De-novo and genome-wide meta-analyses identify a risk haplotype for congenital sensorineural deafness in Dalmatian dogs.

Congenital sensorineural deafness (CSD) has been reported to affect up to 30% of Dalmatian dogs world-wide and while unilaterally deaf dogs can live a close to normal life, dogs suffering bilateral deafness are frequently euthanized. Extreme-white coat patterning as encoded by the gene Melanocyte Inducing Transcription Factor (MITF) has long been postulated as the major risk factor for CSD in the Dalmatian breed. While attempts to identify causative risk variants associated with CSD have been numerous, no genome-wide association study has positively identified MITF as a risk locus for either bilateral or unilateral deafness in the Dalmatian breed to date. In this study, we identified an association with CSD on CFA20 in the vicinity of MITF within Australian Dalmatian dogs. Although not genome-wide significant, the association signal was validated by reanalysing publicly available data and merging the wider data resource with the local data to improve statistical power. The merged data, representing three major global populations of Dalmatian dogs, enabled us to identify a single, well-defined genome-wide significant risk haplotype for CSD. The haplotype was formed by three genome-wide significant associated markers (BICF2G630233852T>C, BICF2G630233861T>C, BICF2G630233888G>A) on CFA20 with 62% of bilaterally deaf dogs homozygous for the risk haplotype (CCA), while 30% of bilaterally deaf and 45% of hearing dogs carried one copy of the risk haplotype. Animals homozygous or heterozygous for the low-risk haplotype were less likely to be unilaterally deaf. While the association between the risk haplotype and deafness is incomplete, animals homozygous for the risk haplotype were 10-times more likely to be bilaterally deaf. Although the underlying causative variants are yet to be discovered, results from this study can now assist with reducing deafness in Dalmatian dogs.

The Burmese cat as a genetic model of type 2 diabetes in humans.

The recent extension of genetic tools to the domestic cat, together with the serendipitous consequences of selective breeding, have been essential to the study of the genetic diseases that affect them. Cats are increasingly presented for veterinary surveillance and share many of human's heritable diseases, allowing them to serve as natural models of these conditions. Feline diabetes mellitus is a common condition in domestic cats that bears close pathological and clinical resemblance to type 2 diabetes in humans, including pancreatic ß-cell dysfunction and peripheral insulin resistance. In Australia, New Zealand and Europe, diabetes mellitus is almost four times more common in cats of the Burmese breed than in other breeds. This geographically based breed predisposition parallels familial and population clustering of type 2 diabetes in humans. As a genetically isolated population, the Australian Burmese breed provides a spontaneous, naturally occurring genetic model of type 2 diabetes. Genetically isolated populations typically exhibit extended linkage disequilibrium and increased opportunity for deleterious variants to reach high frequencies over many generations due to genetic drift. Studying complex diseases in such populations allows for tighter control of confounding factors including environmental heterogeneity, allelic frequencies and population stratification. The homogeneous genetic background of Australian Burmese cats may provide a unique opportunity to either refine genetic signals previously associated with type 2 diabetes or identify new risk factors for this disease.

Ratios derived from an array of standard haematological indices predict the oncological outcome in colon cancer.

AIM: The interaction between inflammation and cancer is well established. Surrogate markers of systemic inflammation, such as the neutrophil/lymphocyte ratio (NLR), may be associated with the long-term oncological outcome. The present study aimed to characterize the relationship between several ratios derived from haematological indices using a classification and regression tree analysis. METHOD: Haematological white-cell ratios were established for all patients undergoing colonic cancer resection with curative intent (n = 436) in a regional cancer centre. The optimal ratios associated with overall survival (OS) were established in a training set (n = 386) using a classification and regression tree (CRT) technique. The association between ratios and OS was assessed in a separate test set (n = 50). Within the test set, two groups were generated based on each ratio (one group above and one group below the cut-off value identified in the training set). The association between ratios and OS was assessed using a stepwise Cox proportional-hazards regression model. RESULTS: The following ratios, identified by the CRT, were associated with adverse OS in the test set: an NLR of ≥ 3.4 [hazard ratio (HR) = 3.4, P < 0.001]; and a white-cell-count/lymphocyte ratio (WLR) of ≥ 5.28 (HR = 4.1, P = 0.03). CONCLUSION: This is the first study to apply recursive partitioning in determining the relationship between haematological ratios and OS in colon cancer. Haematological ratios were predictive of oncological outcome. What does this paper add to the literature? This study suggests an association between systemic inflammation and oncological outcome.

Overall survival is improved in mucinous adenocarcinoma of the colon.

INTRODUCTION: Debate persists regarding the relationship between mucin expression and outcome in colon cancer. This arises due to discrepancy in the definition of mucinous adenocarcinoma and the combination of both colon and rectal cancers in analyses. This study examines the relationship between increased mucin production and outcomes in colon cancer. METHODS: Cases were classified according to the World Health Organization classification of mucinous adenocarcinoma of the colon. Accordingly, tumors were categorized as either (a) mucinous adenocarcinoma of the colon (greater than 50% of the extracellular matrix occupied by mucin) or (b) non-mucinous adenocarcinoma of the colon. Overall survival and disease-free survival were calculated. A stepwise Cox proportional hazards regression model was employed to determine the risk of death/disease recurrence. Kaplan-Meier estimates of overall survival and disease-free survival were plotted for each group and compared using a log-rank test. RESULTS: On univariate analysis, mucinous adenocarcinoma was associated with reduced risk of death (P = 0.01). On multivariate analysis, mucinous adenocarcinoma was also associated with reduced risk of death (hazard ratio (HR) 0.33, 95% confidence interval (CI) 0.14-0.79, P = 0.01). Kaplan-Meier estimates confirmed improved rate of survival in the mucinous vs. non-mucinous group (P = 0.01). Mucinous adenocarcinoma did not affect disease-free survival (HR 0.75, 95% CI 0.46-1.21, P = 0.22). A comparison of Kaplan-Meier estimates for systemic recurrence demonstrated significant increases in systemic recurrence in the group with no mucin production (P = 0.04) but not for locoregional recurrence (P = 0.24). CONCLUSIONS: Histopathological evidence of mucinous adenocarcinoma in colon cancer is associated with improved outcomes.

Collective coping with stress: group reactions to fear, anxiety, and ambiguity.

A review of studies examining the fear-affiliation relationship revealed that none had ever observed groups in interaction while awaiting a fearful event. It was predicted that such groups would, consistent with individual member's previously studied affiliative preferences, spend more time interacting in the service of social comparison needs than would groups facing anxiety or ambiguity. This prediction was strongly supported, and in addition, it was found, as expected, that groups in the fear condition developed a relatively high degree of cohesiveness as measured by intragroup attraction ratings. The implication of these results for the interpretation of the functional relationship between stress and cohesiveness was discussed.