An unexpected pathway for the metabolic degradation of 1,3-dialkyl-3-acyltriazenes

In the presence of NADPH, rat liver microsomes catalyzed the degradation of a series of 1,3-dialkyl-3-acyltriazenes, and the extent of the reaction was correlated with compound lipophilicity. In the case of two methylcarbamoyltriazenes, 1-(2-chloroethyl)-3-benzyl-3- (methylcarbamoyl)triazene (CBzM) and 1-(2-chloroethyl)-3-methyl-3-(methylcarbamoyl)triazene (CMM), microsomal metabolites were isolated. Identification of the CBzM metabolites as 1-(2-chloroethyl)-3-benzyl-3-(hydroxymethylcarbamoyl)triazene and 1-(2-chloroethyl-3-benzyl-3-carbamoyltriazine, and the CMM metabolite as 1-(2-chloroethyl)-3-methyl-3-(hydroxymethylcarbamoyl)triazene indicated that the first metabolic step involves hydroxylation of the methylcarbamoyl substituent. Detailed studies of the metabolism of CBzM indicated that the Km for the reaction was 84 microM, and that metabolism was more efficient if microsomes were prepared from male than from female rats. During prolonged incubation, the metabolites of CBzM were also degraded. The degradation of CBzM and its metabolites was inhibited by SKF-525A and metyrapone, suggesting the involvement of a cytochrome P450 isozyme, and supporting the hypothesis that the process is oxidative rather than hydrolytic in both cases. Metabolic oxidation represents an alternative pathway to chemical or enzymatic hydrolysis for the in vivo decomposition of (methylcarbamoyl)triazenes. This mechanism may ultimately explain the antitumor efficacy and low acute toxicity of selected compounds.     

The management of severe subaortic stenosis, ventricular septal defect, and aortic arch obstruction in the neonate

Neonates with ventricular septal defect and aortic arch obstruction frequently have subaortic stenosis resulting from posterior deviation of the infundibular septum. Because the aortic anulus is often hypoplastic, making direct resection of the infundibular septum through the standard transaortic approach difficult, the optimal method of repair is uncertain. From September 1989 through November 1991, seven patients with ventricular septal defect, coarctation (n = 4), or interrupted aortic arch (n = 3) and severe subaortic stenosis underwent repair with use of a technique that included transatrial resection of the infundibular septum. Their ages ranged from 5 to 63 days (median 15 days) and weights from 1.3 to 5.4 kg (mean 3.1 kg). Only one patient was older than 1 month. The systolic and diastolic ratios of the diameter of the left ventricular outflow tract to that of the descending aorta were 0.53 +/- 0.09 mm (standard deviation) and 0.73 +/- 0.11, respectively. At operation, the posteriorly displaced infundibular septum was partially removed through a right atrial approach by resecting the superior margin of the ventricular septal defect up to the aortic anulus. The resulting enlarged ventricular septal defect was then closed with a patch to widen the subaortic area. In each patient the aortic arch was repaired by direct anastomosis. All patients survived operation; there was one late death from noncardiac causes 3 months after repair. The survivors remain well from 3 to 14 months after repair (mean 8 months). All are in sinus rhythm and none has a residual ventricular septal defect. One patient underwent successful balloon dilation of a residual aortic arch gradient late after repair. No patient has significant residual subaortic stenosis, although one has valvular aortic stenosis. This series suggests that in neonates with ventricular septal defect and severe subaortic stenosis resulting from posterior deviation of the infundibular septum, direct relief can be satisfactorily accomplished from a right atrial approach. This method provides effective widening of the left ventricular outflow tract and is superior to palliative techniques or conduit procedures.     

Electrophoretic and immunoblot analysis of Campylobacter fetus lipopolysaccharides

Proteinase K-digested cell lysates from 25 Campylobacter fetus subspecies fetus and C. fetus subsp. venerealis strains were examined by SDS-PAGE and immunoblotting. Three SDS-PAGE lipopolysaccharide (LPS) profiles were observed. Two profiles were consistent with those previously reported for serogroup A and serogroup B and AB isolates and were distinguished by the relative mobility of bands in the O-chain region and by a strong reaction on immunoblots with homologous antisera. The third profile was similar but had faster migrating O-chain bands. Immunoblot reactions using homologous and heterologous adsorbed antisera showed that the O-antigen of the C. fetus subsp. fetus reference strain and other profile 2-type LPS strains was distinct from the O-antigens of strains with profile 1- or profile 3-type LPS. O-antigens of strains with profile 1- and profile 3-type LPS had shared epitopes. One strain had core components but no detectable O-antigens. Common core LPS antigens appear to be present in all strains and antibodies to common core LPS epitopes may be useful reagents for rapid detection of C. fetus.     

Beyond empathy: confronting certain complexities in self psychology theory

Empathy is often a poorly understood concept. While some feel its value to psychoanalysis cannot be overstated, others feel it has been overemphasized as has the value of properly managing empathic failures that arise during an analysis. This paper will attempt to (1) demonstrate how patients sometimes resist empathy and erect barriers to being understood; (2) illustrate how empathy may sometimes be unachievable due to the difficulties encountered when one tries to empathize with the various aspects of another's experience that are in conflict with one another; and (3) propose that analysts may need to go beyond the common definition of empathy in order to help patients question and discard certain cherished beliefs they hold about themselves.     

An experimental test of adolescents' compliance with dental appointments

This study assessed factors associated with adolescents' compliance with dental appointments. Patients (n = 162) attending an adolescent clinic were administered a pretest questionnaire assessing health locus of control, self-esteem, and beliefs and attitudes about dental health from the Health Belief Model. Adolescents needing dental care were randomly assigned to groups for whom their dental appointment was made by a health professional or one in which the patient made his or her own appointment and to groups receiving an appointment reminder card versus not receiving a reminder card. Dental records were then reviewed to examine previous experiences with dental treatment. Neither the method used for making the appointment nor the use of reminder cards had a significant effect on compliance with the dental appointments. Also, compliance was not associated with health locus of control, self-esteem, or variables from the Health Belief Model. Older patients were more noncompliant than younger patients (tau = 0.14). Noncompliance was negatively correlated with the number of previous dental visits and previous dental procedures, oral hygiene instruction, and x-rays. Number of previous x-rays and previous broken appointments explained 5.1% of the variation in noncompliance. The Health Belief Model was not successful in predicting compliance behavior in this sample of adolescents.     

Analysis of the recent cluster of invasive fungal sinusitis at the Toronto Hospital for Sick Children

OBJECTIVE: The aim of this study was to review the eight histopathologically proven cases of invasive fungal sinusitis that occurred at the Toronto Hospital for Sick Children between 1985 and 1995, seven of which that clustered between March 1990 and February 1992. DESIGN: A retrospective review of the relevant cases and a review of the literature are presented. METHOD: A clinical review of this rare, life-threatening entity, occurring almost exclusively in severely neutropenic patients is presented and compared to the relevant clinical findings from an analysis of this series, the largest reported to date and first to document a significant clustering (p < .01). CONCLUSION: We conclude, based on epidemiologic evidence, that this clustering was directly related to the release of airborne fungal spores from dormant soil reservoirs disturbed during hospital construction. Therefore, we strongly advocate increased vigilance with respect to precautions against airborne pathogens wherever severely neutropenic hosts are treated.     

Order and metric in the stream semantics of elemental concurrency

Summary Two denotational semantics for a language with simple concurrency are presented. The language has parallel composition in the form of the shuffle operation, in addition to the usual sequential concepts including full recursion. Two linear time models, both involving sets of finite and infinite streams, are given. The first model is order-theoretic and based on the Smyth order. The second model employs complete metric spaces. Various technical results are obtained relating the order-theoretic and metric notions. The paper culminates in the proof that the two semantics for the language considered coincide. The paper completes previous investigations of the same language, establishing the equivalence of altogether four semantic models for it.     

An activating mutation in a Caenorhabditis elegans Gs protein induces neural degeneration

Heterotrimeric guanine nucleotide-binding proteins (G proteins) act as signal-transducing molecules that connect serpentine-transmembrane receptors to a variety of intracellular effectors. We characterized a Caenorhabditis elegans G(s) gene, gsa-1, which encodes a G(s) alpha-subunit (G alpha(s)) that is expressed throughout the nervous system and in muscle cells. gsa-1 is an essential gene; a loss-of-function mutation in gsa-1 results in lethality at the first stage of larval development. Partial (mosaic) loss of G alpha(s) expression or overexpression of the protein results in reciprocal defects in movement and egg-laying, suggesting a role for G alpha(s) in the regulation of these behaviors. Expression of a constitutively active form of G alpha(s) from an inducible promotor results in hypercontraction of body-wall muscle cells and vacuolization and degeneration of neurons within hours of induction. Neurons that are susceptible to the degeneration induced by activated G alpha(s) are predominantly motoneurons located within the ventral nerve cord. Phenotypic analysis shows that the induced neural degeneration is not the result of programmed cell death but is probably caused by the activation of ion channels. A genetic suppressor of activated G alpha(s) was isolated that identifies a putative downstream target of G(s) signaling.