Synaptosomal Uptake of Alpha-Ketoglutarate and Glutamine in Thioacetamide-Induced Hepatic Encephalopathy in Rats

The kinetics of uptake of two astroglia-derived glutamate (GLU) precursors, α-ketoglutarate (α-KG) and glutamine (GLN) were determined in synaptosomes derived from rats with acute hepatic encephalopathy (HE) induced with a hepatotoxin, thioacetamide (TAA). TAA treatment increased by 33% Vmax for high affinity, low capacity α-KG uptake, without influencing its Km. The increase of the uptake capacity for α-KG may represent a response of the GLUergic nerve terminals to the decreased cerebral α-KG content, which during HE is associated with depressed activity of pyruvate carboxylase, an enzyme that replenishes α-KG in astrocytes. The result is thus consistent with the notion that HE affects the astroglial control of GLUergic neurotransmission. The Km and Vmax for the low affinity, high capacity GLN uptake was not affected by TAA treatment.     

Mood,cognitive structuring and medication adherence

A study with a placebo was conducted. Healthy university students were given a placebo and were told to make one pill every day for a week. Participants were informed that the medicine improved mood. The extent to which they conformed to this instruction was treated as an index of compliance. Our results show that for women, but not for men, positive mood and cognitive structuring or negative mood and lack of cognitive structuring significantly predicted participants' compliance. A new model of medication adherence, based on the role of the patient's mood and cognitive structuring processes in decision making is presented in the paper.     

DNA Variations in Oculocutaneous Albinism: An Updated Mutation List and Current Outstanding Issues in Molecular Diagnostics

Oculocutaneous albinism (OCA) is a rare genetic disorder of melanin synthesis that results in hypopigmented hair, skin, and eyes. There are four types of OCA caused by mutations in TYR (OCA‐1), OCA2 (OCA‐2), TYRP1 (OCA‐3), or SLC45A2 (OCA‐4). Here we report 22 novel mutations in the OCA genes; 14 from a cohort of 61 patients seen as part of the NIH OCA Natural History Study and eight from a prior study at the University of Minnesota. We also include a comprehensive list of almost 600 previously reported OCA mutations along with ethnicity information, carrier frequencies, and in silico pathogenicity predictions as a supplement. In addition to discussing the clinical and molecular features of OCA, we address the cases of apparent missing heritability. In our cohort, 26% of patients did not have two mutations in a single OCA gene. We demonstrate the utility of multiple detection methods to reveal mutations missed by Sanger sequencing. Finally, we review the TYR p.R402Q temperature‐sensitive variant and confirm its association with cases of albinism with only one identifiable TYR mutation.     

Nitisinone improves eye and skin pigmentation defects in a mouse model of oculocutaneous albinism

Mutation of the tyrosinase gene (TYR) causes oculocutaneous albinism, type 1 (OCA1), a condition characterized by reduced skin and eye melanin pigmentation and by vision loss. The retinal pigment epithelium influences postnatal visual development. Therefore, increasing ocular pigmentation in patients with OCA1 might enhance visual function. There are 2 forms of OCA1, OCA-1A and OCA-1B. Individuals with the former lack functional tyrosinase and therefore lack melanin, while individuals with the latter produce some melanin. We hypothesized that increasing plasma tyrosine concentrations using nitisinone, an FDA-approved inhibitor of tyrosine degradation, could stabilize tyrosinase and improve pigmentation in individuals with OCA1. Here, we tested this hypothesis in mice homozygous for either the Tyrc-2J null allele or the Tyrc-h allele, which model OCA-1A and OCA-1B, respectively. Only nitisinone-treated Tyrc-h/c-h mice manifested increased pigmentation in their fur and irides and had more pigmented melanosomes. High levels of tyrosine improved the stability and enzymatic function of the Tyrc-h protein and also increased overall melanin levels in melanocytes from a human with OCA-1B. These results suggest that the use of nitisinone in OCA-1B patients could improve their pigmentation and potentially ameliorate vision loss.