Diagnostic and therapeutic challenges in the Allan-Herndon-Dudley Syndrome

Thyroid hormone (TH) is important for normal brain development. The TH transporter protein monocarboxylate transporter 8 (MCT8) is crucial to maintain adequate TH levels in the brain during development and throughout life. Mutations in MCT8 result in the Allan-Herndon-Dudley syndrome (AHDS), which is characterized by a severe delay in neurocognitive development, combined with abnormal serum thyroid function tests (TFTs). The combination of an increased (F)T3 and decreased (F)T4 and rT3 serum levels are characteristic for the presence of AHDS in male patients with moderate to severe delay in neurocognitive development. Here, we provide an overview of current insights, challenges and pitfalls in the diagnosis and management of patients with AHDS.</p

Diagnostic and therapeutic challenges in the Allan-Herndon-Dudley Syndrome

Thyroid hormone (TH) is important for normal brain development. The TH transporter protein monocarboxylate transporter 8 (MCT8) is crucial to maintain adequate TH levels in the brain during development and throughout life. Mutations in MCT8 result in the Allan-Herndon-Dudley syndrome (AHDS), which is characterized by a severe delay in neurocognitive development, combined with abnormal serum thyroid function tests (TFTs). The combination of an increased (F)T3 and decreased (F)T4 and rT3 serum levels are characteristic for the presence of AHDS in male patients with moderate to severe delay in neurocognitive development. Here, we provide an overview of current insights, challenges and pitfalls in the diagnosis and management of patients with AHDS.</p

Isolation and sequence of cDNA encoding the motilin precursor from monkey intestine. Demonstration of the motilin precursor in the monkey brain

AbstractThe motilin precursor cDNA has been isolated and sequenced from a cDNA library prepared from monkey small intestine. The sequence indicates a 345 bp open reading frame, a 63 bp 5′ untranslated region and a 154 bp 3′ untranslated region. The sequence encodes a 115 amino acid motilin precursor composed of a 25 amino acid signal peptide, the 22 amino acid motilin peptide and a 68 amino acid motilin associated peptide (MAP). Compared with the human motilin precursor cDNA, there are two amino acid substitutions in the signal peptide, one in motilin and four in the MAP. The presence of the motilin precursor in hypothalamus, hippocampus and cerebellum was demonstrated by RT-PCR

Investigation of intervertebral disc degeneration using multivariate FTIR spectroscopic imaging

Traditionally tissue samples are analysed using protein or enzyme specific stains on serial sections to build up a picture of the distribution of components contained within them. In this study we investigated the potential of multivariate curve resolution-alternating least squares (MCR-ALS) to deconvolute 2nd derivative spectra of Fourier transform infrared (FTIR) microscopic images measured in transflectance mode of goat and human paraffin embedded intervertebral disc (IVD) tissue sections, to see if this methodology can provide analogous information to that provided by immunohistochemical stains and bioassays but from a single section. MCR-ALS analysis of non-degenerate and enzymatically in vivo degenerated goat IVDs reveals five matrix components displaying distribution maps matching histological stains for collagen, elastin and proteoglycan (PG), as well as immunohistochemical stains for collagen type I and II. Interestingly, two components exhibiting characteristic spectral and distribution profiles of proteoglycans were found, and relative component/tissue maps of these components (labelled PG1 and PG2) showed distinct distributions in non-degenerate versus mildly degenerate goat samples. MCR-ALS analysis of human IVD sections resulted in comparable spectral profiles to those observed in the goat samples, highlighting the inter species transferability of the presented methodology. Multivariate FTIR image analysis of a set of 43 goat IVD sections allowed the extraction of semi-quantitative information from component/tissue gradients taken across the IVD width of collagen type I, collagen type II, PG1 and PG2. Regional component/tissue parameters were calculated and significant correlations were found between histological grades of degeneration and PG parameters (PG1: p = 0.0003, PG2: p < 0.0001); glycosaminoglycan (GAG) content and PGs (PG1: p = 0.0055, PG2: p = 0.0001); and MRI T2* measurements and PGs (PG1: p = 0.0021, PG2: p < 0.0001). Additionally, component/tissue parameters for collagen type I and II showed significant correlations with total collagen content (p = 0.0204, p = 0.0127). In conclusion, the presented findings illustrate, that the described multivariate FTIR imaging approach affords the necessary chemical specificity to be considered an important tool in the study of IVD degeneration in goat and human IVDs

Sustained synchronized neuronal network activity in a human astrocyte co-culture system

Impaired neuronal network function is a hallmark of neurodevelopmental and neurodegenerative disorders such as autism, schizophrenia, and Alzheimer's disease and is typically studied using genetically modified cellular and animal models. Weak predictive capacity and poor translational value of these models urge for better human derived in vitro models. The implementation of human induced pluripotent stem cells (hiPSCs) allows studying pathologies in differentiated disease-relevant and patient-derived neuronal cells. However, the differentiation process and growth conditions of hiPSC-derived neurons are non-trivial. In order to study neuronal network formation and (mal) function in a fully humanized system, we have established an in vitro co-culture model of hiPSC-derived cortical neurons and human primary astrocytes that recapitulates neuronal network synchronization and connectivity within three to four weeks after final plating. Live cell calcium imaging, electrophysiology and high content image analyses revealed an increased maturation of network functionality and synchronicity over time for co-cultures compared to neuronal monocultures. The cells express GABAergic and glutamatergic markers and respond to inhibitors of both neurotransmitter pathways in a functional assay. The combination of this co-culture model with quantitative imaging of network morphofunction is amenable to high throughput screening for lead discovery and drug optimization for neurological diseases