Observation of high soft x-ray drive in large-scale hohlraums at the National Ignition Facility.

The first soft x-ray radiation flux measurements from hohlraums using both a 96 and a 192 beam configuration at the National Ignition Facility have shown high x-ray conversion efficiencies of ∼85%-90%. These experiments employed gold vacuum hohlraums, 6.4 mm long and 3.55 mm in diameter, heated with laser energies between 150-635 kJ. The hohlraums reached radiation temperatures of up to 340 eV. These hohlraums for the first time reached coronal plasma conditions sufficient for two-electron processes and coronal heat conduction to be important for determining the radiation drive.

Interleukin-4 induces lipogenesis in porcine endothelial cells, which in turn is critical for induction of protection against complement-mediated injury.

Interleukin (IL)-4 has been shown to induce protection in porcine vascular endothelial cells (ECs) from killing by human complement. This protection is dependent on the PI3K/Akt signaling pathway. In this study, we investigated mechanisms downstream of Akt and found that activation of the lipid biosynthesis pathway is required for protection from complement in ECs treated with IL-4. Cells incubated with IL-4 for 48 hours contained increased fatty acids and phospholipids but cholesterol was not increased when compared with medium-treated controls. The transcription factor SREBP-1, which regulates fatty acid synthesis, was found to be activated in extracts of ECs incubated with IL-4 for 6 hours. Finally, induction of protection from complement killing with IL-4 was fully prevented by the presence of the SREBP inhibitor 25-OH cholesterol. This study showed that IL-4 induces lipid biosynthesis in porcine ECs through activation of SREBP-1 and that the activation of this pathway is critical for IL-4 to induce protection of porcine ECs from killing by human complement. Further study of these mechanisms may provide new strategies for the prevention of complement-mediated vascular injury as it occurs in xenograft rejection.

Spermidine is necessary for, but not the only mediator of, linoleic acid-stimulated alpha-casein accumulation in mouse mammary epithelial cells.

Mammary epithelial cells obtained from virgin mice were induced to accumulate alpha-casein in serum-free two-stage collagen gel culture with insulin, PRL, and linoleic acid. Omission of either PRL or linoleic acid drastically reduces alpha-casein accumulation. Spermidine addition to insulin-containing medium in either the absence or presence of linoleic acid does not stimulate alpha-casein accumulation. We conclude from this that spermidine can not be the sole mediator of PRL action. Spermidine also will not replace linoleic acid for alpha-casein accumulation if the fatty acid is omitted from the culture medium and will not increase casein accumulation when supplemented into PRL- and linoleic acid-containing medium; thus, it is not the sole mediator of linoleic acid action. However, the spermidine synthesis inhibitor methylglyoxal-(bis)-guanylhydrazone does inhibit alpha-casein accumulation in a concentration-dependent and spermidine-recoverable manner in cells stimulated by PRL and linoleic acid. We could not detect changes in polyamine levels in response to any of the medium supplements used in this investigation. Spermidine is, thus, at least a required comediator of the alpha-casein synthesis induction, although its role remains enigmatic.

Casein accumulation in mouse mammary epithelial cells after growth stimulated by different hormonal and nonhormonal agents.

Mammary epithelial cells obtained from virgin mice were cultured in collagen gel with linoleic acid-containing serum-free growth medium supplemented with hormonal (PRL and progesterone, epidermal growth factor, somatomedin-C) or nonhormonal (lithium ion, phosphatidic acid containing phospholipid liposomes) growth stimulating agents. The phenotypes of the resulting progeny cells were compared by examining the ultrastructure, immunohistochemical staining for luminal epithelial and myoepithelial cells and casein, and assessing the quantity of biochemically detectable alpha- and beta-casein. Although there are some differences in ultrastructure and immunostaining in the progeny cell populations induced by different growth-promoting agents, all the cultures were able to accumulate alpha- and beta-casein on subsequent stimulation by PRL and linoleic acid in the second phase of culture. Since, in vivo, luminal epithelial cells of the mammary gland are the only cell type capable of synthesizing milk products, these results indicate that all the different growth stimulants, hormonal and nonhormonal, result in the predominant proliferation of luminal-type epithelial cells. These results have important implications for studies of the mechanism of growth control in and transformation of mammary epithelial cells.

Differential gene expression of cytochrome P450 11beta-hydroxylase in rat adrenal cortex after in vivo activation.

In situ hybridization histochemistry was used to monitor the expression of 3beta-hydroxysteroid dehydrogenase, delta4-isomerase (3betaHSD) and cytochrome P450 11beta-hydroxylase (P45011beta) messenger RNA (mRNA) in adult rat adrenals after stimulation in vivo. In Exp 1, adrenals were collected from rats injected with saline or ACTH for 1, 2, 3, or 4 days. Adrenal sections from saline-treated rats showed uniform expression of 3betaHSD mRNA that extended from the adrenal capsule to the medullary border. In contrast, P45011beta mRNA showed high levels in the outer fasciculata and low levels in the inner fasciculata/reticularis. In response to ACTH, the integrated density of 3betaHSD hybridization did not increase until 4 days. The integrated density of P45011beta hybridization increased in ACTH-treated rats between 1-4 days due to increased hybridization in the inner fasciculata/reticularis. In Exp 2, rats were treated with ACTH or saline, and adrenals were harvested at 4, 8, or 24 h. The hybridization density of 3betaHSD did not change after ACTH or saline injection. Increased expression of P45011beta mRNA was observed at 4 and 8 h, but not 24 h post-ACTH. In Exp 3, to determine the response to acute stress, adrenals were collected from rats 24 h after surgical laparotomy. The integrated density of 3betaHSD labeling did not change, whereas both hybridization area and mean density of P45011beta increased. Increased expression of P45011beta mRNA was observed in the inner fasciculata similar to that observed after ACTH injection. In addition, adrenal cells were more responsive to ACTH in vitro after surgical stress. These results suggest that the rat adrenal cortex can respond to acute stress by up-regulation of the expression of steroidogenic enzyme genes and that this occurs in part by increasing the number of cells actively expressing P45011beta mRNA. The adrenal response after stress most likely results at least in part from stimulation by ACTH. These findings suggest that changes in adrenal steroidogenesis in response to ACTH may result from recruitment of steroidogenic cells to synthesize and secrete corticosteroids.

Development of adrenal zonation in fetal rats defined by expression of aldosterone synthase and 11beta-hydroxylase.

The adult rat adrenal cortex is comprised of three concentric steroidogenic zones that are morphologically and functionally distinguishable: the zona glomerulosa, zona intermedia, and the zona fasciculata/reticularis. Expression of the zone-specific steroidogenic enzymes, cytochrome P450 aldosterone synthase (P450aldo), and P450 11beta hydroxylase (P45011beta), produced by the zona glomerulosa and zona fasciculata/reticularis, respectively, can be used to define the adrenal cortical cell phenotype of these two zones. In this study, immunohistochemistry and in situ hybridization were used to determine the ontogeny of expression of P450aldo and P45011beta to monitor the pattern of development of the rat adrenal cortex. RIA was used to measure adrenal content of aldosterone and corticosterone, the resulting products of the two enzymatic pathways. Double immunofluorescent staining for both enzymes at gestational day 16 (E16) showed P45011beta protein expressed in cells distributed throughout most of the adrenal intermixed with a separate, but smaller, population of cells expressing P450aldo protein. Whereas expression of P45011beta protein retained a similar pattern of distribution from E16 to adulthood (ignoring distribution of SA-1 positive, presumptive medullary cells), P450aldo protein changed its pattern of distribution by E19, becoming localized in a discontinuous ring of cells adjacent to the capsule. By postnatal day 1, P450aldo protein distribution was similar to that observed in adult glands; P450aldo-positive cells formed a continuous zone underlying the capsule. In situ hybridization showed that the pattern of P45011beta messenger RNA expression paralleled protein expression at all times, whereas P450aldo messenger RNA paralleled protein at E19 and after, but was undetectable before E19. However, adrenal aldosterone and corticosterone, as measured by RIA, were detected by E16, supporting the functional capacity of both phenotypes for all ages studied. These data suggest that the development of the adrenal zona glomerulosa occurs in two distinct phases; initial expression of the glomerulosa phenotype in scattered cells of the inner cortex before E17, followed by a change in distribution to the outer cortex between E17 and E19. It is hypothesized that this change in distribution occurs via cell differentiation, rather than cell migration, and that a possible regulator of these events is the fetal renin-angiotensin system.

Biological and immunological characterization of cleaved and 16K forms of rat prolactin.

A cleaved form of rat PRL (rPRL) has been reported to exist in the pituitary gland and to be the main product of PRL proteolysis by its target tissues. A 16K fragment derived from cleaved PRL (cPRL) has mammary mitogenic activity in rats in vivo, and we found that both cleaved and 16K PRLs are capable of binding to hepatic PRL receptors. To analyze the functional significance of cleaved and 16K PRLs, ample amounts of cPRL were generated by incubation of 24K rPRL in vitro with a 25,000 X g rat mammary gland pellet. cPRL was reduced (2-mercaptoethanol), and the 16K and 8K fragments were separated by gel filtration. The purity of the cleaved and 16K samples was established by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and their mitogenic [pigeon crop-sac, Nb2 lymphoma cell, and mammary cell bioassays (BAs)], lactogenic (casein BA), and immunologic (PRL RIA) activities were determined. cPRL had the same mitogenic activity, but half the immunoactivity, as intact PRL. The 16K fragment was biologically active in all assays. Its estimated mitogenic and lactogenic potencies were 65% and 10% those of the 24K PRL, respectively, and it had only 2% the immunoactivity of the intact hormone. Thus, the 16K fragment had higher BA to RIA ratios than cleaved or intact 24K PRLs. The functional significance of 16K PRL may have been underestimated owing to its low RIA activity.

Is plasma serine a marker for psychosis?

There is some disagreement in the literature concerning the use of plasma serine concentrations as a biological marker for psychoses including schizophrenia. The groups studying this phenomenon have used different methodologies, including gas chromatography and classical amino acid analysis. In the present study, using high pressure liquid chromatography to analyze plasma amino acids from schizophrenics and controls, we found no difference in plasma serine concentrations. None of the plasma amino acid concentrations that were measured differed significantly between schizophrenics and controls but the basic amino acids tended toward higher concentrations in schizophrenics.

Flutamide-induced liver toxicity including fatal hepatic necrosis.

PURPOSE: To describe hepatic injuries in three patients who received flutamide prior to and during radiation treatment to make radiation oncologists aware of the need for careful monitoring of liver function during use of this drug. METHODS AND MATERIALS: The records of three patients who developed abnormal liver function tests while undergoing total androgen suppression (TAS), as well as the literature concerning flutamide toxicity were reviewed and summarized. RESULTS: Three of 34 patients treated with a TAS regimen incorporating flutamide developed significant hepatic abnormalities: elevated transaminases [2] and fatal hepatic necrosis [1]. Following the discontinuation of flutamide, two patients recovered fully. Unfortunately, the third patient's hepatic function continued to deteriorate, which culminated in his death. Transient elevations in serum transaminases, which do not exceed four times the upper limits of normal, are common and apparently without clinical significance. Unfortunately, idiosyncratic serious and/or fatal liver damage can occur. Significant liver toxicity may be obviated by monitoring of liver function tests (LFT) early in the course of flutamide therapy. CONCLUSION: The incidence of hepatic toxicity associated with flutamide may be higher than previously suggested. To prevent the development of serious hepatic dysfunction, all patients receiving flutamide should be monitored clinically for signs and symptoms referable to hepatic injury and with serial LFT. We recommend baseline LFT followed by serial LFT at weeks 2, 4, 6, and 8 from the start of treatment with flutamide. Flutamide should be stopped promptly if significant liver abnormalities are detected.

Basic fibroblast growth factor stimulates the growth and inhibits casein accumulation in mouse mammary epithelial cells in vitro.

The effects of basic fibroblast growth factor (bFGF) on the growth and differentiation of mouse mammary epithelial cells in serum-free collagen gel culture were examined. Epithelial cells obtained from virgin or midpregnant mice grew when bFGF was added to medium containing either insulin at a concentration greater than or equal to 1 microgram/ml or somatomedin-C (Sm-C) at 150 ng/ml. This growth-promoting effect is of the same magnitude as, and additive with, the growth-promoting effect of epidermal growth factor (EGF) or mammogenic hormones. The sensitivity of the cells to EGF or mammogenic hormones was not altered by exposure to bFGF. The progeny cells resulting from growth stimulation by bFGF are capable of accumulating casein upon subsequent stimulation by prolactin (PRL), but accumulate less casein than cells grown in response to EGF. bFGF also appears to reduce casein accumulation if it is added to the cultures at the same time as PRL.

Tachycardia as the sole fetal heart rate abnormality after funipuncture.

BACKGROUND: Fetal bradycardia is a common complication of funipuncture. We present a case of fetal exsanguination in which fetal tachycardia was the sole fetal heart rate abnormality. CASE: Funipuncture was performed at 32 weeks' gestation for evaluation of Rh isoimmunization. A persistent fetal tachycardia ensued and, although there was no immediate ultrasound evidence of bleeding, repeat ultrasonography revealed active bleeding at the puncture site. A neonate with an initial hematocrit of 42% was delivered by cesarean. Despite aggressive replacement of blood products, a repeat hematocrit was only 35% and a severe, persistent coagulopathy ensued. The newborn died 18 hours after delivery. Autopsy findings were consistent with neonatal coagulopathy. CONCLUSION: Although fetal bleeding is usually a common, relatively benign complication of funipuncture, streaming may not always be detected on ultrasonographic examination. Our case demonstrates that fetal tachycardia may be the only sign of fetal hemorrhage.

Effects of magnesium sulfate on toxemic patients in labor.

One hundred forty-four toxemic patients were studied by continuous electronic maternal and fetal monitoring. Ninety-seven were treated by intravenous bolus of 2 g MgSO4 every 1-2 hours, and 47 by intravenous drip MgSO4 at a rate of 1 g/hour. Clinical doses of MgSO4 do not affect maternal ECG, temperature, uterine contractions, or fetal heart rate. Intravenous bolus administration is frequently associated with slowing of maternal respirations and hypotension and occasionally with transient apnea.

Acidosis in the vigorous newborn.

Simultaneous measurements of maternal arterial and umbilical cord blood pH, PCO2, and base deficit at delivery were studied in 168 live-born infants and their mothers. The correlations between maternal and umbilical parameters were highly significant (P less than .001) and were greater in vigorous than in depressed newborns. Mothers of vigorous acidotic infants had a lower pH and a higher base deficit than those of vigorous nonacidotic infants (P less than .001). However, the maternal-fetal differences were wider in the vigorous acidotic than in the vigorous nonacidotic newborns for all three parameters, and in both umbilical vein and umbilical artery (P less than .001). The data indicate that maternal acidosis accounts only partially for the acidosis observed at the time of delivery in the apparently normal fetus. With neonatal depression, the degree of acidosis is not dependent on maternal pH but on other factors. These factors may be influenced by maternal acidosis, but they are the major reasons for the neonatal depression, not the maternal acidosis.

Intrapartum fetal cardiac arrhythmias.

Fifteen cases of fetal cardiac arrhythmia were detected by direct fetal electrocardiogram (FECG) during intrapartum fetal monitoring. The frequency of arrhythmia of 12.4/1000 monitored births. Thirteen of the arrhythmias were supraventricular. Atrial bigeminy was the most commonly observed arrhythmia, followed by atrial trigeminy. Two cases of ventricular arrhythmia were noted, one of which was a case of ventricular tachycardia. Arrhythmias were not related to drug treatment or to stage of labor. Variable decelerations occurred in association with arrhythmias in 73% of the cases. There were no nuchal cords seen at delivery, nor were there any instances of intrapartum fetal distress, fetal acidosis, or low Apgar scores associated with any arrhythmia. All arrhythmias resolved spontaneously without treatment. The neonatal course was uncomplicated in all cases. Intrapartum fetal arrhythmia is best detected by direct FECG. Appropriate management should include close observation for ominous fetal heart rate (FHR) patterns and fetal acid-base-studies. At present, there is no indication for drug treatment of intrapartum arrhythmia.

Fetal blood and tissue pH with variable deceleration patterns.

Continuous tissue pH, scalp blood pH, and umbilical artery pH were studied in 89 patients with variable decelerations and 5 control patients in labor. The characteristics of the variable decelerations were analyzed. The deceleration pattern was classified as variable without late component (V), variable with late onset (VLO), or variable with late recovery (VLR). The patterns with a late component showed a greater incidence of falling pH during the decelerations. The VLR pattern was very likely to show a tendency to fetal acidosis and a high incidence of low Apgar scores. Variable decelerations without a late component were found to be innocuous. The VLO was an intermediate pattern, often progressing to the potentially more hazardous pattern of VLR.

Fetal trigeminal rhythm.

A case of fetal trigeminal cardiac arrhythmia in labor is presented. The literature on fetal cardiac arrhythmias is reviewed. The significance and management of abnormal fetal rhythms in labor is discussed. The majority of fetal arrhythmias in labor do not require therapy.

Pregnancy after spinal cord injury: altered maternal and fetal response to labor.

Four pregnancies in three patients with spinal cord injury are presented. The major complications encountered include anemia, pyelonephritis, decubiti, premature labor, precipitate labor, and autonomic hyperreflexia. Autonomic hyperreflexia, a severe mass autonomic reflex response to labor, is associated with tachycardia, hypertension, headache, diaphoresis, and severe anxiety. It is probably due to increased norepinephrine release, as very high urinary metanephrines were measured in the latter two cases presented. Maternal and fetal physiology in labor are altered. Despite severe maternal and fetal stress responses, no fetal depression was observed.

Severe polycystic kidney disease in pregnancy. Report of fetal survival.

Advanced polycystic renal disease associated with pregnancy is very rare. A severely uremic pregnant patient with Landesman's Group C disease was delivered by cesarean section at 33 weeks' gestation, after dexamethasone treatment for fetal lung maturation. This is the first surviving infant in a case of Group C polycystic kidney disease.

Continuous fetal monitoring following third-trimester amniocentesis.

One hundred forty-six patients were monitored for up to 2 hours after third-trimester amniocentesis. The patterns of uterine and fetal activity, as well as fetal heart rate, were analyzed using the criteria for nonstress and contraction stress testing. There was a clear relationship between these observations and perinatal outcome. Postamniocentesis monitoring was associated with an Apgar score of 6 or less in only 10% of cases with reactive patterns, compared with in 75% of cases with nonreactive patterns and reduced variability and in all cases with late-component deceleration. All cases of immediate fetal jeopardy were detected and there was no fetal loss. Postamniocentesis monitoring appears to offer significant prognostic information for perinatal outcome in high-risk pregnancy.

The Apgar score: is it enough?

One thousand thirty-two neonates were evaluated with umbilical venous and arterial blood samples drawn at delivery for assessment of pH, PO2, PCO2, and base deficit. These values were statistically correlated with Apgar scores in all of the neonates studied. Infants were divided into Apgar groupings (group A, greater than or equal to 7 at one and five minutes; group B, less than 7 at one minute, greater than or equal to 7 at five minutes; group C, less than or equal to 7 at both one and five minutes). Generally, umbilical artery and umbilical venous data were parallel. The differences in means for pH, PO2, PCO2, and base deficit was significant when group A was compared with group B in both umbilical artery and umbilical venous data. However, a severe degree of biochemical disturbance must take place before significant association with neonatal depression can be made. It appears that umbilical blood biochemical data are related to fetal metabolic status before birth but only modestly influence the one-minute Apgar score.