Dermal immune responses against Psoroptes ovis in two cattle breeds and effects of anti-inflammatory dexamethasone treatment on the development of psoroptic mange

Psoroptic mange is a common disease of livestock, caused by Psoroptes ovis. Compared to Holstein-Friesian (HF) cattle, the Belgian Blue (BB) cattle breed is highly susceptible to the infestation. However, the mechanism for this difference is still unclear. To determine the factors responsible for this breed susceptibility, the immune response to P. ovis was studied in experimentally infested BB and HF cattle, using clinical signs, histology, immunohistochemical profiling and gene expression analysis of skin biopsies. The mite numbers and lesion area of BB cattle were greater than in HF during the whole study period. Significant influxes of eosinophils in the epidermis and dermis were detected in comparison with the pre-infestation samples in both breeds, with significantly higher eosinophils in BB at 6 weeks post infestation (wpi). Mast cell numbers were unaffected at all stages of infestation in HF, but were significantly elevated relative to pre-infestation in BB cattle at 2 and 6 wpi. The more pronounced cutaneous eosinophilia and higher IL-4 levels at 6 wpi in BB cattle suggest that a Th2-type immune response is underlying the higher susceptibility of the BB breed. In naturally infested BB cattle, development of the psoroptic mange lesions and eosinophils and CD3+ T cell areas were severely depressed after anti-inflammatory treatment with dexamethasone. Together, these results suggest that a stronger Th2-type immune response to P. ovis causes the skin lesions in psoroptic mange in BB cattle and that local anti-inflammatory treatment could potentially be an alternative to control the pathology caused by this parasite

Functional investigation of two simultaneous or separately segregating DSP variants within a single family support the theory of a dose-dependent disease severity

Desmoplakin (DP) is an important component of desmosomes, essential in cell-cell connecting structures in stress-bearing tissues. Over many hundreds of pathogenic variants in DSP have been associated with different cutaneous and cardiac phenotypes or a combination, known as a cardiocutaneous syndrome. Of less than 5% of the reported DSP variants, the effect on the protein has been investigated. Here, we describe and have performed RNA, protein and tissue analysis in a large family where DSPc.273+5G>A/c.6687delA segregated with palmoplantar keratoderma (PPK), woolly hair and lethal cardiomyopathy, while DSPWT/c.6687delA segregated with PPK and milder cardiomyopathy. hiPSC-derived cardiomyocytes and primary keratinocytes from carriers were obtained for analysis. Unlike the previously reported nonsense variants in the last exon of DSP that bypassed the nonsense-mediated mRNA surveillance system leading to protein truncation, variant c.6687delA was shown to cause loss of protein expression. Patients carrying both variants and having a considerably more severe phenotype were shown to have 70% DP protein reduction, while patients carrying only c.6687delA had 50% protein reduction and a milder phenotype. Analysis of RNA from patient cells did not show any splicing effect of the c.273+5G>A variant. However, a minigene splicing assay clearly showed alternative spliced transcripts originating from this variant. This study shows the importance of RNA and protein analyses to pinpoint the exact effect of DSP variants instead of solely relying on predictions. In addition, the particular pattern of inheritance, with simultaneous or separately segregating DSP variants within the same family, strongly supports the theory of a dose-dependent disease severity

Disruption of tuftelin 1, a desmosome associated protein, causes skin fragility, woolly hair and palmoplantar keratoderma

Desmosomes are dynamic complex protein structures involved in cellular adhesion. Disruption of these structures by loss of function variants in desmosomal genes lead to a variety of skin and heart related phenotypes. Here, we report tuftelin 1 as a desmosome-associated protein, implicated in epidermal integrity. In two siblings with mild skin fragility, woolly hair and mild palmoplantar keratoderma, but without a cardiac phenotype, we identified a homozygous splice site variant in the TUFT1 gene, leading to aberrant mRNA splicing and loss of tuftelin 1 protein. Patients' skin and keratinocytes showed acantholysis, perinuclear retraction of intermediate filaments, and reduced mechanical stress resistance. Immunolabeling and transfection studies showed that tuftelin 1 is positioned within the desmosome and its location dependent on the presence of the desmoplakin carboxy-terminal tail. A Tuft1 knock-out mouse model mimicked the patients' phenotypes. Altogether, this study reveals tuftelin 1 as a desmosome-associated protein, whose absence causes skin fragility, woolly hair and palmoplantar keratoderma

Disruption of tuftelin 1, a desmosome associated protein, causes skin fragility, woolly hair and palmoplantar keratoderma

Desmosomes are dynamic complex protein structures involved in cellular adhesion. Disruption of these structures by loss of function variants in desmosomal genes lead to a variety of skin and heart related phenotypes. Here, we report tuftelin 1 as a desmosome-associated protein, implicated in epidermal integrity. In two siblings with mild skin fragility, woolly hair and mild palmoplantar keratoderma, but without a cardiac phenotype, we identified a homozygous splice site variant in the TUFT1 gene, leading to aberrant mRNA splicing and loss of tuftelin 1 protein. Patients' skin and keratinocytes showed acantholysis, perinuclear retraction of intermediate filaments, and reduced mechanical stress resistance. Immunolabeling and transfection studies showed that tuftelin 1 is positioned within the desmosome and its location dependent on the presence of the desmoplakin carboxy-terminal tail. A Tuft1 knock-out mouse model mimicked the patients' phenotypes. Altogether, this study reveals tuftelin 1 as a desmosome-associated protein, whose absence causes skin fragility, woolly hair and palmoplantar keratoderma.</p

Risk factors associated with bacteremia in 334 critically ill calves

Background: Sepsis is one of the main contributors to neonatal calf mortality. Available predictive models were not validated or included diarrheic calves only. Recently, blood culture (BC) positivity was shown to be associated with mortality in critically ill calves. Therefore, the objective of this study was to identify factors associated with BC positivity in critically ill calves. Methods: Logistic regression and decision tree analysis were performed on the medical records of 340 critically ill calves sampled for BC. Blood cultures were aseptically sampled and inoculated in aerobic enrichment media. Data on clinical and ultrasonographic examinations, laboratory findings, and anamnestic details about prior therapy were included. Results: The clinical model of risk factors associated with positive BC consisted of the presence of pneumonia (consolidation>1cm)(OR, 2.0; 95%CI, 1.0-3.8; P=.05), abnormal behavior (OR, 2.4; 95%CI, 1.1-4.9; P=.02) and diarrhea (OR, 0.43; 95%CI, 0.22-0.85; P=.02). Sensitivity, specificity and accuracy were 19%, 95% and 70%, respectively. The model including all parameters consisted of pneumonia (OR, 2.2; 95%CI, 1.2-3.8; P=.008) and hypoglycemia (OR, 3.2; 95%CI, 1.8-4.5; P<.001). Sensitivity, specificity and accuracy were 34%, 89% and 71%, respectively. The decision tree included hypoproteinemia, hypoglycemia, tachypnea, hypocalcemia, abnormal behavior, decreased bicarbonate and a venous hypoxemia as risk factors for sepsis. Sensitivity, specificity and accuracy of the tree were 34.1%, 89.4% and 71.4%, respectively. Conclusions: Pneumonia is associated with BC positivity, in contrast to diarrhea. Hypoglycemia and abnormal behavior appear most relevant in predicting bacteremia. Sensitivity for sepsis prediction in calves, without any ancillary test (e.g. biomarkers), remains disappointing

Clinical and laboratory predictors for bacteremia in critically ill calves

Background: Sepsis is a main contributor to calf mortality, but diagnosis is difficult. Objectives: Develop and validate a predictive model for bacteremia in critically ill calves (CIC). Animals: A total of 334 CIC, sampled for blood culture. Methods: Cross-sectional study. Multivariable logistic regression and classification tree analysis on clinical, ultrasonographic, and laboratory variables were performed on a dataset including all animals. Model validation was done on 30% of the dataset. Similar statistics (except validation) were performed on a subset of the database (n = 143), in which presumed contaminants were excluded. Results: The best performing model to predict bacteremia, taking all detected bacteria into account, included tachypnea, tachycardia, acidemia, hypoglycemia, venous hypoxemia, and hypoproteinemia. Sensitivity and specificity of this model were 70.6% and 98.0%, respectively, but decreased to 61.5% and 91.7% during model validation. The best-performing model, excluding presumed contaminants, included abnormal temperature, heart rate, absence of enteritis, hypocalcemia, and hyperlactatemia as risk factors for bacteremia. Sensitivity and specificity of this model were 71.4% and 93.9%, respectively. Both classification trees performed less well in comparison to logistic regression. The classification tree excluding presumed contaminants, featured hypoglycemia, absence of diarrhea, and hyperlactatemia as risk factors for bacteremia. Sensitivity and specificity were 39.4% and 92.7%, respectively. Conclusions and clinical importance: Hypoglycemia, hyperlactatemia, and hypoproteinemia seem relevant in assessing bacteremia in CIC. The performance of these models based on basic clinical and blood variables remains insufficient to predict bacteremia

Post-operative survival in cattle with colic signs and differentiation upon admission between mesenteric torsion and intussusception.

Background : Intussusception and mesenteric torsions are the most frequent causes of colic requiring surgery in cattle. Whether survival chances of these conditions differ in the same institute is currently unknown. Also, clinical and laboratory factors available upon admission that can differentiate between intussusception and torsion are unknown. Therefore, the objective of this study was to determine mortality and factors associated with mortality in cattle with colic and to identify factors that distinguish between torsion and intussusception pre-surgery. Methods : A retrospective cohort study was conducted based on the medical records of the Large Animal Internal Medicine clinic, Ghent University. Records between January 1, 2020 and December 31, 2023. Inclusion criteria were cattle with colic signs. Clinical examination, blood gas analysis and hospitalization records were used to complete the dataset. Survival analysis was used to determine factors associated with mortality. Logistic regression to identify factors that can differentiate torsion from intussusception upon admission. Results : The dataset included 177 cases whereof 95 mesenteric torsions, 42 intussusceptions and 40 other causes of colic and surgery in cattle. The mortality until discharge was 50.5%, 38.1% and 65.0% in torsion, intussusception and other causes, respectively. There was no significant difference in mortality between dairy and beef cattle nor sex. Multivariable analysis showed that breathing frequency >58/minute (P=.008; OR 1.88; CI 1.2-3.0), lactate >5.925 mmol/L (P=.003; OR=1.9; CI 1.3-3.0) and calcium <1.095 mmol/L (P=.003; OR 1.6; CI 1.0-2.4) resulted in an increased mortality risk with sensitivity, specificity and accuracy of 65.6%, 32.9% and 49.7 respectively. There was no significant difference in prevalence of torsion and intussusception between dairy and beef cattle. A multivariable model to predict intussusception and differentiate from torsion included age at entry (P=<.161; OR=1.001; CI 1.000-1.002), heart rate <114 beats per minute (P=7.395 (P=<.017; OR=3.4; CI 1.3-9.4) and chloride <91.5 mmol/L (P=<.004; OR=4.3; CI 1.6-11.5). Sensitivity, specificity and accuracy of this model were 56.4%, 92.6% and 82.0%, respectively. Conclusions : In the present study, mortality was numerically higher in cases of mesenteric torsion compared to intussusception. Alkalemia, hypochloremia and age show potential for differentiation of these conditions upon arrival which can be used for decision making regarding surgery