Protection from extinction in human fear conditioning.

Two experiments examined the ability of an added stimulus to interfere with extinction of a target excitatory fear stimulus (a predictor of shock) in human autonomic conditioning. Both experiments demonstrated disruption of extinction when the added stimulus was inhibitory (a predictor of no shock, or safety signal). Subjects showed a return of fear when the target stimulus was tested alone, on both self-reported shock expectancy and skin conductance measures. The second experiment also demonstrated disruption of extinction when the added stimulus was excitatory. This results suggests that protection from extinction may occur even when the added stimulus is not inhibitory. Additional factors that may contribute to protection from extinction include context-specificity, occasion-setting and external inhibition. The results highlight the role that concurrent stimuli play in extinction, and emphasise the need to keep concurrent stimuli as similar as possible to the desired transfer context in practical applications of extinction such as exposure therapy for anxiety.

A physiological model for the distribution of injected agents, with special reference to pethidine.

The model is based on Mapleson's Model P for inhaled anaesthetics, but has compartments for lungs, peripheral shunt, kidneys, portal bed, liver, other viscera, muscle, other lean, fat, brain, i.m. injection site and for various blood "pools". Intracellular and extracellular fluids are represented separately in each compartment and in blood. In each fluid, four forms of the agent are distinguished: unionized dissolved in water ("standard" form), ionized dissolved in water, unionized dissolved in lipid, and bound to protein. Equations define the equilibrium between these four forms in any one fluid and between blood and tissue. After changing two of the more uncertain numbers in the quantification for pethidine, good agreement was obtained between computed and published venous concentrations after single i.v. and i.m. injections, continuous i.v. infusions and repeated i.m. injections. The model can be used to make a wide variety of "what if" predictions.

Effects of acute ethanol administration on rat liver 5-aminolaevulinate synthase activity.

1. Liver 5-aminolaevulinate (ALA) synthase activity of 24 h-starved rats is maximally increased at 4 h after intraperitoneal administration of a 1.6 g/kg body wt. dose of ethanol. Larger doses cause a dose-dependent decrease in the extent of this stimulation, exhibiting a reciprocal relationship with an elevation of hepatic haem concentration, as suggested by the simultaneous increase in the haem saturation of tryptophan pyrrolase. 2. ALA synthase induction by ethanol is abolished if the above increase in pyrrolase saturation with haem is enhanced by theophylline, but is potentiated when the increase in the haem saturation is inhibited by anti-lipolytic agents. 3. ALA synthase induction by ethanol is also inhibited by inhibitors of alcohol dehydrogenase and aldehyde dehydrogenase. Acetaldehyde and acetate are, however, not responsible; they both decrease ALA synthase activity and increase the haem saturation of tryptophan pyrrolase. These latter effects of acetaldehyde are not mediated by acetate. 4. ALA synthase activity is also stimulated by succinate, which, however, also increases the haem saturation of tryptophan pyrrolase. 5. Ethanol does not influence the rate of ALA synthase degradation. 6. It is suggested that ethanol increases rat liver ALA synthase activity as a result of its own metabolism by the alcohol dehydrogenase-dependent pathway by a mechanism not involving decreased degradation of the former enzyme or the participation of the metabolites acetaldehyde and acetate.

Valve replacement in children under 14 years of age: a review of 22 years of experience.

From 1964 to 1986, a total of 18 valve replacement operations were performed in 15 children under 14 years of age, with 13% operative mortality. Eleven children had a mitral valve replacement, with 3 subsequently requiring reoperation. Twelve Starr-Edwards caged ball prostheses, 1 Björk-Shiley and 1 Carpentier-Edwards prosthesis were implanted in the mitral position, with 18% operative mortality. Three children underwent aortic valve replacement, 1 with a Björk-Shiley prosthesis and 2 with a Starr-Edwards. One patient had tricuspid valve replacement utilizing a Starr-Edwards valve. Thirteen patients had one or more cardiac operations prior to valve replacement. Two late deaths occurred 8 and 18 months, respectively, group, 1 from a cardiac arrhythmia and 1 from fulminating prosthetic valve endocarditis. There were no late deaths in other patients. There was one thromboembolic episode in the entire group. At follow-up, 10 patients were classified as New York Heart Association Functional Class I and 1 patient was Class III. Valve replacement in children can be carried out with low mortality and good long-term results using the Starr-Edwards caged ball prosthesis.

Repair of traumatic aortic transection: a management protocol and review of twenty-one patients.

Between 1970 and 1987, 21 patients at St. Vincent Hospital and Medical Center underwent surgery for repair of a transected descending aorta. Nineteen of the transections were a result of trauma secondary to motor vehicle accidents, 1 was secondary to compression injury of the chest, and 1 was the result of a fall. All of the patients had diagnostic chest X-rays and all but one X-ray showed a widened mediastinum. Aortography was carried out in 20 cases. Atrio-femoral bypass was used for all but 2 patients, who had femoro-femoral bypass. The mean cross-clamp time was 53 minutes. Interposition graft was used in 16 patients, an intraluminal graft in 1 patient, and primary repair was performed in 2 patients. Survival was 71%, with 4 of the 21 patients expiring in the operating room (2 before the repair could be undertaken), one patient expiring during a laparotomy 2 days after the aortic repair, and one patient expiring 4 days after the repair. Fifteen patients were discharged alive. Survival and patient care could be improved by careful diagnostic assessment and by following a protocol agreed upon by a team of surgeons.

Effects of the haem precursor 5-aminolaevulinate on tryptophan metabolism and disposition in the rat.

5-Aminolaevulinate administration to rats inhibits cerebral 5-hydroxytryptamine synthesis by decreasing tryptophan availability to the brain secondarily to activation of hepatic tryptophan pyrrolase. The results show that tryptophan metabolism and disposition can be influenced by changes in liver haem concentration, and are discussed briefly in relation to mood disorders in the hepatic porphyrias.

Structure and quantification of a physiological model of the distribution of injected agents and inhaled anaesthetics.

Mapleson's (1973) physiological, circulation-time model of the distribution of inhaled anaesthetics has been elaborated to be suitable for modelling agents in which hepatic metabolism and renal excretion are important factors; as well as the obvious improvement of providing separate compartments for liver and kidney, the arterial and portal supplies to the liver are separately represented, as is the portal blood pool. The separate portal pool also leads to a more realistic total circulation time for the majority of the cardiac output. The quantification for a "standard man" is fully documented and makes use of the latest (1975) report of the International Commission on Radiological Protection, Reference Man, and includes data on the water, fat and protein composition of each tissue compartment. Suggestions are included on adapting the quantification to non-standard men and to other species.

Dihydropyridine precursors of elastin crosslinks.

Dihydrodesmosine and dihydroisodemosine are dihydropyridines which are believed to be the immediate biosynthetic precursors of desmosine and isodesmosine, the stable pyridinium ion crosslinks of elastin. It has recently been reported that appreciably amounts of dihydrodesmosine and dihydroisodesmosine accumulate in elastin. In view of the ease with which such dihydropyridines are oxidized to the corresponding pyridinium ions by O2 and other mild oxidants, dihydrodesmosine and dihydroisodesmosine would not be expected to accumulate in elastic tissues. It therefore seemed appropriate to analyse elastin samples for dihydrodesmosine and dihydroisodesmosine using techniques different from these previously employed for this purpose. The results of these investigations indicate that dihydrodesmosine and dihydroisodesmosine do not accumulate to a measurable extent in elastin.

Stable, nonreducible cross-links of mature collagen.

During in vivo maturation, and also during in vitro incubation with physiological buffers, native collagen fibers display a progressive increase in tensile strength and insolubility. Paralleling these physiologically important changes is a progressive loss of the reducible cross-links which initially join the triple-chained subunits of collagen fibers. Although there is evidence suggesting that the reducible cross-links are gradually transformed into more stable, nonreducible cross-links during maturation, the nature of the transformation process and the structure of the stable "mature" cross-links has remained a mystery. In order to test the possibility that cross-link transformation involves addition of a nucleophilic amino acid residue to the reducible cross-links, histidine, arginine, glutamate, aspartate, lysine, and hydroxylysine residues were chemically modified, and the effect of each modification procedure on the in vitro transformation of reducible cross-links was ascertained. The results of these experiments indicated that destruction of histidine, arginine, glutamate, and aspartate residues has no measurable effect on the rate and extent of reducible cross-link transformation in hard tissue collagens. In contrast, modification of lysine and hydrocylysine residues with a wide variety of specific reagents completely blocks the transformation of reducible cross-links. Removal of the reversible blocking groups from lysine and hydroxlylysine residues then allows the transformation to proceed normally. These results indicate that collagen maturation involves nucleophilic addition of lysine and/or hydroxylysine residues to the electrophilic double bond of the reducible cross-links, yielding derivatives which are not only more stable but also capable of cross-linking more collagen molecules than their reducible precursors.

The chemistry of the collagen cross-links. A convenient synthesis of the reduction products of several collagen cross-links and cross-link precursors.

New synthetic routes to the reduction products of several collagen cross-links and cross-link precursors are described. By the use of these routes hydroxynorleucine, 5,6-dihydroxynorleucine, hydroxylysinonorleucine and hydroxylysinohydroxynorleucine can be synthesized via one common synthetic intermediate. The synthetic routes provide a convenient source of these unusual amino acids, as well as confirming the structure of hydroxylysinohydroxynorleucine and the other lysine-derived residues found in borohydride-reduced collagens.