Requirements for a Robust Animal Model to Investigate the Disease Mechanism of Autoimmune Complications Associated With ARF/RHD

The pathogenesis of Acute Rheumatic Fever/Rheumatic Heart Disease (ARF/RHD) and associated neurobehavioral complications including Sydenham's chorea (SC) is complex. Disease complications triggered by Group A streptococcal (GAS) infection are confined to human and determining the early events leading to pathology requires a robust animal model that reflects the hallmark features of the disease. However, modeling these conditions in a laboratory animal, of a uniquely human disease is challenging. Animal models including cattle, sheep, pig, dog, cat, guinea pigs rats and mice have been used extensively to dissect molecular mechanisms of the autoimmune inflammatory responses in ARF/RHD. Despite the characteristic limitations of some animal models, several rodent models have significantly contributed to better understanding of the fundamental mechanisms underpinning features of ARF/RHD. In the Lewis rat autoimmune valvulitis model the development of myocarditis and valvulitis with the infiltration of mononuclear cells along with generation of antibodies that cross-react with cardiac tissue proteins following exposure to GAS antigens were found to be similar to ARF/RHD. We have recently shown that Lewis rats injected with recombinant GAS antigens simultaneously developed cardiac and neurobehavioral changes. Since ARF/RHD is multifactorial in origin, an animal model which exhibit the characteristics of several of the cardinal diagnostic criteria observed in ARF/RHD, would be advantageous to determine the early immune responses to facilitate biomarker discovery as well as provide a suitable model to evaluate treatment options, safety and efficacy of vaccine candidates. This review focuses on some of the common small animals and their advantages and limitations

Cell surface antigens of Mycoplasma species bovine group 7 bind and activate plasminogen

Mycoplasma species bovine group 7 bound plasminogen at the cell surface in a lysine-dependent manner. Cell-bound plasminogen was rapidly activated to plasmin by exogenous urokinase, and this activity was associated with plasminogen binding capacity. Binding assays using plasminogen modified with a trifunctional cross-linking agent revealed several binding proteins

Cell Surface Antigens of Mycoplasma Species Bovine Group 7 Bind to and Activate Plasminogen.

Mycoplasma species bovine group 7 bound plasminogen at the cell surface in a lysine-dependent manner. Cell-bound plasminogen was rapidly activated to plasmin by exogenous urokinase, and this activity was associated with plasminogen binding capacity. Binding assays using plasminogen modified with a trifunctional cross-linking agent revealed several binding proteins

Age-related variations in comparative testosterone concentrations between boys with Autism Spectrum Disorder and their typically-developing peers:A challenge to the ‘extreme male brain’ hypothesis of ASD

There is some disagreement in the literature regarding the presence of elevated testosterone concentrations in boys with Autism Spectrum Disorder (ASD). To explore that disagreement, the presence of significant differences in testosterone concentrations in young males with Autism Spectrum Disorder (ASD) and normally developing controls aged 6 yr. to 17 yr. was investigated. A total of 136 young males with ASD and 48 age-matched non-ASD males contributed samples of saliva at a set time and these were assayed for testosterone concentrations. There was no significant difference in testosterone concentrations between the two entire samples. When examined at two-yearly intervals, ASD participants had significantly lower testosterone concentrations at age 12 yr. to 13 yr. and also exhibited relatively homogeneous testosterone concentrations compared to non-ASD participants. These data challenge the 'extreme male brain' hypothesis for ASD and suggest that ASD young males were delayed in their pubertal development and that the developmental variability expected in the wider population was not present

Further evidence of HPA-axis dysregulation and its correlation with depression in Autism Spectrum Disorders: Data from girls

To further describe Hypothalamus-Pituitary-Adrenal (HPA) axis activity in children with Autism Spectrum Disorder (ASD), the Diurnal Fluctuation (DF) and Cortisol Awakening Response (CAR)were investigated in a sample of 39 high functioning girls with ASD. Although group mean data conformed to the DF and CAR models, over half of the participants showed inverse CAR and over 14% had inverted DF cortisol concentrations. Examination of three potential sets of predictor factors (physiological, ASD-related, and mood) revealed that only self-reported Major Depressive Disorder was significantly associated with CAR status, and that the girls' concern about dying or suicide was the most powerful contributor to the variance in CAR status. These findings add to the literature regarding the HPA axis dysfunction in children with ASD

Eight-month test-retest agreement in morning salivary cortisol, self- and parent-rated anxiety in boys with an Autism Spectrum Disorder

The agreement over time in morning salivary cortisol concentrations and also self- and parent-rated anxiety was investigated in a sample of 16 boys with an ASD. Cortisol and anxiety data were collected eight months apart. Results indicated that there were significant correlations between each pair of measures from the two occasions, suggesting that cortisol concentrations and anxiety did not vary much at all over that time, challenging the assumption that cortisol needs to be measured over multiple days to obtain reliable data from children with an ASD. Implications for research into the ways these children respond to chronic stressors are discussed

Is afternoon cortisol more reliable than waking cortisol in association studies of children with an ASD?

Salivary cortisol may be used as a biomarker of stress and anxiety in children with an Autism Spectrum Disorder (ASD) and is particularly valuable in studies of the association between stress-related cortisol concentrations and other factors such as comorbid disorders or aspects of the ASD phenotype. Although protocols for the collection of cortisol shortly after waking are often based on the assumption of the presence of a diurnal rhythm in cortisol, that rhythm may not be as reliable in children with an ASD as in non-ASD children. Alternatively, collecting cortisol during the afternoon may represent a more reliable procedure with less inter-participant variability

Is daily replication necessary when sampling cortisol concentrations in association studies of children with autism spectrum disorder? A systematic review and discussion paper

Salivary cortisol may be used as a biomarker of stress and anxiety in children with an autism spectrum disorder (ASD). Some suggestions have been made that the measurement of cortisol needs to be undertaken by repeated days' observations to ensure reliability of the data obtained. These requirements are discussed in regard to 14 studies of the test-retest agreement and stability in cortisol data across repeated daily measurements. Results of those studies almost universally fail to support the argument for repeated daily measurements of cortisol. Implications for the research protocols of studies using cortisol as an index of stress in children with ASD are discussed