Personalized medicine approach confirms a milder case of ABAT deficiency.

ABAT deficiency (OMIM 613163) is a rare inborn error of metabolism caused by recessive variants in the gene 4-aminobutyric acid transaminase (ABAT), which is responsible for both the catalysis of GABA and maintenance of nucleoside pools in the mitochondria. To date, only a few patients have been reported worldwide. Their clinical presentation has been remarkably consistent with primary features of severe psychomotor retardation, encephalopathy, hypotonia, and infantile-onset refractory epilepsy. We report a new case of ABAT deficiency that marks an important departure from previous clinical findings. The patient presented at age 6 months with global developmental delay, hypotonia, hypersomnolence and mild choreiform movements. At age 18 months, the subject's clinical presentation was still milder than all previously reported patients and, most notably, did not include seizures. Clinical whole exome sequencing revealed two heterozygous ABAT missense variants that are rare and predicted damaging, but never before reported in a patient and were reported as variants of unknown significance. To test the potential pathogenicity of the variants identified in this patient we developed a cell-based system to test both functions of the ABAT protein via GABA transaminase enzyme activity and mtDNA copy number assays. This systematic approach was validated using vigabatrin, the irreversible inhibitor of ABAT, and leveraged to test the functionality of all ABAT variants in previously reported patients plus the variants in this new case. This work confirmed the novel variants compromised ABAT function to similar levels as variants in previously characterized cases with more severe clinical presentation, thereby confirming the molecular diagnosis of this patient. Additionally, functional studies conducted in cells from both mild and severe patient fibroblasts showed similar levels of compromise in mitochondrial membrane potential, respiratory capacity, ATP production and mtDNA depletion. These results illustrate how cell-based functional studies can aid in the diagnosis of a rare, neurological disorder. Importantly, this patient marks an expansion in the clinical phenotype for ABAT deficiency to a milder presentation that is more commonly seen in pediatric genetics and neurology clinics.

Effect of early supervised progressive resistance training compared to unsupervised home-based exercise after fast-track total hip replacement applied to patients with preoperative functional limitations. A single-blinded randomised controlled trial.

OBJECTIVE: To examine if 2 weekly sessions of supervised progressive resistance training (PRT) in combination with 5 weekly sessions of unsupervised home-based exercise is more effective than 7 weekly sessions of unsupervised home-based exercise in improving leg-extension power of the operated leg 10 weeks after total hip replacement (THR) in patients with lower pre-operative function. METHOD: A total of 73 patients scheduled for THR were randomised (1:1) to intervention group (IG, home based exercise 5 days/week and PRT 2 days/week) or control group (CG, home based exercise 7 days/week). The primary endpoint was change in leg extension power at 10 week follow up. Secondary outcomes were isometric hip muscle strength, sit-to-stand test, stair climb test, 20 m walking speed and patient-reported outcome (HOOS). RESULTS: Sixty-two completed the trial (85%). Leg extension power increased from baseline to the 10 week follow up in both groups; mean [95% CI] IG: 0.29 [0.13; 0.45] and CG: 0.26 [0.10; 0.42] W/kg, with no between-group difference (primary outcome) (P = 0.79). Maximal walking speed (P = 0.008) and stair climb performance (P = 0.04) improved more in the IG compared to CG, no other between-group differences existed. CONCLUSIONS: In this trial, supervised PRT twice a week in addition to 5 weekly sessions of unsupervised exercise for 10 weeks was not superior to 7 weekly sessions of unsupervised home-based exercise for 10 weeks in improving the primary outcome, leg-extension power of the operated leg, at the primary endpoint 10 weeks after surgery in THR patients with lower pre-operative function. TRIAL REGISTRATION: NCT01214954.

Increased amino acids levels and the risk of developing of hypertriglyceridemia in a 7-year follow-up.

BACKGROUND: Recently, five branched-chain and aromatic amino acids were shown to be associated with the risk of developing type 2 diabetes (T2D). AIM: We set out to examine whether amino acids are also associated with the development of hypertriglyceridemia. MATERIALS AND METHODS: We determined the serum amino acids concentrations of 1,125 individuals of the KORA S4 baseline study, for which follow-up data were available also at the KORA F4 7 years later. After exclusion for hypertriglyceridemia (defined as having a fasting triglyceride level above 1.70 mmol/L) and diabetes at baseline, 755 subjects remained for analyses. RESULTS: Increased levels of leucine, arginine, valine, proline, phenylalanine, isoleucine and lysine were significantly associated with an increased risk of hypertriglyceridemia. These associations remained significant when restricting to those individuals who did not develop T2D in the 7-year follow-up. The increase per standard deviation of amino acid level was between 26 and 40 %. CONCLUSIONS: Seven amino acids were associated with an increased risk of developing hypertriglyceridemia after 7 years. Further studies are necessary to elucidate the complex role of these amino acids in the pathogenesis of metabolic disorders.

Preoperative risk factors related to bladder cancer rehabilitation: a registry study.

INTRODUCTION: Patients diagnosed with (muscle-) invasive bladder cancer (IBC) are more likely to harbour comorbidities due to their advanced age at diagnosis. Under-nutrition is a predictor for postoperative morbidity and mortality in cancer patients, but under-reported in urology. Understanding the IBC patient profile before major surgery could facilitate and optimise outcome of the surgical patient. BACKGROUND/OBJECTIVES: To identify preoperative risk factors for early rehabilitation before radical cystectomy (RC). SUBJECTS/METHODS: A historical registry-based study of 76 patients referred for RC at Aarhus University Hospital, Denmark (DK) in 2009. Early rehabilitation was defined by length of stay (LOS) postoperatively with a cutoff ≥11 days. High comorbidity was expressed by the charlson comorbidity index score (CCI) ≥3. LOS was calculated by linking the unique Civil Registration Number with the National Patient Registry. Preoperative nutritional risk was identified using the screening tool, nutritional risk score 2002 (NRS) of the European Society of Clinical Nutrition and Metabolism. Multivariate analysis was used to identify risk factors for early rehabilitation. RESULTS: The proportion of patients at preoperative nutritional risk was 26% (95% confidence interval (CI): (95% CI: 17; 37) and 43% of patients held a high CCI (95% CI: 33; 55). Prolonged LOS was independently associated with female gender (P=0.02) and age ≥70 years (P=0.04). NRS and CCI were not associated with LOS. CONCLUSIONS: Attention should be focused on women and elderly patients undergoing RC to optimise early rehabilitation and reduce LOS. It is still unknown whether preoperative nutritional risk and comorbidity are obstacles in early rehabilitation of RC patients.

Isolation and characterization of the gene encoding EF-1 alpha O, an elongation factor 1-alpha expressed during early development of Xenopus laevis.

In Xenopus laevis, the gene encoding the elongation factor 1-alpha variant EF-1 alpha O, where O stands for oocyte, is expressed in oocytes and early embryos. A genomic library from X. laevis was screened with a cDNA probe coding for EF-1 alpha O. Two recombinant phages were isolated, one of which carries an entire EF-1 alpha O gene. This clone was characterized by restriction enzyme mapping and sequencing. Comparison of cDNA and genomic sequences revealed that EF-1 alpha O consists of seven exons spanning about 6.5 kb. The structure of the gene is very homologous to the human EF-1 alpha gene, as all locations of the splice junctions are conserved between the two genes. The sequence immediately upstream from the transcription start point (tsp) contains a CCAAT box, but does not contain either a TATA box or a Sp1-binding site. Interestingly, this sequence has a sequence homologous to the negative regulatory element from the TFIIIA promoter. A region located about 400 bp upstream from the tsp contains an additional number of possible regulatory sequence elements. The first intron contains G + C-rich elements which exist both isolated and as part of longer inverted repeats. Furthermore, one octamer and four Sp1-binding sites are found in this intron.

Purification and characterization of a growth inhibitory hepatic peptide. A preliminary note.

A pentapeptide isolated from normal mouse liver seems to inhibit DNA synthesis (3H-thymidine incorporation into liver DNA and labeling indices) and the mitotic rate (G2-M cell flux) in regenerating mouse liver. The inhibitor is somewhat similar to the growth inhibitory pentapeptides previously reported for granulocytes and epidermis. It is active at very low dose levels, showing a bell-shaped dose-response curve.