ATP-Citrate lyase as a target for hypolipidemic intervention. 2. Synthesis and evaluation of (3R,5S)-omega-substituted-3-carboxy-3, 5-dihydroxyalkanoic acids and their gamma-lactone prodrugs as inhibitors of the enzyme in vitro and in vivo

A series of (3R,5S)-omega-substituted-3-carboxy-3, 5-dihydroxyalkanoic acids have been synthesized and evaluated as inhibitors of the recombinant human form of ATP-citrate lyase. The best of these have Ki's in the 200-1000 nM range. As the corresponding thermodynamically favored gamma-lactone prodrugs, a number of compounds are able to inhibit cholesterol and fatty acid synthesis in HepG2 cells and reduce plasma triglyceride levels in vivo. The best of these, compound 77, is able to induce clear hypocholesterolemic and hypotriglyceridaemic responses when administered orally to rat and dog. These results provide evidence to support the hypothesis that compounds which inhibit ATP-citrate lyase have the potential to be a novel class of hypolipidemic agent, which possess combined hypocholesterolemic and hypotriglyceridemic activities.     

The effect of an original analog of the C-terminal fragment of vasopressin on the behavior of white rats

Ethinylestradiol (EE) has evident paradoxical effects on cancer risk for human breast and hepatic cancer which parallel in some respects its effects on estrogen-induced neoplasms in the hamster kidney and liver. EE has been shown to be only weakly carcinogenic in the hamster kidney, but the most potent carcinogenic estrogen in the hamster liver following prolonged treatment. Unexpectedly, when EE and potent carcinogenic estrogens, such as diethylstilbestrol (DES), 17beta-estradiol (E2) and Moxestrol (MOX), are administered concomitantly, estrogen-induced carcinogenesis in the kidney is completely prevented. In studying this novel finding, we found that, compared with E2 exposure alone, EE at 0.05 and 1.0 nM significantly (P < 0.001) inhibited the rise in proliferation of cultured primary hamster proximal renal tubular (PRT) cells in the presence of E2 (1.0 nM). Consistent with these findings, combined EE + DES treatment for 5.0 months reduced hamster kidney c-myc, c-fos and c-jun RNA expression to 43, 37 and 52%, respectively, compared with levels observed after DES treatment alone. Interestingly, TAM + DES treatment for the same period also resulted in the same low level of RNA expression of these proto-oncogenes. c-MYC, c-FOS and c-JUN protein products were comparably reduced after either EE + DES or TAM + DES treatment. It appears that c-fos expression and c-FOS protein levels in the hamster kidney were more responsive to TAM inhibition. These data demonstrate that EE possesses unique anti-tumorigenic properties in vivo in the hamster kidney. Additionally, the observed anti-estrogen-like effect of EE on cell proliferation of cultured PRT cells suggests that EE may interfere critically with estrogen receptor (ER)-mediated mitogenic pathway(s) affected by potent carcinogenic estrogens, thus preventing subsequent gene dysregulation and, hence, tumor development. Based on competition studies, the differential binding of EE to hamster kidney ER relative to that of the other estrogens (E2, DES, MOX) appears not to contribute to the prevention of estrogen carcinogenesis at this organ site by EE.     

A comparison of the hypolipidemic action of probucol at doses of 500 and 1000 mg/day in moderate hyperlipoproteinemia

AIM: Evaluation of effectiveness of hypolipidemic action of probucol in doses 500 and 1000 mg/day and comparison of probucol blood concentrations on the treatment month 3 and 6. MATERIALS AND METHODS: Probucol (Akrikhin, Russia) was given to 41 patients with primary hypercholesterolemia in a dose 500 mg/day. 3 months later the patients were divided into two groups. Group 1 patients exhibited a > 10% decrease in cholesterol levels and continued to take probucol in the dose 500 mg/day. Group 2 patients were crossed over to higher cholesterol dose--up to 1000 mg/day. Lipids levels were measured by enzyme tests, apoproteins--by immunoturbidimetry and immunodiffusion, probucol concentrations--by high-performance liquid chromatography. RESULTS: After 3 months of treatment, cholesterol lowered by 14.3 and 9.2% in groups 1 and 2, respectively. After 6 months, by 19.7 and 12.9%, respectively. Probucol concentrations in blood were higher after 6 months of treatment than after 3 months in both groups. No significant differences existed between the groups by probucol concentrations in 3 and 6 months. CONCLUSION: Hypolipidemic effect of probucol depended on the individual features of lipoproteins metabolic disorders rather than the drug blood concentration. Larger probucol doses fail to reduce cholesterol further.     

Identification of a novel endogenous memory facilitating cyclic dipeptide cyclo-prolylglycine in rat brain

Using high-performance liquid chromatography, gas-chromatography and chromato-mass spectrometry methods a novel endogenous cyclic dipeptide cyclo-prolylglycine was identified in rat brain. Its content according to gas chromatography is 2.8 +/- 0.3 nmol/g wet brain. Synthetic cyclo-prolylglycine has demonstrated antiamnesic activity in the passive avoidance test in rats at a dose of 0.1 mg/kg i.p. Cyclic dipeptide cyclo-prolylglycine seems to be a memory facilitating substance and its presence in rat brain suggests the existence of a new mechanism of memory regulation.     

Agreement between rectal and tympanic membrane temperatures in marathon runners

STUDY OBJECTIVE: To determine the agreement between rectal temperature and infrared tympanic membrane temperatures in marathon runners presenting to a field hospital at the finish line. METHODS: The subjects of this prospective, blinded, controlled study were runners 18 years or older who were triaged to the acute care medical area at the finish line for suspected hypothermia, hyperthermia, dehydration, or altered mental status. Rectal and tympanic temperatures were measured simultaneously in all subjects for whom rectal temperature measurement had been deemed necessary and recorded on separate data cards. RESULTS: Of the 239 runners treated in the acute care medical area, 37 required rectal temperature measurement and were enrolled in the study. The mean rectal temperature was 38.45 degrees +/- 1.20 degrees C (range, 35.9 degrees to 41.5 degrees C). The mean tympanic membrane temperature was 37.81 degrees +/- 95 degrees C (range, 36.3 degrees to 40.4 degrees C). Pearson's correlation coefficient revealed a moderate correlation (r = .6902, P = .00023). The mean temperature difference between the two thermometers, mean rectal minus mean tympanic membrane, was .64 degrees C (95% confidence interval, .35 degrees to .93 degrees C). Sixty-Two percent of the tympanic membrane readings were within 1 degree C of their rectal counterparts. Agreement ranged from 1.16 degrees (+2 SD) to -2.95 degrees (-2 SD). The 95% confidence interval was 1.67 degrees to -2.95 degrees C. CONCLUSION: We were able to demonstrate only a moderate correlation between the two thermometer readings, with a wide spread between the limits of agreement. This spread could be clinically significant and therefore limits the usefulness of tympanic temperature in the marathon race setting. Because of the potentially large and clinically significant differences in rectal and tympanic temperatures and the limitations inherent in our study, we cannot endorse the use of tympanic temperature in the setting of a marathon event.     

The use of alisat for correction of level of lipids and their peroxidation products in blood of patients with atherosclerosis

A simple and easy assay for plasma heparin measurement (international units/ml) is described. The method is based upon the heparin neutralization and titration by polybrene. Heparin biological activity is measured first by activated partial thromboplastin time prolongment and then by means of polybrene titration: plasma heparin concentration was evaluated in international units/ml (IU/ml). The design and properties of this method are reported. Application in clinical practice of monitoring heparinization during hemodialysis is evaluated.     

Olfaction and the homing ability of pigeons in the southeastern United States

The importance of atmospheric odors for homing pigeon navigation was tested using birds from a loft located in Savannah, GA, in the southeastern United States. When released from a familiar training site, control pigeons and pigeons given intranasal injections of zinc sulfate to produce anosmia both displayed good homeward orientation and homed quickly. When released from three unfamiliar release sites, in contrast, control birds tended to orient southeast, while zinc sulfate-treated birds were more likely to fly northwest. More importantly, while the majority of control pigeons returned to the home loft, few of the zinc sulfate-treated birds returned. The good performance of both groups from the familiar site indicates that zinc sulfate treatment does not impair the general motor ability or motivation of homing pigeons. Therefore, the observed impairment in homing success of the zinc sulfate-treated pigeons from the unfamiliar locations presumably reflects an impaired ability to use atmospheric odors to navigate home. As such, the data support the hypothesis that successful homing pigeon navigation is based on the perception of atmospheric odors and that olfactory navigation is the primary mechanism used by pigeons over a broad range of geographic areas to approximate their relative position with respect to home from unfamiliar locations.     

Bovine leukocyte adhesion deficiency--clinical course and laboratory findings in eight affected animals

To compare multiple and singleton pregnancies in the treatment of threatened preterm delivery with prolonged intravenous ritodrine, 32 women with multiple pregnancy (26 twins, 6 triplets, 70 fetuses, 30.3 +/- 3.5 weeks) and 51 women with singleton pregnancy (31.3 +/- 2.6 weeks) admitted for threatened preterm delivery without rupture of the membranes were the subjects of a retrospective study of obstetric data, perinatal outcome and maternal adverse effects. Significance was assessed by chi 2 test and Student's t test. Multiple pregnancies were associated with a marked increase in the duration of tocolysis (17.2 +/- 17.3 vs. 7.6 +/- 8.1 days, P < 0.01), incidence of delivery before 37 weeks (87.5 vs. 35.3%, P < 0.01) and incidence of maternal cardiovascular complications (34.4 vs. 4.0%, P < 0.01), including three cases of pulmonary edema. The incidences of delivery before 32 weeks (12.5 vs. 7.8%) and of neonatal death (2.9 vs. 0%) were not significantly different in the two groups. Multiple pregnancies dramatically increased the incidence of maternal adverse effects of prolonged intravenous ritodrine therapy. Neonatal benefit is questionable and was difficult to establish since it was not a randomized study.     

Organization of the genetic locus for chicken myosin light chain kinase is complex: multiple proteins are encoded and exhibit differential expression and localization

We report that the genetic locus that encodes vertebrate smooth muscle and nonmuscle myosin light chain kinase (MLCK) and kinase-related protein (KRP) has a complex arrangement and a complex pattern of expression. Three proteins are encoded by 31 exons that have only one variation, that of the first exon of KRP, and the genomic locus spans approximately 100 kb of DNA. The three proteins can differ in their relative abundance and localization among tissues and with development. MLCK is a calmodulin (CaM) regulated protein kinase that phosphorylates the light chain of myosin II. The chicken has two MLCK isoforms encoded by the MLCK/KRP locus. KRP does not bind CaM and is not a protein kinase. However, KRP binds to and regulates the structure of myosin II. Thus, KRP and MLCK have the same subcellular target, the myosin II molecular motor system. We examined the tissue and cellular localization of KRP and MLCK in the chicken embryo and in adult chicken tissues. We report on the selective localization of KRP and MLCK among and within tissues and on a differential distribution of the proteins between embryonic and adult tissues. The results fill a void in our knowledge about the organization of the MLCK/KRP genetic locus, which appears to be a late evolving regulatory paradigm, and suggest an independent and complex regulation of expression of the gene products from the MLCK/KRP genetic locus that may reflect a basic principle found in other eukaryotic gene clusters that encode functionally linked proteins.