Rifaximin versus ciprofloxacin for the treatment of traveler's diarrhea: a randomized, double-blind clinical trial.

Rifaximin is a poorly absorbed rifamycin derivative under investigation for treatment of infectious diarrhea. Adult students from the United States in Mexico and international tourists in Jamaica were randomized to receive either rifaximin (400 mg twice per day) or ciprofloxacin (500 mg twice per day) for 3 days, following a double-blinded model, from June 1997 to September 1998. A total of 187 subjects with diarrhea were studied. Time from initiation of therapy to passage of last unformed stool was comparable for those receiving rifaximin or ciprofloxacin (median, 25.7 hours versus 25.0 hours, respectively). There was no significant difference in the proportion of subjects in the 2 groups with respect to clinical improvement during the first 24 hours (P=.199), failure to respond to treatment (P=.411), or microbiological cure (P=.222). The incidence of adverse events was low and similar in each group. Rifaximin is a safe and effective alternative to ciprofloxacin in the treatment of traveler's diarrhea.

In vitro activity and fecal concentration of rifaximin after oral administration.

Rifaximin showed moderately high MICs (the MIC at which 90% of the isolates tested were inhibited = 50 microg/ml) for 145 bacterial enteropathogens from patients with traveler's diarrhea acquired in Mexico during the summers of 1997 and 1998. Rifaximin concentrations in stool the day after oral administration (800 mg daily for 3 days) were high (average, 7,961 microg/g), proving the value of the drug.

Regional distribution of the 5-HT innervation in the brain of normal and lurcher mice as revealed by [3H]citalopram quantitative autoradiography.

The neurological cerebellar mutant lurcher is characterized by a primary degeneration of Purkinje cells as well as retrograde secondary partial degeneration of cerebellar granule cells and inferior olivary neurons. Since serotonin (5-HT) has been implicated in the modulation of excitatory amino acid systems of the cerebellum, the 5-HT innervation of the normal and lurcher mice was examined by quantifying uptake sites using [3H]citalopram autoradiography, and by biochemical assays of the indoles 5-HT, 5-hydroxy-L-tryptophan and 5-hydroxyindole-3-acetic acid using high-performance liquid chromatography. Comparable results were found between [3H]citalopram binding and 5-HT tissue concentrations in different brain regions. The highest [3H]citaslopram labelling was observed in defined structures of the mesencephalic and upper pontine regions, in limbic strutures, in hypothalamus and in discrete thalamic divisions, while the lowest labelling of uptake sites was documented in cerebellum and brainstem reticular formation. In lurcher mutants, the histology confirmed cell degeneration and the reduction in width, leading to 65%, 45% and 25% atrophies of total cerebellum, deep nuclei and inferior olivary nucleus, respectively. The [3H]citalopram labelling corrected for surface loss was 45% and 20% higher to cerebellar deep nuclei and red nucleus, respectively, but remained unchanged in the cerebellar cortex and inferior olivary nucleus. Moreover, higher labelling was found in nucleus raphe dorsalis, ventral tegmental area, inferior colliculus, locus coeruleus, pontine central grey and anterior thalamic nuclei, areas known to be part of cerebellar afferent and efferent systems. The present results indicate that in such pathological conditions as described for the lurcher mutant, the 5-HT system may modulate motor function not only at the level of the cerebellum, but also in other forebrain structures functionally related to the motor system.

Interhemispheric transfer in Down's syndrome.

Callosal agenesics and callosotomized epileptics manifest markedly increasing simple visual reaction time (SVRT) from conditions of ipsilateral to contralateral stimulus-response relation (SRR). In the contralateral SRR, a response is presumed possible because of presence of other commissures (anterior, intercollicular). The SRR effect is prolonged presumably because the remaining commissures are less efficient than the corpus callosum in relaying necessary visual or motor information. Consequently, the SRR effect is believed to correspond to callosal relay time (CRT) in the normal subject. However, both callosal agenesics and callosotomy patients manifest general slowing of SVRT in addition to a prolonged SRR effect. These patients have massive extra-callosal damage which could plausibly cause both the SVRT and the CUD prolongation. If such were the case, the CRT inference would be in jeopardy. A test of the CRT inference is therefore required where patients with massive diffuse extra-callosal brain damage and normal callosi would show marked general SVRT prolongation and a normal SRR effect. Four trisomy-21 (T21) males were compared to age and sex-matched normal controls. General SVRT was highly significantly prolonged in T21, but the CUD was nearly identical in both groups.

Effect of placental factors on growth and function of the human fetal adrenal in vitro.

Conditioned medium from human placental monolayer cultures (PM) had a marked stimulatory effect on proliferation (3H-thymidine uptake) of human fetal zone adrenal cells in primary monolayer culture, even in the absence of serum. Epidermal growth factor (EGF) and fibroblast growth factor (FGF) also significantly stimulated fetal adrenal cell growth. However, the effects of PM differed from those of EGF and FGF in several respects: 1) maximal response to PM was 2-5 times greater; 2) mitogenic effects of EGF and FGF were suppressed by adrenocorticotropic hormone (ACTH), whereas that of 50% PM was not; 3) PM inhibited ACTH-stimulated steroidogenesis (dehydroepiandrosterone sulfate and cortisol), but EGF and FGF did not. Preliminary characterization studies have indicated that approximately half of the placental growth-promoting activity is heat resistant and sensitive to bacterial proteases, and that 50-60% of the activity is lost after dialysis with membranes having a molecular weight cutoff of 3500. These findings suggest a role for the placenta in the growth and differentiated function of the human fetal adrenal gland.

Growth-inhibitory effect of TGF-B on human fetal adrenal cells in primary monolayer culture.

We examined the effects of transforming-growth factor-B (TGF-B) on growth ([3H]-thymidine uptake) and function (dehydroepiandrosterone sulfate [DHAS] and cortisol production) of human fetal zone adrenal cells. Results indicate that TGF-B significantly inhibits, in a dose-related manner, both basal and epidermal growth factor (EGF)-stimulated cell growth: IC50 = 0.1-0.25 ng/ml. EGF is ineffective in overcoming the inhibitory effect of TGF-B, suggesting a noncompetitive antagonism between the two factors. Also, the inhibitory effect of TGF-B is additive to that of adrenocorticotropic hormone (ACTH). On the other hand, TGF-B (1 ng/ml) does not significantly change basal or ACTH-stimulated DHAS or cortisol secretion. We conclude that, unlike its effect on other steroid-producing cells, TGF-B inhibits growth of fetal zone cells and does not appear to have a significant inhibitory effect on steroidogenesis.

Cyclooxygenase products formed by primary cultures of cells from human chorion laeve: influence of steroids.

Cells were isolated from human chorion laeve obtained at term (38-40 weeks gestation) by elective caesarean section and were maintained in primary culture for 1 week in defined media supplemented with 10% fetal calf serum. The production of various cyclooxygenase products by the cultures was examined. Little or no prostaglandin (PG) F2 alpha, 6-keto-PGF1 alpha, thromboxane B2, or 13,14-dihydro-15-keto-PGF2 alpha was found. In contrast, the cells produced PGE2 which was low on day 0, increased during culture to a maximum on day 1 or 2, then declined to low levels. When cells were grown in the presence of media containing cortisol, dexamethasone, progesterone, and estradiol (at 10(-7) or 10(-9) M), the glucocorticoids (at 10(-7) and 10(-9) M), but not estrogen or progesterone, markedly inhibited the increase in PGE2 output. There was no difference in the protein content and thymidine incorporation of cells grown in the presence of glucocorticoids when compared with controls. This inhibitory effect was not sensitive to cycloheximide (1 microgram/mL) indicating protein synthesis may not be involved in the process. These studies indicate that PGE2 is the major prostaglandin formed by primary cultures of chorion laeve and that prostaglandin metabolism in the chorion is sensitive to glucocorticoid inhibition.

Comparison of the specific binding of cortisol in human amnion, amniotic fluid, and plasma.

The purpose of this study was to compare the specific cortisol-binding protein found associated with human amnion with specific cortisol binding in human amniotic fluid and plasma. The electrophoretic mobility on polyacrylamide gels of the specific cortisol binding in amnion, amniotic fluid, and maternal plasma was identical. The influence of pH on cortisol binding activity was similar in all tissues and the cortisol binding was immunoprecipitable by a polyclonal antibody raised against human corticosteroid-binding globulin. The interaction of the cortisol binding protein with concanavalin A was studied in preterm amniotic fluid, term amniotic fluid, term amnion, and plasma from pregnant women at term and women under oral contraceptive treatment. Binding to concanavalin A was similar in term amnion and term amniotic fluid but was less than that found with both preterm amniotic fluid and term plasma. These results indicate that the cortisol binding protein associated with human amnion has similar characteristics to plasma corticosteroid-binding globulin, but that its state of glycosylation appears to be more like that of the cortisol binding protein in term amniotic fluid rather than in plasma.

Primary culture of cells from human chorion laeve: steroid metabolism and properties of cells grown in defined media supplemented with 0.1% or 10% fetal calf serum.

The purpose of this study was to develop primary cultures of human chorion laeve cells and examine certain aspects of steroid metabolism during culture. Tissues obtained by elective cesarean section at term (38-40 weeks) were dispersed with collagenase. Cells were isolated on Percoll gradients at the interface between 20% and 40% Percoll and examined in primary culture for up to 1 week. Cultures were carried out in chemically defined media supplemented with 10% or 0.1% fetal calf serum (FCS). The morphological and biochemical properties of the cells were different in the two systems. In 0.1% FCS, cells formed clumps of tissue within 16 h of plating, and there was no cell replication. In contrast, in 10% FCS, the cells formed a carpet of tissue and reached confluence after 5 days in culture, resulting in increased DNA and protein content and thymidine incorporation in the dishes. Three steroidogenic enzymes were studied during culture: alkyl steroid sulfatase, estrogen sulfatase and 3 beta-hydroxysteroid dehydrogenase. The sulfatases had higher activities in 0.1% than in 10% FCS, and their activities decreased markedly during the culture period. In contrast, 3 beta-hydroxysteroid dehydrogenase activity was higher in 10% FCS than in 0.1% FCS. Activity remained constant during the culture period in 0.1% FCS and increased in 10% FCS. In the latter system this increase resulted in the enzyme maintaining a constant specific activity during culture. These studies describe two viable systems of chorion laeve cells in primary culture, which may be valuable for studying long term and/or subtle effects on various metabolic aspects of this tissue.

Circulatory changes in newborn lambs with experimental polycythemia: comparison between fetal and adult type blood.

Hemodynamic effects of increased hematocrit were compared in two groups of newborn lambs. In the first group (fetal type blood), exchange transfusions were carried out using packed red blood cells obtained from newborn lambs within one to two hours after birth. In the second group (adult type blood), the same procedure was carried out using adult sheep blood. In both groups, hematocrit values ranging between 70% and 80% were reached. The increase in hematocrit caused a decrease in cardiac output due to an increase in peripheral resistance. Pulmonary resistance increased more than systemic resistance. However, the increase in pulmonary resistance was significantly greater in the polycythemic newborn lambs with adult blood. A right-to-left shunt through a patent ductus or a foramen ovale was noted in six of the eight lambs included in this group. On the other hand, none of the seven polycythemic newborn lambs with fetal blood developed signs of right-to-left shunting. It is concluded that during neonatal polycythemia, the level of hematocrit is not the sole factor responsible for the hemodynamic changes observed. Other unknown influences related either to the red cells or the plasma must impinge upon the pulmonary circulation to alter vascular resistance.

Steroid metabolism by human chorion laeve from dichorionic twin pregnancies.

Certain steroid metabolic properties of chorion laeve from dichorionic twin pregnancies were examined to determine whether they were present in chorion not contaminated by decidua or serum. In the chorion situated between the two amniotic sacs and not in contact with decidua, aryl sulfatase, 3 beta-hydroxysteroid dehydrogenase, and aromatase activities were found. This indicates that these reactions are present in chorion laeve and were not previously ascribed to this tissue because of decidual contamination. Specific cortisol binding was also present in this area of chorion laeve, which excludes serum contamination. It is suggested that the specific steroid-binding protein in the membranes may be derived from the transcortin-like protein present in amniotic fluid.

The difference between the systolic time intervals of the left and right ventricles during fetal life.

In order to determine if the two ventricles of the fetal heart contract synchronously the systolic time intervals of both ventricles were compared. Eight experiments were carried out on fetal lambs. The studies demonstrated that while the ejection times of both ventricles were the same, the mean pre-ejection period of the right ventricle was significantly greater than that of the left (57 +/- 8 versus 48 +/- 8 msec, p less than 0.005). These findings were further substantiated in serial studies during a 7-day period on the same fetal lamb. If changes in the systolic time intervals are to be useful in evaluating fetal myocardial function, the values should be obtained from the same ventricle.

A comparison of blood viscosity between the adult sheep and newborn lamb. The role of plasma and red blood cell type.

Adult sheep and newborn lamb blood viscosity (Vc) have been compared by taking into account not only the hematocrit, but also the type of the red cells (adult or fetal) in the circulation and the plasma Vc. At all shear rates studied the whole blood Vc of the adult was higher than that of the newborn. Plasma Vc was 1.58 +/- 0.18 centipoises in the adult compared to 1.21 +/- 0.19 in the newborn group (P less than 0.001). The mean relative apparent viscosity (whole blood Vc/plasma Vc) was higher in the newborn although the difference was not significant.

Blood viscosity during the neonatal period: the role of plasma and red blood cell type.

Adult and newborn infant blood viscosity have been compared, taking into account not only the hematocrit, but also the type of red blood cells (fetal or adult) in the circulation and the plasma viscosity. At all shear rates studied, the viscosity of the adults' blood was higher than that of the newborn infant. At shear rates of 11.5 and 46 second-1, an increase in the hematocrit influences the viscosity of neonatal and adult blood similarly. At 115 and 230 second-1, the rise in hematocrit was associated with a greater increase in viscosity in the presence of fetal red blood cells, probably because of their lesser deformability. Plasma viscosity was 1.18 +/- 0.17 centipoises in the newborn compared to 1.36 +/- 0.10 in the adult group (P less than 0.001). The relative apparent viscosity (apparent viscosity/plasma viscosity) was higher in the neonate at a hematocrit of 65% (P less than 0.05). In normal conditions, blood viscosity is lower in the neonatal period because of a lower plasma viscosity.