Effects of hypophysectomy and ACTH on opiate tolerance and physical dependence.

In opiate-naive hypophysectomized rats, the enhanced potency of parenterally injected morphine was almost completely normalized by chronic ACTH in doses that maintained adrenal weight. Following morphine pellet implantation, the amount of morphine required for antinociception, catalepsy, and colonic temperature effects in tolerant rats was identical among hypophysectomized and sham-operated rats whether or not chronic ACTH was administered. However, brain levels of morphine were greater in tolerant, hypophysectomized rats, an effect blocked by chronic ACTH. Hypophysectomy thus appears to enhance the magnitude of tolerance development by a mechanism that is reversed by doses of ACTH that maintain adrenal weight. On the other hand, in sham-control rats this dose and schedule of ACTH were without effect on morphine potency in opiate-naive or tolerant rats or on brain levels of morphine. In general, hypophysectomy and/or ACTH did not modify the intensity of abstinence signs following naloxone-precipitated withdrawal. Therefore, little evidence was obtained to suggest a direct, commanding role of the pituitary in chronic opiate effects. Instead, a secondary adrenal involvement may be important.     

Cytolysin A-mediated protein exportation efficiency and its role in enhancing the fitness of live recombinant Salmonella Typhi vaccine strain

The genetic fusion of cytolysin A (clyA) to heterologous antigen expressed in live Salmonella vector demonstrated efficient translocation into periplasmic space and extracellular medium. Accumulating evidence has shown that clyA-mediated antigen delivery improved growth fitness and enhanced immunogenicity of live vector vaccine, but the factors influencing this protein exportation has not been investigated. In this study, Toxoplasma gondii antigen fused at C-terminal of clyA protein was expressed in live S. Typhi vector via both plasmid and chromosomal-based expressions. The bivalent strains showed comparable growth rates as monovalent strains, but in varies antigen exportation efficiency. ClyA-fusion antigen with positive charges was translocated to the extracellular spaces, whereas those with negative charges were retained in the cytoplasm. Furthermore, excessive cellular resources expenditure on antigen expression, especially antigen with larger size, could limit the clyA-fusion antigen exportation, resulting in undesirable metabolic burden that eventually affects the growth fitness. Altogether, the present work indicates potential linkage of factors mainly on antigen properties and expression platforms that may affect clyA-mediated antigen delivery to enhance the growth fitness of live vector strain.     

Immunoreactive peptides related to dynorphin B (=rimorphin) in the rat brain

We have developed a radioimmunoassay for synthetic dynorphin B, a novel opioid tridecapeptide, which shares a common precursor molecule with dynorphin_1–17 (=dynorphin A) and the neo-endorphins. The levels of immunoreactivity towards this peptide in rat brain and pituitary show a pattern quantitatively and qualitatively similar to those found for dynorphin A and -neo-endorphin in earlier studies. The antiserum used was highly specific with only dynorphin-32 and dynorphin B-29, both of which contain the dynorphin B sequence, showing substantial cross-reactivity. Gel filtration of whole rat brain extracts in combination with HPLC analysis provide strong evidence for the existence of these latter two peptides in rat brain.     

Determination of chlorpromazine and its major metabolites by gas chromatography/mass spectrometry: application to biological fluids

A method for the quantitative determination of chlorpromazine and five of its major metabolites in a single sample of biological fluid in the ng/ml range has been developed utilizing gas chromatography/mass spectrometry with selected ion recording. The assay is highly specific and quantification is accomplished by an inverse stable isotope dilution technique, using deuterium-labeled variants of the compounds as internal standards. In this way the concentrations of chlorpromazine and five of its major metabolites (the sulfoxide, the N-oxide, the monodemethylated, the didemethylated, and the 7-hydroxylated compounds) can be determined in biological fluids. Levels in humans have been measured both in plasma and in red blood cells and are compared to those found in related in vitro studies.     

A model for opiate-receptor interactions: mechanism of opiate-cerebroside sulfate interaction.

Narcotic analgetics were shown to bind cerebroside sulfate (CS) with high affinity. The binding correlated well with their pharmacological potency. In order to understand opiate receptor interaction at the molecular level, we have proposed the use of CS as a model opiate receptor. In these studies, our data indicate that the binding of opiates is determined by the heptane solubility of the drugs and their affinity to CS. The affinity of the agonist to CS is higher than that of its corresponding antagonist. The difference in affinity between an agonist and its corresponding antagonist is mainly due to the strength of electrostatic bond formed between the protonated nitrogen of the drug and the sulfate group of CS. Furthermore, we have concluded that narcotic agonist-CS complexes are more hydrophobic (intimate ion pairs formation) while the antagonist-CS complexes are more hydrophilic (hydrated ion pairs) in nature.     

Risk stratification and subclinical phenotyping of dilated and/or arrhythmogenic cardiomyopathy mutation-positive relatives: CVON eDETECT consortium

In relatives of index patients with dilated cardiomyopathy and arrhythmogenic cardiomyopathy, early detection of disease onset is essential to prevent sudden cardiac death and facilitate early treatment of heart failure. However, the optimal screening interval and combination of diagnostic techniques are unknown. The clinical course of disease in index patients and their relatives is variable due to incomplete and age-dependent penetrance. Several biomarkers, electrocardiographic and imaging (echocardiographic deformation imaging and cardiac magnetic resonance imaging) techniques are promising non-invasive methods for detection of subclinical cardiomyopathy. However, these techniques need optimisation and integration into clinical practice. Furthermore, determining the optimal interval and intensity of cascade screening may require a personalised approach. To address this, the CVON-eDETECT (early detection of disease in cardiomyopathy mutation carriers) consortium aims to integrate electronic health record data from long-term follow-up, diagnostic data sets, tissue and plasma samples in a multidisciplinary biobank environment to provide personalised risk stratification for heart failure and sudden cardiac death. Adequate risk stratification may lead to personalised screening, treatment and optimal timing of implantable cardioverter defibrillator implantation. In this article, we describe non-invasive diagnostic techniques used for detection of subclinical disease in relatives of index patients with dilated cardiomyopathy and arrhythmogenic cardiomyopathy.     

The stimulation of indoleacetic acid synthesis in bush bean plants (Phaseolus vulgaris L.) by naphthenates

A 12 hr seed soak in a solution of 100 ppm of potassium naphthenatesresulted in 140.5% stimulation of IAA synthesis determined in5–8 cm tips of epicotyls of 14-day-old dark-grown Phaseolusvulgaris seedlings. (Received September 1, 1973; )     

FOXO1 constrains activation and regulates senescence in CD8 T cells

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