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Dietary cholesterol affects chenodeoxycholic acid action on biliary lipids.

Chenodeoxycholic acid (CDC) decreases biliary saturation and dissolves gallstones in one-half of the treated patients. Dietary cholesterol also affects biliary lipids and is a possible factor explaining unsuccessful CDC therapy. The aim of this investigation was to study the effect of high and low dietary cholesterol on the CDC-induced decrease of biliary saturation and activity of hepatic hydroxymethylglutaryl coenzyme A reductase (HMG-CoAR). Seventy two hamsters in six groups were fed for 1 month one of three diets: 0.8 mg of cholesterol per g of food, 2.4 mg of cholesterol per g, or cholesterol-free. On each diet hamsters received no CDC or CDC 30 mg per kg per day. When animals were killed, biliary lipids were determined and the activity of hepatic HMG-CoAR was assayed. CDC administration decreased the saturation index (SI)(P less than 0.01) in hamsters on the high cholesterol and standard diets but not on the cholesterol-free diet. The SI in CDC-treated hamsters on the high cholesterol (0.78 +/- 0.03) and cholesterol-free (0.68 +/- 0.02) diets were greater (P less than 0.02) than in CDC-treated hamsters on the standard diet (0.48 +/- 0.03). CDC decreased (P less than 0.01) HMG-CoA reductase activity on each diet. In comparison to HMG-CoAR activity (190 +/- 7.6 pmoles per mg per min) in CDC-treated hamsters on the standard diet, the activity in CDC-treated hamsters on the high cholesterol diet (176 +/- 5.8 pmoles per mg per min) was decreased ( less than 0.05), whereas the activity on the cholesterol-free diet (495 +/- 11.5 pmoles per mg per min) was greater (P less than 0.01). It is concluded that: (1) dietary cholesterol is necessary for optimum CDC inhibition of HMG-CoAR; (2) high cholesterol and cholesterol-free diets prevent maximum CDC decrease of the biliary saturation index; (3) dietary cholesterol alterations may therefore be one cause of the failure of CDC dissolution of gallstones.

Animals

Regulation of mating in the cell cycle of Saccharomyces cerevisiae.

The capacity of haploid a yeast cells to mate (fuse with a haploid strain of alpha mating type followed by nuclear fusion to produce a diploid cell) was assessed for a variety of temperature-sensitive cell division cycle (cdc) mutants at the permissive and restrictive temperatures. Asynchronous populations of some mutants do not mate at the restrictive temperature, and these mutants define genes (cdc 1, 4, 24, and 33) that are essential both for the cell cycle and for mating. For most cdc mutants, asynchronous populations mate well at the restrictive temperature while populations synchronized at the cdc block do not. Populations of a mutant carrying the cdc 28 mutation mate well at the restrictive temperature after synchronization at the cdc 28 step. These results suggest that mating can occur from the cdc 28 step, the same step at which mating factors arrest cell cycle progress. The cell cycle interval in which mating can occur may or may not extend to the immediately succeeding and diverging steps (cdc 4 and cdc 24). High frequency mating does not occur in the interval of the cell cycle extending from the step before the initiation of DNA synthesis (cdc 7) through DNA synthesis (cdc 2, 8, and 21), medial nuclear division (cdc 13), and late nuclear division (cdc 14 and 15).

Cell Cycle

Regulation of neurosecretory activity in the freshwater pulmonate Lymnaea stagnalis (L.) with particular reference to the role of the eyes: a quantitative electron microscopical study.

The process of neurosecretion in the Caudo-Dorsal Cells (CDC) of the freshwater snail Lymnaea stagnalis, which produce an ovulation hormone, shows a diurnal rhythmicity. Synthesis, transport and release of the neurosecretory material (NSM) is high during the evening and the early night and low during the rest of the day, while storage of NSM mainly occurs during the daytime. In the present study the role of the eyes in the regulation of the CDC-rhythm was investigated. During a 24-hr period, at time intervals of 6 hrs, cerebral ganglia, which contain CDC, of blinded and control snails (5 per group) were fixed and the CDC were studied with quantitative electron microscopical methods. The CDC of the controls showed a distinct diurnal thythmicity. Blinding, on the other hand, clearly affected this rhythmicity. The results indicate that after blinding the circadian CDC-rhythms of individual snails are no longer synchronous with each other ("interanimal desynchronization"). It is suggested that the rhythm of CDC neurosecretory activity is synchronized by the natural light/dark cycle via the eyes. The information from the eyes probably reaches the CDC via a nervous pathway. True snyapses and three types of synapse-like structures were found on the CDC. Their role in the regulation of CDC-activity is discussed. The effect of blinding is specific for the CDC; blinding does not influence the diurnal rhythmicity of another type of cerebral neurosecretory cells, the Light Green Cells (LGC). The CDC within a cluster act synchronously. This synchrony does not depend upon the presence of the eyes. Some structures which may be involved in establishing this synchrony, such as subsurface cisterns, desmosome-like structures and "specific release sites", are described.

Animals

Appetite stimulant activity of 3-carboxy-10,11-dihydrocyproheptadine.

The orexigenic and ancillary pharmacologic properties of 3-carboxy-10,11-dihydrocyproheptadine (CDC) were compared to those of cyproheptadine. The threshold dose, 0.0312 mg/kg p.o., of CDC for increasing food intake in the cat is similar to that of cyproheptadine, but CDC has a broader effective dose range, extending to 8 mg/kg p.o., compared with 1 mg/kg p.o. for cyproheptadine. Using an increase in food consumption of 20% or more as the criterion of a positive response, the dose effective in 50% of the animals was 0.35 mg/kg p.o. for both CDC and cyproheptadine. Both CDC and cyproheptadine possess a long duration of appetite-stimulant action, exceeding 18 hr following 0.5 mg/kg p.o. The ancillary pharmacologic properties of CDC are considerably reduced over those of cyproheptadine, except for antihistaminic activity, CDC being about two times more potent (protection against lethality in guinea-pigs exposed to an aeosol of histamine). As an anticholinergic in mice, CDC is greater than thirteen times less active than cyproheptadine as a mydriatic agent and greater than forty-two times less potent as an antagonist of oxotremorine-induced tremors. CDC retains only about 1/25 of the antiserotonin potency of the parent compound (inhibition of serotonin-elicited edema in the rat paw and 5-hydroxytryptophan provoked head twitch in rats). CDC reduced locomotor activity in rats to a significantly lesser degree than cyproheptadine. CDC thus is a more selective agent for the therapy of anorexia.

Animals

Assessment of availability and efficacy of commercial Salmonella grouping antisera.

Salmonella somatic antisera for groups A to E were purchased from four commercial producers directly by the Center for Disease Control (CDC) and indirectly through two hospitals. CDC specifications and methods were used to evaluate antisera shipped directly to CDC. To assess the performance of the products under simulated user conditions, we used the commercial antisera purchased indirectly through the hospitals to group coded cultures. Of the 23 antisera ordered by CDC and the hospitals, the CDC received all 23, a large medical complex received 20, and a private hospital received 9. Similar results were obtained with producer and CDC test methods. Forty-five different lots of antisera were evaluated, of which 20% did not meet CDC specifications. The CDC specifications and latest revisions are discussed.

Antigens, Bacterial

Gallstone dissolution by chenodeoxycholic acid and phenobarbital.

Gallstone dissolution and biliary lipids were determined and compared in patients receiving either chenodeoxycholic acid (CDC), or CDC and phenobarbital (PB) for 11/2 to 2 years. Among patients with radiolucent gallstones, dissolution occurred in 53% of those receiving CDC alone and in only 25% of those receiving both CDC and PB. No dissolution occurred in 13 other patients with calcified gallstones. Patients with dissolution had a significantly greater molar percentage of CDC and a significantly lower saturation index in bile than those without dissolution. Diarrhea and transiently abnormal liver function tests were the most frequently observed side-effects but only diarrhea necessitated a reduction of the CDC dose. Gallstones recurred following dissolution in one of six patients followed for six months after discontinuation of CDC. In conclusion, PB did not enhance CDC-induced desaturation of bile or gallstone dissolution.

Chenodeoxycholic Acid

The role of nationwide nosocomial infection surveillance in detecting epidemic bacteremia due to contaminated intravenous fluids.

Since January, 1970, the Center for Disease Control (CDC) has corridnated surveillance of nosocomial infections in a group of voluntarily cooperating hispitals in the United States. In 1970, this surveillance system failed to realize one of its major goals: detection of a nationwide epidemic of septicemia caused by contaminated intravenous products. However, retrospective review of infections reported to CDC revealed that the data received were sufficient for the outbreak to have been recognized. Beginning in July, 1970, one month after the contaminated products were first distributed and five months before the outbreak was actually detected. CDC data showed a persistent increase in the incidence of Enterobacter and Erwinia (presently designated Enterobacter agglomerans) bacteremia. Furthermore, monthly rates of cases of bacteremia caused by these organisms were higher in hospitals using the contaminated intravenous products than for hospitals not using them. Failure to detect this outbreak at the time of its occurrence was due to delays in data processing and insufficiently sophisticated data analysis. Based on this experience, CDC has modified the surveillance system to aid recognition of future outbreaks.

Cross Infection

Chenodeoxycholic acid induced liver injury in pregnant and neonatal baboons.

The prolonged feeding of chenodeoxycholic acid produces hepatic injury in both pregnant and non-pregnant baboons. CDC feeding does not adversely affect ovarina function and no teratogenic effects of this bile acid were noted in 16 live birth and two stillborn progeny of CDC fed animals. However, 10 of the 16 live birth neonates and one stillborn had focal hepatic lesions histologically similar to those observed in the adult animals. In addition one neonate had gross hepatic necrosis. The severity of the liver damage was related to the content of lithocholic acid in the bile of both the neonates and their mothers. Experiments with 14C-chenodeoxycholic and 14C-lithocholic acid demonstrate that the lithocholate in the enterohepatic circulation of the neonate is derived from the CDC fed to the pregnant adult. In the gallbladder bile of the neonate most, but not all, of the lithocholate is conjugated but unsulfated. Both newborn and adult baboons sulfate lithocholic acid but to an extent less than that reported for man. Less efficient sulfation of lithocholic acid in the baboon may exaggerate the toxicity of CDC feeding in this species compared to man. Nevertheless, the potential for adverse effects on the fetal liver must be recognized as a risk associated with the use of chenodeoxycholic acid in women of child-bearing age.

Animals