Heritabilities of a population of German Shepherd Dogs with a complex interrelationship structure

Summary Heritabilities of conformation characteristics of a German Shepherd Dog population were estimated. The interrelationship structure was complex, with more than one generation, some related parents, and some diallel crossings. These problems were overcome by a simple, practical method of estimation of heritability. Relatively high heritability estimates were obtained.     

Genome-Wide Analysis in German Shepherd Dogs Reveals Association of a Locus on CFA 27 with Atopic Dermatitis

Humans and dogs are both affected by the allergic skin disease atopic dermatitis (AD), caused by an interaction between genetic and environmental factors. The German shepherd dog (GSD) is a high-risk breed for canine AD (CAD). In this study, we used a Swedish cohort of GSDs as a model for human AD. Serum IgA levels are known to be lower in GSDs compared to other breeds. We detected significantly lower IgA levels in the CAD cases compared to controls (p = 1.1×10⁻⁵) in our study population. We also detected a separation within the GSD cohort, where dogs could be grouped into two different subpopulations. Disease prevalence differed significantly between the subpopulations contributing to population stratification (λ = 1.3), which was successfully corrected for using a mixed model approach. A genome-wide association analysis of CAD was performed (n _cases = 91, n _controls = 88). IgA levels were included in the model, due to the high correlation between CAD and low IgA levels. In addition, we detected a correlation between IgA levels and the age at the time of sampling (corr = 0.42, p = 3.0×10⁻⁹), thus age was included in the model. A genome-wide significant association was detected on chromosome 27 (p_raw = 3.1×10⁻⁷, p_genome = 0.03). The total associated region was defined as a ∼1.5-Mb-long haplotype including eight genes. Through targeted re-sequencing and additional genotyping of a subset of identified SNPs, we defined 11 smaller haplotype blocks within the associated region. Two blocks showed the strongest association to CAD. The ∼209-kb region, defined by the two blocks, harbors only the PKP2 gene, encoding Plakophilin 2 expressed in the desmosomes and important for skin structure. Our results may yield further insight into the genetics behind both canine and human AD.     

Polymorphism in the tyrosine hydroxylase (TH) gene is associated with activity-impulsivity in German Shepherd Dogs

We investigated the association between repeat polymorphism in intron 4 of the tyrosine hydroxylase (TH) gene and two personality traits, activity-impulsivity and inattention, in German Shepherd Dogs. The behaviour of 104 dogs was characterized by two instruments: (1) the previously validated Dog-Attention Deficit Hyperactivity Disorder Rating Scale (Dog-ADHD RS) filled in by the dog owners and (2) the newly developed Activity-impulsivity Behavioural Scale (AIBS) containing four subtests, scored by the experimenters. Internal consistency, inter-observer reliability, test-retest reliability and convergent validity were demonstrated for AIBS.Dogs possessing at least one short allele were proved to be more active-impulsive by both instruments, compared to dogs carrying two copies of the long allele (activity-impulsivity scale of Dog-ADHD RS: p = 0.007; AIBS: p = 0.023). The results have some potential to support human studies; however, further research should reveal the molecular function of the TH gene variants, and look for the effect in more breeds.     

Estimated Breeding Values for Canine Hip Dysplasia Radiographic Traits in a Cohort of Australian German Shepherd Dogs

Canine hip dysplasia (CHD) is a serious and common musculoskeletal disease of pedigree dogs and therefore represents both an important welfare concern and an imperative breeding priority. The typical heritability estimates for radiographic CHD traits suggest that the accuracy of breeding dog selection could be substantially improved by the use of estimated breeding values (EBVs) in place of selection based on phenotypes of individuals. The British Veterinary Association/Kennel Club scoring method is a complex measure composed of nine bilateral ordinal traits, intended to evaluate both early and late dysplastic changes. However, the ordinal nature of the traits may represent a technical challenge for calculation of EBVs using linear methods. The purpose of the current study was to calculate EBVs of British Veterinary Association/Kennel Club traits in the Australian population of German Shepherd Dogs, using linear (both as individual traits and a summed phenotype), binary and ordinal methods to determine the optimal method for EBV calculation. Ordinal EBVs correlated well with linear EBVs (r = 0.90–0.99) and somewhat well with EBVs for the sum of the individual traits (r = 0.58–0.92). Correlation of ordinal and binary EBVs varied widely (r = 0.24–0.99) depending on the trait and cut-point considered. The ordinal EBVs have increased accuracy (0.48–0.69) of selection compared with accuracies from individual phenotype-based selection (0.40–0.52). Despite the high correlations between linear and ordinal EBVs, the underlying relationship between EBVs calculated by the two methods was not always linear, leading us to suggest that ordinal models should be used wherever possible. As the population of German Shepherd Dogs which was studied was purportedly under selection for the traits studied, we examined the EBVs for evidence of a genetic trend in these traits and found substantial genetic improvement over time. This study suggests the use of ordinal EBVs could increase the rate of genetic improvement in this population.     

Common and Distinct Clinical Features in Adult Patients with Anti-Aminoacyl-tRNA Synthetase Antibodies: Heterogeneity within the Syndrome

Objective

To identify similarities and differences in the clinical features of adult Japanese patients with individual anti-aminoacyl-tRNA synthetase antibodies (anti-ARS Abs).

Methods

This was a retrospective analysis of 166 adult Japanese patients with anti-ARS Abs detected by immunoprecipitation assays. These patients had visited Kanazawa University Hospital or collaborating medical centers from 2003 to 2009.

Results

Anti-ARS Ab specificity included anti-Jo-1 (36%), anti-EJ (23%), anti-PL-7 (18%), anti-PL-12 (11%), anti-KS (8%), and anti-OJ (5%). These anti-ARS Abs were mutually exclusive, except for one serum Ab that had both anti-PL-7 and PL-12 reactivity. Myositis was closely associated with anti-Jo-1, anti-EJ, and anti-PL-7, while interstitial lung disease (ILD) was correlated with all 6 anti-ARS Abs. Dermatomyositis (DM)-specific skin manifestations (heliotrope rash and Gottron’s sign) were frequently observed in patients with anti-Jo-1, anti-EJ, anti-PL-7, and anti-PL-12. Therefore, most clinical diagnoses were polymyositis or DM for anti-Jo-1, anti-EJ, and anti-PL-7; clinically amyopathic DM or ILD for anti-PL-12; and ILD for anti-KS and anti-OJ. Patients with anti-Jo-1, anti-EJ, and anti-PL-7 developed myositis later if they had ILD alone at the time of disease onset, and most patients with anti-ARS Abs eventually developed ILD if they did not have ILD at disease onset.

Conclusion

Patients with anti-ARS Abs are relatively homogeneous. However, the distribution and timing of myositis, ILD, and rashes differ among patients with individual anti-ARS Abs. Thus, identification of individual anti-ARS Abs is beneficial to define this rather homogeneous subset and to predict clinical outcomes within the “anti-synthetase syndrome.”     

食管鳞癌患者血清血管内皮生长因子与内皮抑素表达及其与临床病理特征的关系

目的:探讨食管鳞癌患者血清中血管内皮生长因子(VEGF)和内皮抑素(Endostatin)的表达及其与食管鳞癌临床病理特征和预后的关系。方法:采用ELISA法检测126例食管鳞癌患者和14例正常健康人血清VEGF及Endostatin表达水平。结果:126例食管鳞癌患者血清中VEGF(20.68±3.09)ug/L水平和Endostatin水平(4.96±1.72)ug/mL均显著高于正常健康人(3.82±6.28)μg/L和(1.60±0.37)μg/L(P<0.05),V/E比值也非常显著高于正常人。食管鳞癌患者血清中VEGF、endostatin水平以及V/E比值与其分化程度、P-TNM分期、病变长度、淋巴结转移状态等显著相关(P<0.01),与其年龄、性别、肿瘤部位、浸润深度等无明显关系(P>0.05)。食管鳞癌患者血清中VEGF与Endostatin表达呈非常显著正相关(r=0.594,P<0.01)。结论:食管鳞癌患者血清中VEGF、Endostatin水平升高,与食管鳞癌的恶性程度及肿瘤负荷密切相关,其两者的比值(V/E)对食管鳞癌患者预后、生物学行为评估具有重要意义。     

Identification and Validation of Quantitative Trait Loci (QTL) for Canine Hip Dysplasia (CHD) in German Shepherd Dogs

Canine hip dysplasia (CHD) is the most common hereditary skeletal disorder in dogs. To identify common alleles associated with CHD, we genotyped 96 German Shepherd Dogs affected by mild, moderate and severe CHD and 96 breed, sex, age and birth year matched controls using the Affymetrix canine high density SNP chip. A mixed linear model analysis identified five SNPs associated with CHD scores on dog chromosomes (CFA) 19, 24, 26 and 34. These five SNPs were validated in a by sex, age, birth year and coancestry stratified sample of 843 German Shepherd Dogs including 277 unaffected dogs and 566 CHD-affected dogs. Mean coancestry coefficients among and within cases and controls were <0.1%. Genotype effects of these SNPs explained 20–32% of the phenotypic variance of CHD in German Shepherd Dogs employed for validation. Genome-wide significance in the validation data set could be shown for each one CHD-associated SNP on CFA24, 26 and 34. These SNPs are located within or in close proximity of genes involved in bone formation and related through a joint network. The present study validated positional candidate genes within two previously known quantitative trait loci (QTL) and a novel QTL for CHD in German Shepherd Dogs.     

A case of Trypanosoma evansi in a German Shepherd dog in Vietnam

A 2.5-year-old male German Shepherd was presented to a private veterinary clinic in Hanoi, Vietnam showing anorexia, weakness, lethargy, reluctant to go for walks with a recent history of intermittent fever. Clinical examination of the dog showed pale mucous membrane, impaired eyesight, edema of the back legs. Complete blood count revealed severe anemia; red blood cell 3.8 × 10¹²/l, hemoglobin 8.7 g/dl, hematocrit 26.4%, associated with thrombocytopenia 145 × 10⁹/l. Biochemical analysis showed a moderate increase of alanine transaminase (150.7 UI/l) and alkaline phosphatase activities (266 UI/I) with mild hypoglycemia (71.46 mg/dl). Trypanosoma evansi was observed in Giemsa-stained blood smears under microscopic observation which was confirmed by PCR. This is the first report of canine trypanosomiasis caused by T. evansi in Vietnam.     

CD90在肝细胞肝癌组织中的表达及其与肝癌临床病理特征的关系

目的:探讨CD90在肝细胞肝癌(HCC)患者肿瘤组织中的表达及其与临床病理参数的关系,为HCC的临床治疗提供参考。方法:选择2014年3月-2015年3月在我院接受治疗的HCC患者80例,收集患者肿瘤组织及癌旁组织,另选择同期就诊的80例正常肝脏组织作为对照组。观察并比较CD90在肝癌组织、癌旁组织及正常肝脏组织中的表达情况。结果:CD90在肝癌组织、癌旁组织及正常肝脏组织中呈不同程度阳性表达(P0.05)。CD90在肝癌组织和癌旁组织中的表达显著高于正常肝脏组织,差异具有统计学意义(P0.05)。CD90在肝癌组织中的表达显著高于癌旁组织,差异具有统计学意义(P0.05)。CD90在HCC组织中的表达与肿瘤大小、肝内转移、TMN分期和病理分级有关(P0.05)。结论:CD90在肝癌组织中呈高表达,其表达水平与肝癌临床病理参数有关,可以作为HCC诊断、治疗及预后评估的参考指标。     

Clinical,Pathological, and Molecular Features of Lung Adenocarcinomas with AXL Expression

The receptor tyrosine kinase AXL is a member of the Tyro3-Axl-Mer receptor tyrosine kinase subfamily. AXL affects several cellular functions, including growth and migration. AXL aberration is reportedly a marker for poor prognosis and treatment resistance in various cancers. In this study, we analyzed clinical, pathological, and molecular features of AXL expression in lung adenocarcinomas (LADs). We examined 161 LAD specimens from patients who underwent pulmonary resections. When AXL protein expression was quantified (0, 1+, 2+, 3+) according to immunohistochemical staining intensity, results were 0: 35%; 1+: 20%; 2+: 37%; and 3+: 7% for the 161 samples. AXL expression status did not correlate with clinical features, including smoking status and pathological stage. However, patients whose specimens showed strong AXL expression (3+) had markedly poorer prognoses than other groups (P = 0.0033). Strong AXL expression was also significantly associated with downregulation of E-cadherin (P = 0.025) and CD44 (P = 0.0010). In addition, 9 of 12 specimens with strong AXL expression had driver gene mutations (6 with EGFR, 2 with KRAS, 1 with ALK). In conclusion, we found that strong AXL expression in surgically resected LADs was a predictor of poor prognosis. LADs with strong AXL expression were characterized by mesenchymal status, higher expression of stem-cell-like markers, and frequent driver gene mutations.     

Genetic Correlations among Canine Hip Dysplasia Radiographic Traits in a Cohort of Australian German Shepherd Dogs,and Implications for the Design of a More Effective Genetic Control Program

Canine hip dysplasia (CHD) is a common musculoskeletal disease in pedigree dog populations. It can cause severe pain and dysfunction which may require extensive medication and/or surgical treatment and often ultimately requires humane euthanasia. CHD has been found to be moderately heritable and, given its impact on welfare, should be considered an imperative breeding priority. The British Veterinary Association/Kennel Club scoring method is one of several measures used to assess the genetic propensity of potential breeding stock for dysplastic changes to the hips based on radiographic examination. It is a complex measure composed of nine ordinal traits, intended to evaluate both early and late dysplastic changes. It would be highly desirable if estimated breeding values (EBVs) for these nine traits were consolidated into a simpler, EBV-based, selection index more easily usable by breeders. A multivariate analysis on the phenotype scores from an Australian cohort of 13,124 German Shepherd Dogs (GSDs) returned genetic correlations between 0.48–0.97 for the nine traits which fell into two trait groups, Group 1 reflecting early changes (“laxity”) and Group 2 reflecting late changes (“osteoarthritis”). Principal components analysis of the ordinal EBVs suggested the same pattern, with strong differentiation between “laxity” and “osteoarthritis” traits in the second component. Taking account of all results, we recommend interim use of two selection indexes: the first being the average of ordinal EBVs for “laxity” traits and the second being the average of ordinal EBVs for “osteoarthritis” traits. The correlation between these two selection indexes (0.771–0.774) is sufficiently less than unity enabling the selection of dogs with different genetic propensity for laxity and for osteoarthritic CHD changes in GSDs; this may also be applicable in other breeds. Dogs with low propensity for severe osteoarthritic change in the presence of laxity may be of interest both in molecular research and breeding programs.     

发热伴血小板减少综合征患者血清中核蛋白抗体的动态变化

目的:观察新发传染病发热伴血小板减少综合征(SFTS)的病原体新型布尼亚病毒(SFTSV)核蛋白(NP)IgM和IgG型抗体在SFTS患者外周血中的变化规律,为疾病的早期诊断和发病机制的认识提供依据.方法:用ELISA方法检测28例SFTS患者不同病程阶段血清中NP特异性IgM、IgG抗体.结果:①28例SFTS患者中,IgM阳性检出率为89.3 ％(25/28),IgG阳性检出率为85.7 ％(24/28).②IgM和IgG均在发病5天后开始出现,随着病程延长血清中抗体水平逐渐上升,其峰值出现在发病2周左右.③死亡组患者的抗体检出时间迟于痊愈组患者,且抗体水平低下.结论:①在SFTSV感染早期,SFTS患者血清中NP特异性抗体IgG和IgM的变化趋势一致,NP特异性抗体IgG和IgM一样是SFTS早期诊断的重要指标.②因疾病严重而死亡的患者,抗体出现延迟、抗体水平低下可能与患者细胞免疫系统严重受损及多脏器功能障碍有关,致使机体体液免疫应答减退或应答无能.③抗体出现延迟且抗体水平低下可能是病情严重患者预后不良的预测指标.     

SNP genotypes of olfactory receptor genes associated with olfactory ability in German Shepherd dogs

To find out the relationship between SNP genotypes of canine olfactory receptor genes and olfactory ability, 28 males and 20 females from German Shepherd dogs in police service were scored by odor detection tests and analyzed using the Beckman GenomeLab SNPstream. The representative 22 SNP loci from the exonic regions of 12 olfactory receptor genes were investigated, and three kinds of odor (human, ice drug and trinitrotoluene) were detected. The results showed that the SNP genotypes at the OR10H1‐like:c.632C>T, OR10H1‐like:c.770A>T, OR2K2‐like:c.518G>A, OR4C11‐like:c.511T>G and OR4C11‐like:c.692G>A loci had a statistically significant effect on the scenting abilities (P < 0.001). The kind of odor influenced the performances of the dogs (P < 0.001). In addition, there were interactions between genotype and the kind of odor at the following loci: OR10H1‐like:c.632C>T, OR10H1‐like:c.770A>T, OR4C11‐like:c.511T>G and OR4C11‐like:c.692G>A (P < 0.001). The dogs with genotype CC at the OR10H1‐like:c.632C>T, genotype AA at the OR10H1‐like:c.770A>T, genotype TT at the OR4C11‐like:c.511T>G and genotype GG at the OR4C11‐like:c.692G>A loci did better at detecting the ice drug. We concluded that there was linkage between certain SNP genotypes and the olfactory ability of dogs and that SNP genotypes might be useful in determining dogs' scenting potential.     

膀胱尿路上皮肿瘤合并2型糖尿病患者临床和病理特点的比较性研究

目的:对比分析膀胱尿路上皮肿瘤合并2型糖尿病患者的临床和病理特点,为临床诊疗工作提供一定的参考。方法:回顾性分析2015年1月至2019年2月于我院泌尿外科手术治疗且经病理确诊为原发性膀胱尿路上皮肿瘤的患者资料,合并2型糖尿病的膀胱肿瘤患者59例设为糖尿病组(T2DM组),根据性别和年龄按照1:2的比例匹配同时期未合并2型糖尿病的膀胱肿瘤118例患者为非糖尿病组(NT2DM组),比较两组患者的临床特征和病理特点。结果:T2DM组的高血压患者比例和血肌酐值高于NT2DM组(P<0.05),而在教育程度、吸烟、饮酒、BMI、前列腺增生、泌尿系感染、血常规、肝功、尿常规、肿瘤大小、数量方面无明显统计学差异(P>0.05)。T2DM组和NT2DM组在膀胱尿路上皮肿瘤良恶性分类、肿瘤数量、肿瘤大小的构成比上无明显统计学差异(P>0.05);然而,对膀胱恶性肿瘤患者进行亚组分析显示,T2DM亚组中肌层浸润性癌的比例和高级别癌的比例明显高于NT2DM亚组,差异有统计学意义(P<0.05)。结论:2型糖尿病可能使膀胱癌的病理分级和分期更高,导致患者预后更差,临床上应更加关注膀胱恶性肿瘤合并2型糖尿病患者的诊治。     

核周型抗中性粒细胞胞浆抗体在狼疮性肾炎中的临床意义

目的:探讨核周型抗中性粒细胞胞浆抗体( P-ANCA)在狼疮性肾炎(LN)中的临床意义.方法:应用酶联免疫吸附分析( ELISA)的方法,检测92例LN患者血清中的P-ANCA及其他自身抗体的水平,并进一步分析P-ANCA与LN的临床表现以及辅助检查结果之间的关系.结果:P-ANCA在LN中的阳性率是21.8 ％(20/92),P-ANCA阳性组LN患者合并颧部红斑、皮肤血管炎、贫血以及补体C3偏低的频率均显著高于P-ANCA阴性组LN患者(P＜0.05).结论:P-ANCA在LN中的阳性率为21.8％,且P-ANCA与SLE特定的临床表现相关,提示P-ANCA可能参与了LN的发病过程.     

血清肿瘤标志物与宫颈癌病理特征的关系及对术后复发的预测研究

摘要 目的：探讨血清肿瘤标志物与宫颈癌病理特征的关系及对术后复发的预测研究。方法：选择2015年1月至2017年12月来我院诊治的宫颈癌患者82例作为观察组,选择同期来我院体检的健康女性者50例,两组均使用电化学发光免疫分析法检测血清中的CA125、CA153、CA199、CEA水平,观察组患者随访时间截至2022年12月。对比两组血清CA125、CA153、CA199、CEA水平,分析观察组患者血清CA125、CA153、CA199、CEA水平与临床病理特征的关系,分析观察组患者术后随访复发情况,宫颈癌根治术后患者复发的单因素与多因素Cox回归结果,血清CA125、CA153、CA199、CEA水平对宫颈癌根治术后复发的预测价值。结果：观察组的血清CA125、CA153、CA199、CEA水平明显较对照组高（P<0.05）。宫颈癌患者不同FIGO分期、间质浸润深度及是否存在淋巴结转移间血清CA125、CA153、CA199、CEA水平对比有统计学意义（P<0.05）。82例患者随访时间为13~60个月,中位生存时间为39个月,截止2022年12月末次随访,82例患者术后复发18例（21.95%）。单因素及多因素Cox回归分析表明,FIGO分期在ⅡA期、间质浸润深度≥1/2、有淋巴结转移、CA125≥307.41 U/mL、CA153≥185.89 U/mL、CA199≥153.23 U/mL、CEA≥30.15 ng/mL是影响宫颈癌术后复发的独立危险因素。ROC曲线显示,CA125+CA153+CA199+CEA预测宫颈癌术后复发的AUC明显较CA125、CA153、CA199、CEA单独指标预测价值高（P<0.05）。结论：宫颈癌患者血清CA125、CA153、CA199、CEA高表达,其与间质浸润深度、FIGO 分期、淋巴结转移、术后复发有关,四者联合可作为宫颈癌术后复发的预测指标。     

A de novo mutation in KIT causes white spotting in a subpopulation of German Shepherd dogs

Although variation in the KIT gene is a common cause of white spotting among domesticated animals, KIT has not been implicated in the diverse white spotting observed in the dog. Here, we show that a loss‐of‐function mutation in KIT recapitulates the coat color phenotypes observed in other species. A spontaneous white spotting observed in a pedigree of German Shepherd dogs was mapped by linkage analysis to a single locus on CFA13 containing KIT (pairwise LOD = 15). DNA sequence analysis identified a novel 1‐bp insertion in the second exon that co‐segregated with the phenotype. The expected frameshift and resulting premature stop codons predicted a severely truncated c‐Kit receptor with presumably abolished activity. No dogs homozygous for the mutation were recovered from multiple intercrosses (P = 0.01), suggesting the mutation is recessively embryonic lethal. These observations are consistent with the effects of null alleles of KIT in other species.