SHR/NCrl rats as a model of ADHD can be discriminated from controls based on their brain, blood, or urine metabolomes

Attention-Deficit Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental disorder characterized by inattention, impulsivity, and hyperactivity. The neurobiological mechanisms underlying ADHD are still poorly understood, and its diagnosis remains difficult due to its heterogeneity. Metabolomics is a recent strategy for the holistic exploration of metabolism and is well suited for investigating the pathophysiology of diseases and finding molecular biomarkers. A few clinical metabolomic studies have been performed on peripheral samples from ADHD patients but are limited by their access to the brain. Here, we investigated the brain, blood, and urine metabolomes of SHR/NCrl vs WKY/NHsd rats to better understand the neurobiology and to find potential peripheral biomarkers underlying the ADHD-like phenotype of this animal model. We showed that SHR/NCrl rats can be differentiated from controls based on their brain, blood, and urine metabolomes. In the brain, SHR/NCrl rats displayed modifications in metabolic pathways related to energy metabolism and oxidative stress further supporting their importance in the pathophysiology of ADHD bringing news arguments in favor of the Neuroenergetic theory of ADHD. Besides, the peripheral metabolome of SHR/NCrl rats also shared more than half of these differences further supporting the importance of looking at multiple matrices to characterize a pathophysiological condition of an individual. This also stresses out the importance of investigating the peripheral energy and oxidative stress metabolic pathways in the search of biomarkers of ADHD.

Local Pulmonary Immunological Biomarkers in Tuberculosis

Regardless of the eventual site of disease, the point of entry for Mycobacterium tuberculosis (M.tb) is via the respiratory tract and tuberculosis (TB) remains primarily a disease of the lungs. Immunological biomarkers detected from the respiratory compartment may be of particular interest in understanding the complex immune response to M.tb infection and may more accurately reflect disease activity than those seen in peripheral samples. Studies in humans and a variety of animal models have shown that biomarkers detected in response to mycobacterial challenge are highly localized, with signals seen in respiratory samples that are absent from the peripheral blood. Increased understanding of the role of pulmonary specific biomarkers may prove particularly valuable in the field of TB vaccines. Here, development of vaccine candidates is hampered by the lack of defined correlates of protection (COPs). Assessing vaccine immunogenicity in humans has primarily focussed on detecting these potential markers of protection in peripheral blood. However, further understanding of the importance of local pulmonary immune responses suggests alternative approaches may be necessary. For example, non-circulating tissue resident memory T cells (TRM) play a key role in host mycobacterial defenses and detecting their associated biomarkers can only be achieved by interrogating respiratory samples such as bronchoalveolar lavage fluid or tissue biopsies. Here, we review what is known about pulmonary specific immunological biomarkers and discuss potential applications and further research needs.

Concordant peripheral lipidome signatures in two large clinical studies of Alzheimer’s disease

Changes to lipid metabolism are tightly associated with the onset and pathology of Alzheimer’s disease (AD). Lipids are complex molecules comprising many isomeric and isobaric species, necessitating detailed analysis to enable interpretation of biological significance. Our expanded targeted lipidomics platform (569 species across 32 classes) allows for detailed lipid separation and characterisation. In this study we examined peripheral samples of two cohorts (AIBL, n = 1112 and ADNI, n = 800). We are able to identify concordant peripheral signatures associated with prevalent AD arising from lipid pathways including; ether lipids, sphingolipids (notably GM3 gangliosides) and lipid classes previously associated with cardiometabolic disease (phosphatidylethanolamine and triglycerides). We subsequently identified similar lipid signatures in both cohorts with future disease. Lastly, we developed multivariate lipid models that improved classification and prediction. Our results provide a holistic view between the lipidome and AD using a comprehensive approach, providing targets for further mechanistic investigation.

D-dimer from central and peripheral blood samples in asymptomatic central venous catheter-related thrombosis in patients with cancer

Objectives To evaluate the usefulness of a negative D-dimer in peripheral or central venous blood to screen for asymptomatic catheter-related thrombosis in cancer patients. Methods D-dimer was measured in blood from central venous catheter and peripheral venous samples in 48 patients with cancer. Asymptomatic catheter-related thrombosis was identified via Doppler ultrasound. Bland and Altman’s limits of agreement analysis was used to compare sample sites. Sensitivity and specificity of D-dimer was calculated. Results Overall, 33 of the central samples and 32 of the peripheral samples had D-dimer levels below the cutoff (≥0.3 mg/l). Mean central D-dimer was 0.31 ± 0.35 mg/l; peripheral 0.24 ± 0.22 mg/l (p = 0.5). Bland–Altman plot showed that the two sample sites were not equivalent. Catheter-related thrombosis was demonstrated in five patients, and there were three false negatives. Peripheral D-dimer had a negative predictive value of 90.9%. Conclusions A negative D-dimer may be useful for screening asymptomatic catheter-related thrombosis in patients with cancer, but the central and peripheral sample sites are not equivalent.

The neurobiology of autism spectrum disorders

Data is progressively and robustly accumulating regarding the biological basis of autism. Autism spectrum disorders (ASD) are currently considered a group of neurodevelopmental disorders with onset very early in life and a complex, heterogeneous, multifactorial aetiology. A comprehensive search of the last five years of the Medline database was conducted in order to summarize recent evidence on the neurobiological bases of autism. The main findings on genetic influence, neuropathology, neurostructure and brain networks are summarized. In addition, findings from peripheral samples of subjects with autism and animal models, which show immune, oxidative, mitochondrial dysregulations, are reported. Then, other biomarkers from very different systems associated with autism are reported. Finally, an attempt is made to try and integrate the available evidence, which points to a oligogenetic, multifactorial aetiology that converges in an aberrant micro-organization of the cortex, with abnormal functioning of the synapses and abnormalities in very general physiological pathways (such as inflammatory, immune and redox systems).

Median charge of gonadotrophin isoforms in the pituitary gland and in the circulation of sheep fetuses from mid- to late gestation

The heterogeneity of LH and FSH in the sheep fetus was studied by determining the median charge of pituitary and circulating isoforms. Pituitary extracts from male and female fetuses at days 75, 95, 120 and 135 of gestation were subjected to agarose suspension electrophoresis. For all fetuses except the day 75 age group, the median mobility of the gonadotrophin isoforms in matching serum samples from the individual fetuses were also determined. LH and FSH in extracts, peripheral samples and column eluates were measured using sensitive and specific sandwich fluoroimmunoassays for ovine gonadotrophins. The median charge of pituitary LH became more basic (P<0·001) with gestational age, whereas for pituitary FSH more acidic forms (P<0·001) were present in the older groups. The female fetuses had more basic pituitary isoforms of LH than the males (P<0·01) between days 95 and 135, and for FSH at day 75 (P<0·05). In the matching serum samples, the median charge of the LH (P<0·001) and FSH (P<0·05) isoforms were more acidic than those in the pituitary gland. No significant effects of age or sex were detected in the median charge of the gonadotrophin isoforms in serum, but in a number of instances the median charge could not be determined due to low serum concentrations which affected the group sizes. These data show that in the sheep fetus LH and FSH are differentially regulated in qualitative as well as quantitative terms, and that the charge of fetal gonadotrophin isoforms changes according to the age and sex of the fetus. Journal of Endocrinology (1996) 149, 29–39