Rebound Rise in Renin Concentrations after Cessation of Salicylates

Salicylates are widely used in the treatment of rheumatic disorders, and they have been shown to induce minor changes in renal function. One of the major mechanisms of action of salicylates is the suppression of prostaglandin synthetase activity, and in animal rnodels renal prostaglandin production is closely related to renin release and the regulation of renal blood flow. Indomethacin has been shown to decrease the glomerular filtration rate and to lower plasma renin activity in human beings, and to reduce the antihypertensive effectiveness of cer¬tain beta-adrenoreceptor-blocking agents. We there-fore studied the effects of aspirin, another commonly prescribed non-steroidal anti-inflammatory agent, on plasma renin concentration, both during administra¬tion and after withdrawal

Salicylates and Creatinine Clearance Re-evaluated

Salicylates have been shown to increase the serum creatinine and decrease the creatinine clearance in normal volunteers and patients with rheumatoid arthritis and systemic lupus erythmatosus. Our clinical impression is that patients on long term salicylate therapy do not have creatinine clearances or serum creatinines which differ from the norm. We decided to study the effect of a five-week period of salicylate therapy on the creatinine clearance and serum creatinine of normal volunteers

Eliciting the Low-Activity Aldehyde Dehydrogenase Asian Phenotype by an Antisense Mechanism Results in an Aversion to Ethanol

A mutation in the gene encoding for the liver mitochondrial aldehyde dehydrogenase (ALDH2–2), present in some Asian populations, lowers or abolishes the activity of this enzyme and results in elevations in blood acetaldehyde upon ethanol consumption, a phenotype that greatly protects against alcohol abuse and alcoholism. We have determined whether the administration of antisense phosphorothioate oligonucleotides (ASOs) can mimic the low-activity ALDH2–2 Asian phenotype. Rat hepatoma cells incubated for 24 h with an antisense oligonucleotide (ASO-9) showed reductions in ALDH2 mRNA levels of 85% and ALDH2 (half-life of 22 h) activity of 55% equivalent to a >90% inhibition in ALDH2 synthesis. Glutamate dehydrogenase mRNA and activity remained unchanged. Base mismatches in the oligonucleotide rendered ASO-9 virtually inactive, confirming an antisense effect. Administration of ASO-9 (20 mg/kg/day for 4 d) to rats resulted in a 50% reduction in liver ALDH2 mRNA, a 40% inhibition in ALDH2 activity, and a fourfold (P < 0.001) increase in circulating plasma acetaldehyde levels after ethanol (1 g/kg) administration. Administration of ASO-9 to rats by osmotic pumps led to an aversion (−61%, P < 0.02) to ethanol. These studies provide a proof of principle that specific inhibition of gene expression can be used to mimic the protective effects afforded by the ALDH2–2 phenotype

"Fear of Success" among female and male freshmen engineering majors and degreed working engineers

The purpose of this research was to examine the "Fear of Success" (FOS) construct among 220 white female and male freshmen engineering majors and degreed working engineers. The relationship between FOS and the independent variables of sex of subject, student versus worker status of subject, sexappropriateness of occupational behavior, sex-appropriateness of occupational behavior for same sex versus opposite sex, and congruence of personality type with environment was investigated. The research design allowed a comparison of two interpretations of FOS: Horner's contention that it is an intrapsychic motive unique to women, and the alternative view that it is a reflection of cultural stereotypes shared by men and women. Subjects were freshmen engineering students attending two public universities in a southwestern state and degreed working engineers employed in the public and private sectors of the same geographic area. FOS scores were obtained from a content analysis of written fantasies according to an empirically derived system developed by Horner, Tresemer, Berens, and Watson and revised by Horner and Fleming. A baseline FOS measure was calculated by averaging the scores for two standard Thematic Apperception Test (TAT) verbal cues. FOS scores were also obtained for three success-toned, sex-linked occupational cues, subtracting the baseline measure from each. Holland's Vocational Preference Inventory (VPI) was used to determine raw score and scaled score (sex-normed) summary codes for personality types. The level of congruence between personality type and the field of engineering was measured using an adaptation of a method proposed by Zener and Schnuelle. To examine baseline FOS as a function of sex, status, and sex of story character, a three-way analysis of variance was used. To study FOS as a function of sex, status, occupation, and sex of story character, a four-way repeated measures analysis of variance was performed. The relationship between baseline FOS and congruence was investigated by computing Pearson product-moment correlation coefficients. Among the subjects in this investigation it was found that: 1. The observed mean difference for levels of baseline FOS between the sexes was not significant. 2. The observed mean difference for levels of FOS between students and workers was significant. Specifically, students scored higher than workers on baseline FOS while workers scored higher than students on FOS elicited by success toned occupational cues. 3. No significant differences were found for FOS as a function of sex-appropriateness of occupational behavior. 4. No significant differences were found for FOS as a function of a match between sex of subject and sex of story character for sex-inappropriate occupational behavior. 5. A low but significant negative correlation between baseline FOS and congruence was observed for males but not for females. This result was obtained whether congruence was based on raw score or scaled score summary codes. The results of this study indicate a generally low level of FOS in the population sampled. It was suggested that this finding relates to personality type since all groups were characterized as "independent" and "achieving" according to Holland's classification system. The findings of this study argue against generalizing FOS results across populations and across time. While results do not support either Horner's "intrapsychic" nor the "cultural" explanation of FOS, an analysis of thematic content and anecdotal comments suggest the phenomenon may be real. An idiographic approach for further FOS research was thus recommended.Education, College o

Increasing language adequacy in the disadvantaged preschool child

The problem of increasing the language adequacy of the disadvantaged preschool child is examined within the theoretical framework proposed by Bernstein. It is Bernstein's thesis that the early linguistic environment of the disadvantaged child typically limits him to a restricted language code adequate for maintaining immediate physical and social needs but inadequate for dealing with the language tasks of the early primary grades. The goal of intervention models is thus defined as providing for the disadvantaged preschool child the structural and functional elements of an elaborated language system to facilitate future academic performance. Four approaches to early language training are described and evaluated: the 'inventory' model which seeks to match specific verbal deficits with appropriate remedial training; the 'computer' model which programs the child with information processing skills essential to academic success; the 'operant' model which systematically reinforces desired verbal behaviors; and the 'recapitulation' model which identifies developmental stages and provides remedial training at levels the child has missed. It was concluded that well designed longitudinal studies with appropriate controls must be conducted before the effectiveness of the intervention models can be determined.Psychology, Department o

Pharmacokinetics and pharmacodynamics of nitroglycerin and aspirin

The pharmacokinetics and pharmacodynamics of nitroglycerin and aspirin have been evaluated with emphasis being placed on the in vitro and in vivo metabolism of these drugs in various tissues of the body. Nitroglycerin (GTN) was metabolized by blood components to the dinitro- (GDN) and in turn mononitroglycerin (GMN) metabolites. The rate of GTN and GDN metabolism was concentration dependent. The rate of GTN metabolism was reduced in the presence of GDNs and prevented by iodoacetamide which was used to stabilize GTN in blood samples obtained for pharmacokinetic studies. Intravenous (IV) bolus doses of GTN administered to sheep evoked rapid and substantial changes in haemodynamic parameters in a dose-dependent manner. The magnitude of the responses was related to the peak GTN femoral arterial A or V plasma concentration. Large differences in peak GTN concentrations and area under the plasma-time curves (AUC) for A and V were observed. The extent of this femoral A-V gradient, and of gradients across the liver and lungs, was further examined at apparent steady state plasma GTN concentrations attained by continuous IV GTN infusions in sheep. These studies demonstrated substantial extra-hepatic metabolism of GTN; the availability of GTN was in the rank order leg < liver < lung. In vitro studies showed that GTN was metabolized to GDNs and GMNs by sheep liver, leg muscle, lung, venous and arterial tissue homogenates and that the presence of GDNs reduced the rate of GTN metabolism. Administration of bolus doses of GDNs to sheep receiving GTN infusion reversed the femoral A-V gradient and reduced the systemic clearance of GTN. GDN and GMN pharmacokinetics were monitored in some sheep receiving GTN infusions. Extra-hepatic metabolism of aspirin (ASA) was also investigated in the sheep. During continuous IV ASA infusions an A-V gradient in apparent steady state plasma ASA concentrations across the leg and liver was observed but not across the lungs. In vitrostudies of the metabolism of ASA by sheep leg muscle, liver and lung tissue homogenates showed that hydrolysis of ASA to salicylic acid (SA) occurred in all three tissues. The presence of SA had no effect on the rate of ASA hydrolysis by any of the tissues. Bolus doses of SA administered during ASA infusions failed to modify the pharmacokinetics or A-V gradients of plasma ASA concentrations except at the largest SA dose when the rate of elimination of ASA was increased. This was due to the displacement, by SA, of ASA from plasma protein binding sites. ASA metabolite pharmacokinetics were monitored in sheep receiving ASA infusions. Human platelet function was used to evaluate the pharmacodynamics of ASA administered as a single 300 mg dose of a soluble or a slow-release preparation. Despite marked differences in peak plasma ASA concentrations and AUCs, there was similar inhibition of platelet function elicited by the two doses of ASA. Dose ranging studies using the slow-release preparation once daily for 7 days indicated that maximal inhibition of platelet function occurred using doses of 100-200 mg ASA daily