Fabio Sereni

Correlation between Fetal and Maternal Serum Bile Acid Concentrations

ABSTRACT: Serum concentrations of different bile acids (BA) were determined by radioimmunoassay in 56 human fetuses and mothers. Serum was obtained immediately after legal abortion, performed between the 14th and the 21st wk of gestation. Conjugated cholic (CCA) and chenodeoxycholic acid (CCDCA) concentrations were determined in 33 cases, conjugated lithocholic (CLCA) and deoxycholic acid (CDCA) in 20, and sulfolithocholyglycine (SLCG) in 15. In fetal blood, mean concentrations of CCA (0.80 ± 0.40 μmol/liter), CCDCA (4.50 ± 2.70 μmol/liter), and CLCA (1.70 ± 1.04 μmol/liter) were significantly higher than those in the mother (CCA 0.34 ± 0.17 μmol/liter; CCDCA 0.79 ± 0.34 μmol/liter; CLCA: 0.70 ± 0.30 μmol/liter; p < 0.001); fetal serum levels of CDCA (0.46 ± 0.32 μmol/liter) and SLCG (0.15 ± 0.09 μmol/liter) were lower than in the mothers (CDCA 1.20 ± 0.80 μmol/liter, p < 0.001; SLCG 0.40 ± 0.30 μmol/liter, p < 0.01). There was no correlation between levels of BA and gestational age. Serum total protein and albumin concentrations were both reduced in 10 fetuses as compared with the mothers. These data support the concept of a state of physiologic cholestasis during development and suggest that placental transfer of primary BA occurs mostly in the fetal to maternal direction. This transfer could be facilitated by the reduced fetal plasma albumin concentration, since BA in free solution diffuse more easily through the placenta. There is evidence of lithocholic acid synthesis in the fetal liver, while deoxycholic acid appears to be mostly of maternal origin. Finally, sulfation of BA is poorly developed at this age of gestation.

Cortisol-induced increase of tyrosine-α-ketoglutarate transaminase in the isolated perfused rat liver and its relation to ribonucleic acid synthesis

Abstract It was shown that cortisol increases the level of tyrosine-α-ketoglutarate transaminase ( l -tyrosine: 2-oxoglutarate aminotransferase, EC 2.6.1.5) of the isolated rat liver, when perfused with diluted rat blood containing an amino acid mixture; a more striking increase was obtained in the presence of a supplementary amount of tyrosine. This enhancement of activity was blocked by inhibitors both of protein synthesis (chloramphenicol, puromycin, ethionine) and of ribonucleic acid synthesis (actinomycin D and mitomycin C). Adding [6-14C]orotate to the perfusing blood, caused a rapid incorporation of radioactivity into nuclear ribonucleic acid to take place; cytoplasmic ribonucleic acid was poorly labelled after 30 min, but its radioactivity rose thereafter. Cortisol stimulated the labelling of both the nuclear and the cytoplasmic ribonucleic acid; moreover it induced the increase of tyrosine transaminase after a lag of about 30 min. In both cases, the effect of the hormone was prevented by actinomycin D, or by mitomycin C. It was finally found that livers perfused with cortisol have a higher nuclear ribonucleic acid polymerase (nucleosidetriphosphate: RNA nucleotidyltransferase, EC 2.7.7.6) activity than control ones. The facts that the synthesis of nuclear ribonucleic acids precedes the increase of tyrosine transaminase and also that cortisol stimulates ribonucleic acid polymerase strongly suggest that the action of the hormone can be related to an increase in the synthesis of messenger ribonucleic acid molecules for the synthesis of the enzyme.

Factors influencing the glucocorticoid-induced increase of ribonucleic acid polymerase activity of rat liver nuclei

Abstract Liver nuclei from adrenalectomized rats receiving cortisone have a nuclear RNA polymerase activity higher than controls. The induced and control polymerase activity present the same general characteristics. However, ammonium sulfate added in vitro enhances RNA polymerase activity of controls more than that of treated nuclei and obliterates the hormonal response. The stimulating effect of cortisone on RNA polymerase activity is prevented in vivo by puromycin and actinomycin D. Cortisone abolishes in vivo the toxic effects of histones; however, neither cortisone nor cortisol reverses in vitro the inhibitory action of these compounds on RNA polymerase activity. Irradiation with X-rays (600 r) results in a reduced response of RNA polymerase to cortisone. Liver RNA polymerase activity is very low at birth and reaches the adult values after about 15 days of extrauterine life. No response to cortisone or cortisol is observed in vivo before the 13th day of life, whereas other enzymic activities, such as tyrosine transaminase and alanine transaminase, respond much earlier. Therefore it cannot be stated at present that the increase of liver enzyme activities induced by glucocorticoids is mediated by RNA polymerase, at least in newborn rats. Administration of cortisone has no appreciable effect on the hydrolysis of pulse-labeled nuclear RNA, but it reduces the hydrolysis of microsomal RNA. The possibility is prospected that this effect together with the increased RNA polymerase activity may contribute to increase the amount of liver RNA, which is a typical effect of glucocorticoid treatment.

Kinetics and efficacy of theophylline in the treatment of apnea in the premature newborn.

SummaryAminophylline (theophylline-ethylenediamine) was administered to 27 premature newborns to prevent apneic spells. Of the 22 patients monitored for theophylline concentration, a therapeutic blood level was reached in 19 in 1–2 days, and 3 stayed below it. ‘Toxic’ blood levels (≥20 µg/ml) were reached in 3 cases, one of whom showed signs of toxicity. Theophylline treatment was not efficient in the prevention of apnea when a serious underlying disease was present. Theophylline blood half-life (mean : 27.0 h) and clearance (mean 12.9 ml/h/kg) confirmed the slow elimination pattern of the drug in the premature infant.

Increased renal tubular Na-K-ATPase activity in Milan hypertensive rats in the prehypertensive period

Milan hypertensive (MSH) rats develop hypertension around the 3rd–4th week of life and exhibit increased Na-pump activity in adulthood. The present study was performed to evaluate whether or not hypertension is preceded by an increase in Na−K-ATPase activity. Total and ouabain-sensitive ATPase activities were studied in single microdissected medullary thick ascending limb of Henle (mTAL) tubules from MHS, Milan normotensive (MNS) and Sprague-Dawley (SD) rats at 22–24, 26–28 and 45–60 days of age. Data are given as mean±SEM. Total and Na−K-ATPase activity exhibited a developmental pattern in MHS, MNS and SD rats. At 22–24 days no difference was seen between MHS and MNS animals. At 26–28 days MHS had a higher total and Na−K-ATPase activity than MNS (3031+171 vs 2471+178 pmol phosphate/mm tubule per hour,P<0.05; 2289+205 vs 1653+151,n=10,P<0.05). At this age there was still no difference in mean arterial blood pressure (88+4 vs 86+3 mm Hg,n=15). Adult MHS rats had higher blood pressure (140+9 vs 112+8 mm Hg,P<0.001) and higher total (3544+136 vs 2718+215 pmol phosphate/mm tubule per hour,n=10,P<0.01) and Na−K-ATPase activity (2670+99 vs 1942+217 pmol phosphate/mm tubule per hour,n=10,P<0.05) than adult MNS rats. We conclude that increased Na−K-ATPase activity in mTAL precedes the development of hypertension in the Milan strain of rats.

Immune response to hepatitis B vaccine in staff and patients in renal dialysis units

Anti-HBs response was detected in 96 per cent of staff members in three haemodialysis units after three 20 microgram doses of hepatitis B vaccine and in 82 per cent of adult patients treated with three 40 microgram doses. The percentage of responders and levels of antibody remained unchanged at 12 months from the beginning of the trial. Three out of six children injected with three 20 microgram doses in a paediatric haemodialysis unit remained free from markers of HBV infection and had high levels of anti-HBs after the second dose of vaccine. The other three children who developed serological markers of HBV infection seroconverted to anti-HBc within six months from the first dose and, in one of them, antigenaemia at three and four months was detected.

Percutaneous transluminal renal angioplasty in neurofibromatosis

A 9-year-old boy with hypertension was found to have neurofibromatosis associated with stenosis of the right renal artery. Percutaneous transluminal angioplasty (PTA) was performed. Immediately post angioplasty angiography showed that the stenosis persisted, but over the next few days his blood pressure rapidly decreased and remained well controlled even when treatment was discontinued. The captopril stimulation test, performed after PTA, confirmed the return of plasma renin activity to normal values. A digital subtraction aortogram, performed 2.5 years after PTA, was unchanged. His blood pressure remained persistently normal, without anti-hypertensive agents. Based on these results, PTA is suggested as the first step in correcting renal artery stenosis due to neurofibromatosis. A complete anatomical resolution of the stenosis is probably not required since slight improvements in the renal artery lumen may be accompanied by important functional improvement.

Control of antibiotic therapy in paediatric patients. II. Appropriateness of antibiotic choice in selected diseases.

SummaryThe adequacy of antibiotic choice and the importance of the physicians knowledge of antibiotic use in causing errors in prescribing were investigated. A prospective three-month study was conducted in nine Italian pediatric hospital wards, involving every patient admitted to hospital for otitis, pneumonia or pharyngotonsillitis. The suspected aetiology and the antibiotic prescribed were recorded on a special form by the physician in charge. Each choice of antimicrobial agent was judged as adequate, justifiable or not justified. Out of 314 prescriptions 56.1% were assessed as adequate, 4.1% as justifiable and 39.8% as not justified. Analysis of the suspected bacteria, and of the correlation between the presumed aetiological agent and the prescribed antibiotic, demonstrates that inadequate knowledge of the physician plays a major role in producing a high percentage of unjustified prescriptions.

Renal effects of cyclosporin A in children treated for idiopathic nephrotic syndrome

Little data have been published on tubular renal function during cyclosporin A treatment in children without transplants. We studied 12 young subjects (mean age 10 years) with steroid‐responsive idiopathic nephrotic syndrome and with signs of steroid toxicity. After achieving remission with prednisone 60 mg/m2, 8 children started cyclosporin A therapy (6 mg/kg/day) (group A) and 4 children were given cyclophosphamide 2.5 mg/kg/day (group B). The latter were considered as controls together with 10 other children with idiopathic nephrotic syndrome in complete remission and off therapy (group C). We monitored creatinine clearance and tubular handling of β2‐microglobulin, sodium, phosphorus and uric acid for one year. Cyclosporin A induced a decrease in creatinine clearance with a decrease in fractional excretion of β2‐microglobulin; sodium excretion was similar in the two treated groups and a transient decrease in fractional excretion of uric acid was seen only in patients receiving cyclosporin A. Both groups showed an increased renal threshold phosphate concentration. Our results suggest that in children, cyclosporin A therapy induces a decrease in glomerular filtration rate associated with increased reabsorption activity of proximal tubular cells.

Spontaneous development of tyrosine aminotransferase activity in fetal liver cultures

Tyrosine aminotransferase (l-tyrosine:2-oxoglutarate aminotransferase, EC 2.6.1.5) activity of explants of rat fetal liver cultured in vitro, if cultured after 18 days of gestation, increased very sharply after a short period of time in culture. Increases in activity up to five times the basal values were commonly observed. When liver explants from more immature rat fetuses were cultured, several days in culture were usually required before the increase in tyrosine aminotransferase activity was observed. The spontaneous in vitro induction of tyrosine aminotransferase mimics in many respects the many-fold increase in this enzyme which is observed in vivo in the immediate post-natal period of life. A series of experiments were performed to better understand the factors controlling tyrosine aminotransferase activity during fetal life and to elucidate the mechanisms by which the spontaneous induction occurs in vitro. Serum from fetal or newborn rats did not influence the tyrosine transferase activity of the in vitro cultures. No change in the spontaneous enzyme development was observed when serum from adrenalectomized rats was used instead of horse serum. Hydrocortisone (2 × 10−6m) showed an additive effect, whereas glucagon was effective in inducing the enzyme only if added before the spontaneous development had occurred. Actinomycin D partially prevented the spontaneous development of tyrosine aminotransferase. These results are consistent with the hypothesis that synthesis of this enzyme is repressed during gestation. It seems probable that development of tyrosine aminotransferase in vitro occurs by a mechanism similar to that involved in induction by glucagon.