Effect of alae nasi activation on maximal nasal inspiratory airflow in humans

The upper airway is a complicatedstructure that is usually widely patent during inspiration. However, oninspiration during certain physiological and pathophysiological states,the nares, pharynx, and larynx may collapse. Collapse at theselocations occurs when the transmural pressure (Ptm) at a flow-limitingsite (FLS) falls below a critical level (Ptm'). On airwaycollapse, inspiratory airflow is limited to a maximal level(I_max)determined by (Ptm')/Rus, where Rus is the resistanceupstream to the FLS. The airflow dynamics of the upper airway areaffected by the activity of its associated muscles. In this study, weexamine the modulation ofI_maxby muscle activity in the nasal airway under conditions of inspiratoryairflow limitation. Each of six subjects performed sniffs through onepatent nostril (pretreated with an alpha agonist) while flaring thenostril at varying levels of dilator muscle (alae nasi) EMG activity(EMGan). For each sniff, we located the nasal FLS with an airwaycatheter and determinedI_max,Ptm', and Rus. Activation of the alae nasi from the lowest to thehighest values of EMGan increasedI_maxfrom 422 ± 156 to 753 ± 291 ml/s (P < 0.01) and decreasedPtm' from 3.6 ± 3.0 to 6.0 ± 4.7 cmH₂O (P < 0.05). Activation of the alaenasi had no consistent effect on Rus.I_maxwas positively correlated with EMGan, and Ptm' was negativelycorrelated with EMGan in all subjects. Our findings demonstrate thatalae nasi activation increasesI_maxthrough the nasal airway by decreasing airway collapsibility.

     

Behavioral effects and in vivo degradation of intraventricularly administered dynorphin-(1-13) and D-Ala2-dynorphin-(1-11) in rats

Lateral intraventricular (LV) or cerebral aqueduct (CA) administration of the opioid peptide, dynorphin-(1-13), induced catalepsy and analgesia in rats. Onset was earlier and duration shorter than with morphine or β_c-endorphin. The dose required to induce analgesia was reduced at least tenfold when dynorphin-(1-13) was administered into CA rather than LV. An analogue, D-Ala²-dynorphin-(1-11), was more stable than dynorphin-(1-13) in brain, and produced a comparable degree of catalepsy and even more profound analgesia at one-tenth the dose. These effects of dynorphin-(1-13) and D-Ala²-dynorphin-(1-11) were significantly antagonized by naloxone pretreatment. Rats treated with dynorphin-(1-13) or a high dose of D-Ala²-dynorphin-(1-11) exhibited bizarre postures immediately following LV administration, with limb rigidity and “barrel-rolling”. These effects were not blocked by naloxone.     

Occurrence of a polyubiquitin structure in ubiquitin-protein conjugates

In the ubiquitin-mediated pathway for the degradation of intracellular proteins, several molecules of ubiquitin are linked to the protein substrate by amide linkages. It was noted that the number of ubiquitin-protein conjugates and their apparent molecular size are higher than expected from the number of amino groups in the protein. When the amino groups of ubiquitin were blocked by reductive methylation, it was efficiently conjugated to lysozyme, but the higher-molecular-weight conjugates were not formed. This suggests that the higher-molecular-weight conjugates with native ubiquitin contain structures in which one molecule of ubiquitin is linked to an amino group of another molecule of ubiquitin. Methylated ubiquitin stimulated protein breakdown at about one half the rate obtained with native ubiquitin, and isolated conjugates of 125I-lysozyme with methylated ubiquitin were broken down by reticulocyte extracts. These findings indicate that the formation of polyubiquitin chains is not obligatory for protein breakdown, though it may accelerate the rate of this process.     

Regulation of the initial segment of the murine epididymis by dihydrotestosterone and testicular exocrine secretions studied by expression of specific proteins and gene expression

The murine caput epididymidis responded to deprivation of luminal fluid from the testis by regression of the initial segment but maintenance of the adjacent proximal and distal caput regions, as judged by immuno-histochemical staining of the glutamate transporter EAAC1 and the lipocalin MEP17 and enzymatic activity of -galactosidase (-Gal). Additional removal of circulating androgens by bilateral castration similarly led to loss of the initial segment and of the proximal caput but the distal caput was transformed into an epithelium containing more apical than principal cells staining for EAAC1; this epithelium resembled the precursor epithelium usually only seen in prepubertal juveniles. Administration of dihydrotestosterone (DHT) to the castrates maintained the proximal and distal caput epithelia and induced a proximal epithelium, which resembled the initial segment in its prominent staining for Golgi, EAAC1 and -Gal activity, although it was short and exhibited no MEP17 expression. DHT was present in the c-ros knockout caput epididymidis lacking the initial segment and in the heterozygous organ but the DHT concentration was lower in the knockout corpus. The maintenance of the full complement of epithelia in the murine caput epididymidis in the adult thus requires a combination of luminal fluid from the testis, tissue DHT and the presence of the c-ros oncogene.     

Development of the caput epididymidis studied by expressed proteins (a glutamate transporter,a lipocalin and β-galactosidase) in the c-<Emphasis Type="Italic">ros</Emphasis> knockout and wild-type mice with prepubertally ligated efferent ducts

Expression of a glutamate transporter (EAAC1), a lipocalin (MEP17) and -galactosidase (-Gal) in histological sections was used to monitor post-natal development of the murine epididymis. Three epithelia in the adult caput of wild-type mice were distinguished: I, the initial segment; II, the proximal caput; and III, the distal caput. The regions in which epithelia I, II and III were situated were called regions I, II and III, respectively. Regions I, II and III developed from a precursor epithelium present on day 14; from day 16, a presumptive region I epithelium was evident and, by day 21, epithelia characteristic of future regions II and III appeared. The relationship between the c-ros gene and the initial segment was studied by investigating the development of the caput epididymidis in transgenic homozygous c-ros knockout (–/–) mice that lack the initial segment, heterozygous (+/–) males and wild-type males in which the efferent ducts had been ligated prepubertally so that the initial segment failed to develop. In mice with prepubertally ligated efferent ducts, regions II and III developed normally but region I was missing in the adult and expression of c-ros was partially decreased. In (–/–) mice, the precursor epithelium was present, differentiation of epithelium II was delayed until day 32 and epithelium I never developed. Thus, caput region I develops before c-ros expression, high testosterone secretion and differentiation of regions II and III but not if the organ is deprived of the oncogene c-ros or testicular exocrine secretions. The caput of the knockout male lacks solely the initial segment so that the efferent ducts are in continuity with the post-initial segment, proximal caput region. The ligand for c-ros may be present in testicular fluid and both ligand and receptor may be necessary for differentiation of epithelia I and II.This work was funded by the Deutsche Forschungsgemeinschaft (the male gamete: production, maturation, function, FOR 197/3-1)     

Quantitative structure-activity relationship by CoMFA for cyclic urea and nonpeptide-cyclic cyanoguanidine derivatives on wild type and mutant HIV-1 protease

Abstact 3D-QSAR studies using the Comparative Molecular Field Analysis (CoMFA) methodology were conducted to predict the inhibition constants, K_i, and the inhibitor concentrations, IC₉₀ of 127 symmetrical and unsymmetrical cyclic urea and cyclic cyanoguanidine derivatives containing different substituent groups such as: benzyl, isopropyl, 4-hydroxybenzyl, ketone, oxime, pyrazole, imidazole, triazole and having anti-HIV-1 protease activities. A significant cross-validated correlation coefficient (q²) of 0.63 and a fitted correlation coefficient r² of 0.70 were obtained, indicating that the models can predict the anti-protease activity from poorly to highly active compounds reliably. The best predictions were obtained for: XV643 (predicted log 1/K_i=9.86), a 3,5-dimethoxy-benzyl cyclic urea derivate (molec60, predicted log 1/K_i=8.57) and a benzyl cyclic urea derivate (molec 61, predicted log 1/IC₉₀=6.87). Using the CoMFA method, we also predicted the biological activity of 14 cyclic urea derivatives that inhibit the HIV-1 protease mutants V82A, V82I and V82F. The predicted biological activities of the: (i) XNO63 (inhibitory activity on the mutant HIV-1 PR V82A), (ii) SB570 (inhibiting the mutant HIV-1 PR V82I) and also (iii) XV652 (during the interaction with the mutant HIV-1 PR V82F) were in good agreement with the experimental values.Figure Stereoview of the contour plots of the CoMFA steric and electrostatic fields. The favorable (indicated by blue polyhedra) and unfavorable (represented by red polyhedra) electrostatic areas and also the favorable (shown by green polyhedra) and unfavorable (shown by yellow polyhedra) steric areas formed around the most active molecule, 6a.     

Attempts to demonstrate complement fixing antibodies in mycetoma

Complement fixation test has a diagnostic value only when it is positive and specific. In some mycetomas caused byM. apiospermum andC. falciforme the diagnosis could be made a few days earlier before the identification of the causative agent by culture. In cases produced by opportunistic organisms such asA. fumigatus, S. albus, C. falciforme, the specific serological tests together with the repeated isolation of the fungus in culture, constituted the evidence in favor of the validity of the isolate.

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Zusammenfassung Die Komplementfixierung hat einen diagnostischen Wert nur in dem Falle, wenn sie positiv und spezifisch ist. In manchen Mycetomen, verursacht durchM. apiospermum undC. falciforme konnte die Diagnose etliche Tage früher gemacht worden vor der Identifizierung des Pilzes durch Kultur. In den durch opportunistische Organismen verursachten Fällen, z. B. durchA. fumigatus, S. albus, C. falciforme lieferte der spezifische serologische Test in Zusammenhang mit der wiederholten Isolierung des Pilzes den Beweis für die Erregernatur des durch Kultur isolierten Pilzes.

     

Death Squad: The Anthropology of State Terror

Death Squad: The Anthropology of State Terror. Jeffrey A. Sluka. ed. Philadelphia: University of Pennsylvania Press, 2000. 260 pp.