Aspartylglucosaminuria: Clinical Presentation and Potential Therapies.

Aspartylglucosaminuria (AGU) is a recessively inherited neurodegenerative lysosomal storage disease characterized by progressive intellectual disability, skeletal abnormalities, connective tissue overgrowth, gait disturbance, and seizures followed by premature death. AGU is caused by pathogenic variants in the aspartylglucosaminidase (AGA) gene, leading to glycoasparagine accumulation and cellular dysfunction. Although more prevalent in the Finnish population, more than 30 AGA variants have been identified worldwide. Owing to its rarity, AGU may be largely underdiagnosed. Recognition of the following early clinical features may aid in AGU diagnosis: developmental delays, hyperactivity, early growth spurt, inguinal and abdominal hernias, clumsiness, characteristic facial features, recurring upper respiratory and ear infections, tonsillectomy, multiple sets of tympanostomy tube placement, and sleep problems. Although no curative therapies currently exist, early diagnosis may provide benefit through the provision of anticipatory guidance, management of expectations, early interventions, and prophylaxis; it will also be crucial for increased clinical benefits of future AGU disease-modifying therapies.

The Role of Apoptin in Chicken Anemia Virus Replication.

Apoptin is the Vp3 protein of chicken anemia virus (CAV), which infects the thymocytes and erythroblasts in young chickens, causing chicken infectious anemia and immunosuppression. Apoptin is highly studied for its ability to selectively induce apoptosis in human tumor cells and, thus, is a protein of interest in anti-tumor therapy. CAV apoptin is known to localize to different subcellular compartments in transformed and non-transformed cells, depending on the DNA damage response, and the phosphorylation of several identified threonine residues. In addition, apoptin interacts with molecular machinery such as the anaphase promoting complex/cyclosome (APC/C) to inhibit the cell cycle and induce arrest in G2/M phase. While these functions of apoptin contribute to the tumor-selective effect of the protein, they also provide an important fundamental framework to apoptin's role in viral infection, pathogenesis, and propagation. Here, we reviewed how the regulation, localization, and functions of apoptin contribute to the viral life cycle and postulated its importance in efficient replication of CAV. A model of the molecular biology of infection is critical to informing our understanding of CAV and other related animal viruses that threaten the agricultural industry.

Auricular Acupressure in the Prevention of Postoperative Nausea and Emesis A Randomized Controlled Trial.

INTRODUCTION: Successful antiemesis contributes significantly to quality, safety, and patient satisfaction. Patients undergoing general anesthesia often experience postoperative nausea and vomiting (PONV). Acupressure offers a side effect-free alternative to common first-line antiemetics. Because the patient may perceive needle acupuncture as uncomfortable, acupressure is a desirable alternative for the prevention of PONV. METHODS: This study was a randomized, prospective, double-blinded clinical trial investigating the effect of acupressure in patients with a history of PONV and motion sickness. The three auricular acupressure points chosen were shen men, point zero, and the subcortex point. Rescue treatment for PONV with 4 mg intravenous ondansetron was used if the patient reported persistent nausea. A blinded observer recorded antiemetic rescue data, and postoperative analgesic use was recorded over 24 hours. Nausea, vomiting, and retching were assessed in the post-anesthesia care unit (PACU). RESULTS: Using univariate analysis, we ruled out the null hypothesis of equal means as a function of intervention group (p = 0.001). Pair-wise comparisons revealed a difference between placebo and test groups (p = 0.000) and also sham and test groups (p = 0.033) where age (p = 0.048) and gender (p = 0.003) were significant covariates. DISCUSSION: Our data reveal that auricular acupressure significantly decreases nausea during the PACU stay and within the 24 hours postoperatively. It is not clear whether the intervention decreases nausea as a primary effect or as a secondary result by decreasing narcotic requirements. Also, perception of nausea may be in part subjective. This is evidenced by our results in which subjects who received sham points fared better than the placebo subjects.

Cytotoxic molecular mechanisms and cytoprotection by enzymic metabolism or autoxidation for glyceraldehyde, hydroxypyruvate and glycolaldehyde.

Previously, we showed that dietary fructose or its carbonyl metabolites, glyceraldehyde and glycolaldehyde, could be oxidized by inflammatory reactive oxygen species (ROS), products of immune cells, to form highly toxic and genotoxic products, such as glyoxal. Glycolaldehyde-caused hepatocyte protein carbonylation likely resulted from glyoxal, an autoxidation product formed by ROS. Although hepatocyte protein carbonylation by glyoxal or d-glycolaldehyde was rapid, the product was unstable. Glyceraldehyde-induced protein carbonylation was slower and was also less cytotoxic. Non-toxic concentrations of H(2)O(2) were then used to mimic inflammation and oxidative stress associated with fructose-induced non-alcoholic steatohepatitis (NASH). A slow infusion of H(2)O(2) markedly increased glyoxal, glyceraldehyde, and glycolaldehyde-induced cytotoxicity and protein carbonylation. However, it had a smaller effect on glyceraldehyde-induced protein carbonylation. The cytotoxicities of both aldehydes were increased if glutathione (GSH)-depleted hepatocytes were used, presumably because of the increased ROS formation and subsequent glyoxal-induced protein carbonylation. Catalytic amounts of Cu or Fe increased the glycolaldehyde and glyceraldehyde-induced cytotoxicity and protein carbonylation resulting from autoxidation to glyoxal. Glyceraldehyde and glycolaldehyde were also detoxified by mitochondrial aldehyde dehydrogenase (ALDH2) as ALDH2 inhibitors increased their cytotoxicity. Hydroxypyruvate has not been previously tested for toxicity and was found to be the most toxic fructose metabolite. Catalytic amounts of Cu or Fe caused hydroxypruvate autoxidation, which formed extensive ROS, glycolaldehyde and glyoxal. Iron chelators EGTA or deferoxamine inhibited cytotoxicity as well as the extensive ROS formation. The Girard assay confirmed that glyoxal was a common autoxidation product from glyceraldehyde, glycolaldehyde and hydroxypyruvate.

Cytotoxic effects of polychlorinated biphenyl hydroquinone metabolites in rat hepatocytes.

Polychlorinated biphenyls (PCBs) are persistent organic pollutants that exhibit various toxic effects in animals and exposed human populations. The molecular mechanisms of PCB toxicity have been attributed to the toxicological properties of its metabolites, such as hydroquinones, formed by cytochrome-P-450 oxidation. The effects of PCB hydroquinone metabolites towards freshly isolated rat hepatocytes were investigated. Hydroquinones can be oxidized to semiquinones and/or quinone metabolites. These metabolites can conjugate glutathione or can oxidize glutathione as a result of redox cycling. This depletes hepatocyte glutathione, which can inhibit cellular defence mechanisms, causing cell death and an increased susceptibility to oxidative stress. However in the following, glutathione-depleted hepatocytes became more resistant to the hydroquinone metabolites of PCBs. This suggested that their glutathione conjugates were toxic and that there was a third type of quinone toxicity mechanism which involved a hydrogen peroxide-accelerated autoxidation of the hydroquinones to form toxic electrophilic quinone and semiquinone-glutathione conjugates.