkscrew claw and hoof quality (-0.86), which are supposed to measure the same trait. The genetic correlations between rear leg rear view (new) and infectious claw disorders (-0.20) and laminitis-related claw disorders (0.26), and between hoof quality and laminitis-related claw disorders (-0.33) were moderate. Eight of the 15 genetic correlations between claw disorders and feet and leg conformation traits had 0 included in the 95% highest posterior density interval. These results imply that selection for feet and leg conformation is not an efficient approach to genetically improve claw health in Norwegian Red cattle., (Copyright © 2014 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Perineurioma is an uncommon benign peripheral nerve sheath tumor with advanced perineurial differentiation. Two distinct subtypes are recognized: intraneural and soft tissue. We herein present a unique case of soft tissue perineurioma in the right foot of a 43-year-old man. Radiographs showed a non-specific soft tissue mass. On computed tomography scan, the mass was iso- to slightly hypodense relative to muscle. On T1- and T2-weighted images, the mass exhibited iso- to slightly low signal intensity relative to muscle with foci of high signal intensity. Slight contrast enhancement was noted on enhanced T1-weighted images with fat suppression. A marginal excision of the tumor was performed and histopathologic examination confirmed the diagnosis of soft tissue perineurioma. The clinicopathologic, radiologic, and cytogenetic findings are described, and the relevant literature is reviewed.

The aim of this study was to estimate genetic correlations between milk yield, somatic cell score (SCS), mastitis, and claw and leg disorders (CLDs) during first lactation in Holstein cows by using a threshold-linear random regression test-day model. We used daily records of milk, fat and protein yields; somatic cell count (SCC); and mastitis and CLD incidences from 46 771 first-lactation Holstein cows in Hokkaido, Japan, that calved between 2000 and 2009. A threshold animal model for binary records (mastitis and CLDs) and linear animal model for yield traits were applied in our multiple trait analysis. For both liabilities and yield traits, additive genetic effects were used as random regression on cubic Legendre polynomials of days on milk. The highest positive genetic correlations between yields and disease incidences (0.36 for milk and mastitis, 0.56 for fat and mastitis, 0.24 for protein and mastitis, 0.32 for milk and CLD, 0.44 for fat and CLD and 0.31 for protein and CLD) were estimated at about the time of peak milk yield (36 to 65 days in milk). Selection focused on early lactation yield may therefore increase the risk of mastitis and CLDs. The positive genetic correlations of SCS with mastitis or CLD incidence imply that selection to reduce SCS in the early stages of lactation would decrease the incidence of both mastitis and CLD.

Equine laminitis, a disease of the lamellar structure of the horse's hoof, can be incited by numerous factors that include inflammatory and metabolic aetiologies. However, the role of inflammation in hyperinsulinaemic laminitis has not been adequately defined. Toll-like receptor (TLR) activation results in up-regulation of inflammatory pathways and the release of pro-inflammatory cytokines, including interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α), and may be a pathogenic factor in laminitis. The aim of this study was to determine whether TLR4 expression and subsequent pro-inflammatory cytokine production is increased in lamellae and skeletal muscle during equine hyperinsulinaemia. Standardbred horses were treated with either a prolonged, euglycaemic hyperinsulinaemic clamp (p-EHC) or a prolonged, glucose infusion (p-GI), which induced marked and moderate hyperinsulinaemia, respectively. Age-matched control horses were treated simultaneously with a balanced electrolyte solution. Treated horses developed clinical (p-EHC) or subclinical (p-GI) laminitis, whereas controls did not. Skeletal muscle and lamellar protein extracts were analysed by Western blotting for TLR4, IL-6, TNF-α and suppressor of cytokine signalling 3 (SOCS3) expression. Lamellar protein expression of TLR4 and TNF-α, but not IL-6, was increased by the p-EHC, compared to control horses. A significant positive correlation was found between lamellar TLR4 and SOCS3. Skeletal muscle protein expression of TLR4 signalling parameters did not differ between control and p-EHC-treated horses. Similarly, the p-GI did not result in up-regulation of lamellar protein expression of any parameter. The results suggest that insulin-sensitive tissues may not accurately reflect lamellar pathology during hyperinsulinaemia. While TLR4 is present in the lamellae, its activation appears unlikely to contribute significantly to the developmental pathogenesis of hyperinsulinaemic laminitis. However, inflammation may have a role to play in the later stages (e.g., repair or remodelling) of the disease., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Acral melanoma (AM) is still one of the most poorly studied melanomas. It generally presents beyond the fifth decade of life and usually is a BRAF wild-type melanoma., Objective: To report the first cases of multiple primary AM in Caucasians., Methods: Clinical, dermoscopic, pathological and molecular profiles., Results: A healthy 34- year-old male presented an in situ subungual melanoma on his finger, and 22 months later a fast-growing nodular melanoma appeared in an existing nevus on the sole. Both melanomas carried the V600E BRAF mutation. A 19-year-old female patient presented 2 in situ melanomas on different parts of her left foot within a 6-year period of time. The patients have neither familiar melanoma nor germline mutations in CDKN2A/CDK4 genes., Conclusion: Multiple AM in Caucasians is very rare. BRAF mutations are possible, especially in a high-risk set of patients with multiple nevi. Specific acral examination must be recommended since AM still suffers delayed detection., (© 2014 S. Karger AG, Basel.)

Random regression threshold animal models were applied to binary longitudinal claw disorder data for studying genetic parameters of all claw disorders (ACD), as well as to claw disorders divided into different categories: non-purulent claw disorders (NPCD), purulent claw disorders (PCD), dermatitis digitalis (DD), sole ulcer (SU), phlegmona (PH), laminitis (LAM) and interdigital hyperplasia (IH) in the course of lactation. Claw disorder data were obtained from 26,651 Holstein cows kept in 15 large-scale contract herds in the region of Thuringia over a period of 5 years from 2007 to 2012. If a cow had one or more entries of the same disorder, for example, sole ulcer, within an interval of 30 days, she was scored with a '1', and otherwise, she received a score of '0' for healthy. Heritabilities for the same disorder were relatively stable between DIM 50 and DIM 300, but they tended to increase in early and late lactation. Highest heritabilities in the range from 0.20 to 0.34 were estimated for IH, and lowest heritabilities were realized for LAM (~ 0.05). Genetic correlations for same traits between different DIMs were high for adjacent test days, but close to zero for distant test days. The relationship between the sire EBVs for claw disorders and official sire EBVs for the type traits 'foot angle' was slightly antagonistic with correlation coefficients in the range from 0.05 (DD) to 0.33 (PH). Correlations between lactation EBVs for hock quality, rear leg rear view and the feet and leg index with EBVs for claw disorders were slightly favourable and ranged between -0.01 (rear leg rear view correlated with SU) and -0.43 (hock quality correlated with PH). Regarding daily EBVs for claw disorders, the strongest correlation coefficient was of value -0.46 (LAM early in lactation correlated with the feet and leg index). Genetic parameters from the random regression model were verified by applying a single-trait repeatability model. Correlation coefficients between lactation EBVs from the random regression model and lactation EBVs from the repeatability model for the same claw disorder were close to 1. Correlations were lower between EBVs from single test days and lactation EBVs from the repeatability models, with a minimal value of 0.58 for PCD measured at day 20., (© 2013 Blackwell Verlag GmbH.)

Tissue sensitisation and chronic pain have been described in chronic-active laminitis in the horse, making treatment of such cases difficult. Purinergic P2X receptors are linked to chronic pain and inflammation. The aim of this study was to examine the expression of purinergic P2X receptor subtypes 1, 2, 3 and 7 in the hoof, palmar digital vessels and nerve, dorsal root ganglia and spinal cord in horses with chronic-active laminitis (n=5) compared to non-laminitic horses (n=5). Immunohistochemical analysis was performed on tissue sections using antibodies against P2X receptor subtypes 1-3 and 7. In horses with laminitis, there was a reduction in the thickness of the tunica media layer of the palmar digital vein as a proportion of the whole vessel diameter (0.48±0.05) compared to the non-laminitic group (0.57±0.04; P=0.02). P2X receptor subtype 3 was expressed in the smooth muscle layer (tunica media) of the palmar digital artery of horses with laminitis, but was absent in horses without laminitis. There was strong expression of P2X receptor subtype 7 in the proliferating, partially keratinised, epidermal cells of the secondary epidermal lamellae in the hooves of horses with laminitis, but no immunopositivity in horses without laminitis., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Although clinical evidence of endotoxemia has been associated with the development of acute laminitis in hospitalized horses with gastrointestinal diseases and endotoxins have been detected in the circulation of horses with experimentally-induced laminitis, it is unclear what role, if any, endotoxins have play the pathogenesis of the disease. Therefore, in the present study we compared the effects of endotoxin infusion to that of intra-gastric administration of mixed carbohydrate (CHO) on clinical signs of laminitis, plasma concentrations of TNF-α and IL-10, and laminar tissue expression of 20 genes associated with inflammation. Horses were divided into 4 groups: Control (water placebo, n=7), endotoxin infusion (LPS, n=6), CHO/Developmental (30% decrease in central venous pressure, n=6) and CHO/Lame (Obel grade I laminitis, n=7). Horses in the LPS group developed clinical signs consistent with systemic inflammation, had rapid increases in plasma concentrations of both TNF-α and IL-10, and leukopenia, but did not have any changes in laminar tissue expression of the genes associated with inflammation. In contrast, horses administered CHO developed clinical signs consistent with systemic inflammation, had more delayed increases in TNF-α, IL-10 and total leukocyte counts, and had marked increases in laminar tissue expression of the genes associated with inflammation. Only the horses administered CHO developed clinical signs of laminitis, providing additional credence to the concept that factors other than endotoxin are responsible for the changes in laminar tissue gene expression that occur during the development of acute equine laminitis., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Digital dermatitis is a painful foot disease compromising welfare in dairy cattle. The disease has a complex multibacterial aetiology, but little is known about its pathogenesis. In this study, gene expression in skin biopsies from five bovine digital dermatitis lesions and five healthy bovine feet was compared using RNA-Seq technology. Differential gene expression was determined after mapping transcripts to the Btau 4.0 genome. Pathway analysis identified gene networks involving differentially expressed transcripts. Bovine digital dermatitis lesions had increased expression of mRNA for α2-macroglobulin-like 1, a protein potentially involved in bacterial immune evasion and bacterial survival. There was increased expression of keratin 6A and interleukin 1β mRNA in bovine digital dermatitis lesions, but reduced expression of most other keratin and keratin-associated genes. There was little evidence of local immune reactions to the bacterial infection present in lesions., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Claw disorders are important traits relevant to dairy cattle breeding from an economical and welfare point of view. Selection for reduced claw disorders can be based on hoof trimmer records. Typically, not all cows in a herd are trimmed. Our objectives were to estimate heritabilities and genetic correlations for claw disorders and investigate the effect of selecting cows for trimming. The data set contained 50,238 cows, of which 20,474 cows had at least one claw trimming record, with a total of 29,994 records. Six claw trimmers scored 14 different claw disorders: abscess (AB), corkscrew claw (CC), (inter-)digital dermatitis or heel erosion (DER), double sole (DS), hardship groove (HG), interdigital hyperplasia (IH), interdigital phlegmon (IP), sand crack (SC), super-foul (SF), sole hemorrhage (SH), sole injury (SI), sole ulcer (SU), white line separation (WLS), yellow discoloration of the sole (YD), and a combined claw disorder trait. Frequencies of the claw disorders for trimmed cows ranged from 0.1% (CC, YD, HG) to 23.8% (DER). More than half of the cows scored had at least one claw disorder. Heritability on the observed scale ranged from 0.02 (DS, SH) to 0.14 (IH) and on the underlying scale from 0.05 to 0.43 in trimmed cows. Genetic correlations between laminitis-related claw disorders were moderate to high, and the same was found for hygiene-related claw disorders. The effect of selecting cows for trimming was first investigated by including untrimmed cows in the analyses and assuming they were not affected by claw disorders. Heritabilities on the underlying scale showed only minor changes. Second, different subsets of the data were created based on the percentage of trimmed cows in the herd. Heritabilities for IH, DER, and SU tended to decrease when a higher percentage of cows in the herd were trimmed. Finally, a bivariate model with a claw disorder and the trait "trimming status" was used, but heritabilities were similar. Heritability for trimming status was relatively high (0.09). Genetic correlations of trimming status with claw disorders were generally moderate to high. To conclude, the effect of selecting cows for trimming on the heritability for claw disorders is negligible. Selecting herds with a high fraction of cows being trimmed tended to decrease heritability. Trimming status, as such, is a heritable trait and correlated with claw disorders and is therefore an interesting trait to include in the genetic evaluation., (Copyright © 2013 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

The purpose of this study was to concurrently estimate the effect of different digital dermatitis (DD) treatment regimens and herd management practices on the occurrence of a new DD lesion. A controlled clinical trial was conducted and involved 4678 dairy cows from 52 French dairy farms where DD was endemic. Farms were allocated by minimisation to one of 4 treatment regimens, varying through the mode (footbath or collective spraying) and the frequency of application (2 days every 4 weeks or fortnightly). They were visited 7 times every 4 weeks by 14 trained investigators. Frailty Cox proportional hazards models were used to estimate the relative effect of potential risk factors and treatment practices on the time until the first occurrence of a DD lesion. At herd level, high initial DD prevalence strongly increased the risk for DD occurrence (HR=1.93, CI 1.23-3.04), as well as absence of hoof-trimming (HR=1.75, CI 1.36-2.27) and poor leg cleanliness (HR=2.44, CI 1.80-3.31). At animal level, Holstein breed (HR=1.92, CI 1.35-3.57) and high-productive cows (HR=1.26, CI 1.01-1.56) were identified to be at higher risk for DD compared to Normande breed and low-productive cows, respectively. Compared to individual topical antibiotic treatments alone, collective treatments tended to decrease the risk of DD occurrence only when applied over 2 days at least every fortnight (HR range=0.64-0.73)., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Campylobacter spp. are frequently carried by poultry, but they are not believed to cause significant disease in these animals. Modern poultry breeds have been selected to grow rapidly under intensive conditions, but recently, consumers have moved toward purchasing birds produced in higher welfare, free-range or organic systems. Birds reared in these systems tend to be a slower growing breed and are fed a different diet. Birds reared in such systems are stocked at a lower density compared with the standard conventional broilers, and they have access to environmental enrichment, such as perches. In previous research, these slower growing birds have been shown to have different levels of Campylobacter carriage in commercial rearing conditions, but the reasons for, and effect of, these different levels are unknown; is it the bird breed, diet, or environmental conditions? In this study, experimental flocks of fast- and slow-growing breeds of broiler chickens were reared to a standard commercial slaughter weight, with their weight gain being measured during the growing period. At 21 days, birds were either infected with Campylobacter jejuni or given a placebo as control. Cohorts of birds were euthanatized at various intervals, and samples were taken for examination for Campylobacter. The fast-growing birds gained weight more rapidly than the slow-growing birds. By 2 days postinfection (dpi), C. jejuni was detected in the caeca and by enrichment from the liver and spleen samples from both breeds of birds. Low-level colonization persisted in the spleen and liver samples but was undetectable by 28 dpi. Fast- and slow-growing birds did not show detectably different levels of Campylobacter carriage. Infection with C. jejuni affected the incidence of hock marks and pododermatitis in both breeds of birds, but the differences were greater with the fast-growing breed compared with the uninfected control birds. In addition, the incidence of pododermatitis was significantly higher in Campylobacter-positive fast-growing birds than in their slower-growing counterparts. The results show that infection with Campylobacter can have an indirect welfare effect on birds via increased incidence of hock marks and pododermatitis.

The aims of the present study were (1) to investigate the repeatability of foot lesions [sole ulcers (SU), white line disease (WLD), and digital dermatitis (DD)] across multiple lactations, (2) to evaluate the effect of foot lesions on cow survivability and milk production across multiple lactations, and (3) to investigate the role of sire predicted transmitting ability (PTA) for conformation and production traits as risk factors for the incidence of SU, WLD, and DD. Data were collected from a dairy farm located in Cayuga County, New York. A total of 11,442 cows having first calved during the period from May 13, 2001, to March 26, 2012, were enrolled in the study. Data regarding sire genetic evaluations were obtained from DairyBulls.com (http://www.DairyBulls.com). Lameness was detected and treated and lesions were recorded into a dairy record database (DairyCOMP 305; Valley Agricultural Software, Tulare, CA) by trained farm employees. All demographic, production, and foot lesion data were extracted from DairyCOMP 305 and merged with the sires' PTA information to form a unique database. Mixed logistic regression, general linear mixed, and multivariable Cox proportional hazards models were used to analyze the data. Sole ulcers, WLD, and DD incidence was significantly higher for cows affected with SU, WLD, or DD in previous lactations. Cows affected with WLD or DD during the first lactation had significantly higher WLD or DD incidence during the second and the third lactations. Cows affected with SU or WLD during their first lactation had significantly lower milk production during the second lactation and cows diagnosed with SU, WLD, or DD during their second lactation had higher second-lactation mature-equivalent 305-d milk yield. Sire PTA for milk and protein yield were significantly associated with the incidence of SU, WLD, and DD and incidence of SU and WLD, respectively. Sire PTA for several conformation traits were found to be associated with SU, WLD, and DD incidence. Cows that were affected with SU or WLD during their first lactation were at 1.18 or 1.43 higher hazard of culling than unaffected cows, respectively. In summary, we conclude that SU, WLD, and DD are highly repeatable across lactations and that high genetic merit for milk and protein production as well as milk production (phenotype) were significantly associated with higher risk of SU, WLD, and DD. Additionally, sire PTA for several conformation traits were significantly associated with their daughters' foot lesion incidence., (Copyright © 2013 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

1. An experiment was conducted to compare the development and clinical significance of foot pad dermatitis (FPD) in 4 lines of turkey poults kept on wet or dry litter for 6 d. 2. Turkeys kept on wet litter were less active and expressed fewer unique sequences of behaviour than poults kept on dry litter, suggesting that high FPD scores are associated with pain during movement. 3. Heavier lines of turkeys had higher mean foot scores that developed earlier, than those in a traditional line, but the effect was relatively small and not statistically significant after 6 d, whereas there were large differences between individuals within line. 4. Body weight gains were greater, and feed intake was lower in the commercial lines kept on dry litter compared with wet litter. There were no differences in water intake between poults kept on wet or dry litter.

Hoof disorders are a major welfare problem in dairy farming and result in considerable costs to the farms. In this study, the data from 24,685 Holstein cows from 1,337 herds between 2003 and 2010 were used to evaluate the correlation between hoof disorders and feet and leg conformation traits using a binomial mixed model for hoof disorders in Finnish Holstein cows. Heritabilities and correlations among the hoof disorders and feet and leg conformation traits were also estimated. Heritability estimates from univariate logistic models for 8 hoof disorders ranged from 0.02 (sole hemorrhage, chronic laminitis, and heel horn erosion) to 0.13 (digital dermatitis). Heritability estimates using the liability scale from the multivariate linear model for the 5 most-common hoof disorders ranged from 0.02 (sole hemorrhage) to 0.11 (corkscrew hoof). Estimates of heritability for feet and leg conformation traits from the multivariate linear model ranged from 0.10 (rear leg rear view) to 0.19 (rear leg side view). Genetic correlations among hoof disorders ranged from -0.36 to 0.57, and genetic correlations among feet and leg conformation traits ranged from -0.30 to 0.83. The genetic correlations between hoof disorders and feet and leg conformation traits ranged from -0.51 to 0.45. Most of the genetic correlations between various hoof disorders and feet and leg conformation traits were low and most were nonsignificantly different from zero. This indicates that indirect selection for better hoof health using feet and leg conformation traits as indicator traits is not efficient in the Finnish Holstein breed., (Copyright © 2013 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)