Low myo-inositol and high glutamine levels in brain are associated with neuropsychological deterioration after induced hyperammonemia

The neuropsychological effect of hyperammonemia is variable. This study tests the hypothesis that the effect of ammonia on the neuropsychological function in patients with cirrhosis is determined by the ability of the brain to buffer ammonia-induced increase in glutamine within the astrocyte by losing osmolytes like myo-inositol (mI) and not by the magnitude of the induced hyperammonemia. Fourteen cirrhotic patients with no evidence of overt hepatic encephalopathy were given a 75-g amino acid (aa) solution mimicking the hemoglobin molecule to induce hyperammonemia. Measurement of a battery of neuropsychological function tests including immediate memory, ammonia, aa, and short-echo time proton magnetic resonance spectroscopy were performed before and 4 h after administration of the as solution. Eight patients showed deterioration in the Immediate Memory Test at 4 h. Demographic factors, severity of liver disease, change in plasma ammonia, and as profiles after the as solution were similar in those that showed a deterioration compared with those who did not. In patients who showed deterioration in the memory test, the mI-to-creatine ratio (mI/Cr) was significantly lower at baseline than those that did not deteriorate. In contrast, the glutamate/glutamine-to-Cr ratio was significantly greater in the patients that deteriorated. The observation that deterioration in the memory test scores was greater in those with lower mI/Cr supports the hypothesis that the neuropsychological effects of induced hyperammonemia is determined by the capacity of the brain to handle ammonia-induced increase in glutamine

Nitisinone causes acquired tyrosinosis in alkaptonuria.

For over two decades, nitisinone (NTBC) has been successfully used to manipulate the tyrosine degradation pathway and save the lives of many children with hereditary tyrosinaemia type 1. More recently, NTBC has been used to halt homogentisic acid accumulation in alkaptonuria (AKU) with evidence suggesting its efficacy as a disease modifying agent. NTBC-induced hypertyrosinaemia has been associated with cognitive impairment and potentially sight-threatening keratopathy. In the context of a non-lethal condition (ie, AKU), these serious risks call for an evaluation of the wider impact of NTBC on the tyrosine pathway. We hypothesised that NTBC increases the tyrosine pool size and concentrations in tissues. In AKU mice tyrosine concentrations of tissue homogenates were measured before and after treatment with NTBC. In humans, pulse injection with l-[13 C9 ]tyrosine and l-[d8 ]phenylalanine was used along with compartmental modelling to estimate the size of tyrosine pools before and after treatment with NTBC. We found that NTBC increased tyrosine concentrations in murine tissues by five to nine folds. It also significantly increased the tyrosine pool size in humans (P < .001), suggesting that NTBC increases tyrosine not just in serum but also in tissues (ie, acquired tyrosinosis). This study provides, for the first time, the experimental proof for the magnitude of NTBC-related acquired tyrosinosis which should be overcome to ensure the safe use of NTBC in AKU

The Nature of the Dietary Protein Impacts the Tissue-to-Diet 15N Discrimination Factors in Laboratory Rats

Due to the existence of isotope effects on some metabolic pathways of amino acid and protein metabolism, animal tissues are 15N-enriched relative to their dietary nitrogen sources and this 15N enrichment varies among different tissues and metabolic pools. The magnitude of the tissue-to-diet discrimination (Δ15N) has also been shown to depend on dietary factors. Since dietary protein sources affect amino acid and protein metabolism, we hypothesized that they would impact this discrimination factor, with selective effects at the tissue level. To test this hypothesis, we investigated in rats the influence of a milk or soy protein-based diet on Δ15N in various nitrogen fractions (urea, protein and non-protein fractions) of blood and tissues, focusing on visceral tissues. Regardless of the diet, the different protein fractions of blood and tissues were generally 15N-enriched relative to their non-protein fraction and to the diet (Δ15N>0), with large variations in the Δ15N between tissue proteins. Δ15N values were markedly lower in tissue proteins of rats fed milk proteins compared to those fed soy proteins, in all sampled tissues except in the intestine, and the amplitude of Δ15N differences between diets differed between tissues. Both between-tissue and between-diet Δ15N differences are probably related to modulations of the relative orientation of dietary and endogenous amino acids in the different metabolic pathways. More specifically, the smaller Δ15N values observed in tissue proteins with milk than soy dietary protein may be due to a slightly more direct channeling of dietary amino acids for tissue protein renewal and to a lower recycling of amino acids through fractionating pathways. In conclusion, the present data indicate that natural Δ15N of tissue are sensitive markers of the specific subtle regional modifications of the protein and amino acid metabolism induced by the protein dietary source

Dietary Education Provision Within a Cardiac Rehabilitation Programme in the UK: A Pilot Study Evaluating Nutritional Intakes Alongside Physical Activity Levels

Background/aims: The primary aim of this study was to evaluate the effectiveness of two 30-minute dietary education sessions, within cardiac rehabilitation (CR), as a means to optimise nutrient and energy intakes (EI). A secondary aim was to evaluate patients’ habitual physical activity (PA) levels. Methods: Thirty patients (males: n = 24, 61.8 ± 11.2 years; females: n = 6, 66.7 ± 8.5 years) attended a six-week early outpatient CR programme in the UK and received two 30-minute dietary education sessions emphasising Mediterranean diet principles. EI and nutrient intakes were measured through completion of three-day food diaries in weeks one and six (before and after the dietary education sessions) to assess the impact of these sessions on nutrient intakes. At the same time-points, a sub-group (n = 13) of patients had their PA levels assessed via accelerometery to assess the impact of the CR programme on PA. Findings: Estimated energy requirements (EER) at week one (1988 ± 366 kcal . d -1 ) were not matched by actual EI (1785 ± 561 kcal . d -1 ) ( P = 0.047, d = -0.36). EI reduced to 1655 ± 470 kcal . d -1 at week six ( P = 0.66, d = -0.33) whereas EER increased as a function of increased activity (CR sessions). Nutrient intakes remained suboptimal, while no significant increases were observed in healthy fats and fibre, which consist core elements of a Mediterranean diet. Statistically significant increases were not observed in PA however patients decreased sedentary time by 11 ± 12% in week six compared to week one ( P = 0.009; d = -0.54). Conclusion : The present study findings suggest that two 30-minute dietary education sessions did not positively influence EI and nutrient intakes, while habitual PA levels were not significantly increased as a result of the CR programme. Future research should explore means of optimising nutrition and habitual PA within UK CR