Missense mutations in codon 225 of ornithine transcarbamylase (OTC) result in decreased amounts of OTC protein: A hypothesis on the molecular mechanism of the OTC deficiency

Mutations P225L and P225R were identified in codon 225 of the gene for ornithine transcarbamylase (OTC) in two patients with the neonatal form of OTC deficiency. The mutations occur at a CpG dinucleotide and eliminate a unique MspI restriction site in exon 7 of the OTC gene. They do not alter existing splice sites or create new sites, as judged from the nucleotide sequence. Both mutations are associated with undetectable levels of OTC antigen in liver homogenates, and with either complete lack of OTC activity (P225R mutation) or very small residual activity (0.15% of normal in the P225L mutation). The residual activity observed with P225L exhibits normal pH dependence, little or no increases in the Km values for ornithine and carbamoyl phosphate and normal stability at either 37°C or, in the presence of 0.66 mol/L urea, at 0°C. The latter conditions were used to examine whether the P225L mutation favours dissociation of the active OTC trimer. Given the normal stability and lack of tendency to dissociation of the mutant enzyme, it appears likely that the dramatic reduction in the level of OTC protein is due to inefficient conversion of the mutant OTC precursor polypeptide (pOTC) into the correctly localized, appropriately folded, mature enzyme trimer, suggesting degradation of pOTC in transit to the mitochondria.     

Disposition of [3H]flobufen and its active metabolite in rats

The present authors investigated the excretion, distribution and pharmacokinetics of the novel potential antirheumatic agent flobufen and its active metabolite after p.o. and i.v. doses of 2, 10 and 50 mg/kg administered to rats. The drug is resorbed well from the digestive tract and mostly it is metabolized to the principal metabolite M, which is only slowly excreted from the organism mainly by renal clearance. Within the whole dose range the kinetics of the drug is linear. Binding of flobufen and M to proteins is high (95-99%). The highest concentrations of radioactive metabolites (mostly M) were found in the plasma, liver, lungs, kidneys, connective tissue and inflammatory foci. The penetration of metabolites through the placenta and excretion in human milk are relatively important.     

Aluminiumoxidkeramik in der rekonstruktiven Nasenchirurgie. Histologische Untersuchungen am Kaninchen

Summary In cases where a reconstruction of defects in the larynx, oral cavity, the pharynx or in the ear region has been performed using skin flaps, a temporary fistula is formed at the point of entry.This fistula can be closed later after the flap has taken and the flap pedicle dissected.We would like to demonstrate with some examples that with the use of deepithelisation it is possible to achieve a primary wound closure. This way no temporary fistula results and additional surgery is avoided in many cases.Furthermore flap deepithelisation offers a way to bring good vascularised tissue under the skin and cover subcutaneous defects, for example those after radiotherapy.

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Die Veröffentlichung des Manuskripts soll in Laryngol Rhinol Otol (Stuttg) erfolgen     

Melatonin modifies the spontaneous multiunit activity recorded in several brain nuclei of freely behaving rats.

Melatonin, a pineal hormone, released photoperiodically, was administered systemically in rats, previously implanted with semimicroelectrodes into six different brain structures. The multiunit electrical activity of these structures was recorded for 10 min before and 60 min after melatonin administration in unanesthetized, freely moving rats. Different melatonin doses (100, 200, 500, and 1000 micrograms/kg) produced changes in the electrical activity of all tested structures. However, amygdala, rostral hypothalamus and mesencephalic reticular formation showed the most important changes. The main effect induced by melatonin was a dose-related decrease of the spontaneous electrical activity. The significance of these effects is discussed within the context of the behavioral and endocrinological effects of melatonin.     

Long-lasting effects of chronic chlorimipramine treatment of rats on exploratory activity on a hole-board, and on immobility in the forced swimming test

The study concerned the effects of acute and chronic clomipramine administration to male rats on exploratory activity in a novel environment (hole-board) and on immobility in the forced swimming test. Acute clomipramine administration did not alter either exploratory activity on a hole-board as measured 3 or 20 h after drug administration, or immobility in the forced swimming test as measured 20 h after drug administration. Approximately 20 h after the last injection of clomipramine, the rats chronically treated with the drug showed reduced exploratory activity on the hole-board. In contrast, chronic clomipramine treatment significantly increased the activity in the forced swimming test. The effects of the drug on exploratory and forced swimming activities persisted for 14 days after the cessation of clomipramine administration. These data indicate that chronic clomipramine administration exerted profound and long-lasting effects on central nervous system function. The long-lasting action of the drug on behaviour in the forced swimming test might explain the long-term beneficial effect of antidepressant drugs in counteracting behavioral depression.     

Specific sensitization to common allergens and pulmonary function in the European Community Respiratory Health Survey

BACKGROUND: The role of atopy in the evolution to chronic obstructive disease remains controversial. AIM: We aimed to assess the association between individual sensitization to common allergens and lung function. METHOD: We analysed data from 12,687 subjects aged 20 to 44 years, from 34 centres in 15 countries participating in the European Community Respiratory Health Survey (ECRHS). Participants performed a blood test, lung function test, methacholine challenge, and answered an administered questionnaire. The relationships between specific IgE, FEV1 and FEV1/FVC ratio were assessed for each study centre stratified by sex, followed by random effects meta-analysis. RESULTS: Asthmatics sensitized to house dust mite had a lower FEV1 (-119 mL in women and -112 mL in men) and FEV1/FVC ratio (-1.95%, and -2.48%) than asthmatics without sensitization. Asthmatics sensitized to cat had a lower FEV1 (statistically significant for women only) and a lower FEV1/FVC ratio. Asthmatic women sensitized to grass had a lower FEV1 and a lower ratio, and those sensitized to Cladosporium had a lower FEV1. A weak association was found with sensitization to cat and to Cladosporium among non-asthmatic women, which disappeared after adjusting for BHR. CONCLUSION: We conclude that atopy was related to a lower lung function, which was only apparent among asthmatics. This relationship was explained by specific sensitization to cat and to house dust mite, the latter being homogeneous across areas.