N-acetylglutamate synthase deficiency and the treatment of hyperammonemic encephalopathy

Carbamylphosphate synthase is the first enzymatic reaction of the urea cycle. Its activator, N-acetylglutamate, is synthesized from acetyl-CoA and glutamate in a reaction catalyzed by N-acetylglutamate synthase (NAGS). We have identified the putative human NAGS gene and report the first mutation in this gene in a family with carbamylglutamate responsive hyperammonemia and normal activity of the urea cycle enzymes. Mutation analysis has a higher diagnostic specificity than the enzymatic assay in NAGS deficiency. A therapeutic trial with carbamylglutamate is recommended whenever hyperammonemia without an organic aciduria, increased orotate excretion, or diagnostic amino acidemia/uria is detected.     

The effect of continuous intraabdominal nebulization of lidocaine during gynecological laparoscopic procedures- a pilot study

Although laparoscopic surgery is known to cause less postoperative pain when compared to laparotomy, some patients still suffer from excessive pain, especially during the first stages of recovery. The purpose of our study was to assess the effect of intraperitoneal nebulization of lidocaine during gynecological laparoscopic procedures on perioperative pain. The study was a prospective, randomized, double-blinded, placebo-controlled trial (Canadian task force classification I) that included 23 patients who underwent outpatient gynecological laparoscopic procedures. Patients were randomly assigned either to a study group that received 5 mg/kg of lidocaine intraperitonealy during surgery (n=15) or to a control group that received sterile water in the same manner (n=8). The fluid was infuslated along with the CO₂ through a Insuflow® device. All patients received the same anesthetic technique. Intraoperative pain as assessed by changes in the vital signs was treated with fentanyl. Postoperative pain was evaluated according to postoperative opioid requirements and by the Visual Analogue Scale (VAS) at 15 min, 1 h and 24 h postoperatively. The VAS score was found to be lower for the study group 1 h after surgery (p=0.023). There was no difference in the VAS scores at 15 min (p=0.9) and 24 h (p=0.11) after surgery. A correlation analysis showed no association between the amount of lidocaine insufflated and the severity of the postoperative pain. There was no difference in terms of fentanyl administration during surgery or opiod consumption following surgery between the groups. We concluded that continuous intraperitoneal insuflation of lidocaine using an Insuflow® device may significantly reduce pain in the initial stage of postoperative recovery.     

The molecular background of glycogen metabolism disorders

The molecular pathology of classical glycogen storage disorders, glycogen synthase deficiency and Fanconi-Bickel syndrome is reviewed. The isolation of the respective cDNAs, the chromosomal localization of the genes and the elucidation of the genomic organization enabled mutation analysis in most disorders. The findings have shed light on the multi-protein structure of the glucose-6-phosphatase system, the phosphorylase kinase enzymatic complex and the molecular background of the differential tissue expression in debranching enzyme deficiency. The immediate practical benefit of these studies is our extending ability to predict the outcome of clinical variants and to offer genetic counseling to most families. The elucidation of the tertiary structure of these proteins and their structure-function relationship poses major challenges for the future.     

Rasagiline: neurodegeneration, neuroprotection, and mitochondrial permeability transition

Mitochondria are involved directly in cell survival and death. The assumption has been made that drugs that protect mitochondrial viability and prevent apoptotic cascade-induced mitochondrial permeability transition pore (MPTp) opening will be cytoprotective. Rasagiline (N-propargyl-1R-aminoindan) is a novel, highly potent irreversible monoamine oxidase (MAO) B inhibitor anti-Parkinson drug. Unlike selegiline, it is not derived from amphetamine, and is not metabolized to neurotoxic L-methamphetamine derivative. In addition, it does not have sympathomimetic activity. Rasagiline is effective as monotherapy or adjunct to levodopa for patients with early and late Parkinson's disease (PD) and adverse events do not occur with greater frequency in subjects receiving rasagiline than in those on placebo. Phase III controlled studies indicate that it might have a disease-modifying effect in PD that may be related to its neuroprotective activity. Its S isomer, TVP1022, is more than 1,000 times less potent as an MAO inhibitor. Both drugs, however, have neuroprotective activity in neuronal cell cultures in response to various neurotoxins, and in vivo in response to global ischemia, neurotrauma, head injury, anoxia, etc., indicating that MAO inhibition is not a prerequisite for neuroprotection. Their neuroprotective effect has been demonstrated to be associated directly with the propargylamine moiety, which protects mitochondrial viability and MTPp by activating Bcl-2 and protein kinase C (PKC) and by downregulating the proapoptotic FAS and Bax protein families. Rasagiline and its derivatives also process amyloid precursor protein (APP) to the neuroprotective, neurotrophic, soluble APP alpha (sAPPalpha) by PKC- and MAP kinase-dependent activation of alpha-secretase. The identification of the propargylamine moiety as the neuroprotective component of rasagiline has led us to development of novel bifunctional anti-Alzheimer drugs (ladostigil) possessing cholinesterase and brain-selective MAO inhibitory activity and a similar neuroprotective mechanism of action.     

It's not because I'm fat: perceived overweight and anger avoidance in marriage

Employed married Israeli women responded to questions about their perceived weight, their husbands' evaluation of their appearance, and their expression of anger in marriage. Our data, based on 125 questionnaires and five in-depth interviews, supports the possibility that women who perceive themselves as overweight, that is, "fail" to live up to the standards of female beauty in society, often suppress their anger and express it in limited areas. Our findings suggest that women who have not been able to resist the appearance-directed normative imperative in the constitution of their feminine self have to work harder to meet gender norms that require "emotion work" in the form of anger avoidance.     

Hypocarnitinemia in lysinuric protein intolerance

Carnitine deficiency in lysinuric protein intolerance (LPI) has been reported only in a single case. We describe hypocarnitinemia in a 11 year-old male patient with LPI and relate its development to intake, biosynthesis, and uptake of carnitine.     

Characterization of T cell differentiation in the murine gut

Gut intraepithelial CD8 T lymphocytes (T-IEL) are distinct from thymus-derived cells and are thought to derive locally from cryptopatch (CP) precursors. The intermediate stages of differentiation between CP and mature T-IEL were not identified, and the local differentiation process was not characterized. We identified and characterized six phenotypically distinct lineage-negative populations in the CP and the gut epithelium: (a) we determined the kinetics of their generation from bone marrow precursors; (b) we quantified CD3-epsilon, recombination activating gene (Rag)-1, and pre-Talpha mRNAs expression at single cell level; (c) we characterized TCR-beta, -gamma, and -alpha locus rearrangements; and (d) we studied the impact of different mutations on the local differentiation. These data allowed us to establish a sequence of T cell precursor differentiation in the gut. We also observed that the gut differentiation varied from that of the thymus by a very low frequency of pre-Talpha chain mRNA expression, a different kinetics of Rag-1 mRNA expression, and a much higher impact of CD3 epsilon/delta and pre-Talpha deficiencies. Finally, only 3% of CP cells were clearly involved in T cell differentiation, suggesting that these structures may have additional physiological roles in the gut.