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To compare the quality of life (QoL) in children with spina bifida with a control group of their peers using a validated questionnaire, the Neurogenic Bowel Dysfunction Score (NBDS). The NBDS questionnaire was prospectively distributed to children attending a multi-disciplinary Spina Bifida clinic and healthy controls attending pediatric urology clinics. A score (out of 41) was assigned to each child based on their responses to the validated questionnaire. A lower score indicates better bowel function-related quality of life. SPSS software (v.25) was used for all statistical analysis. There were 98 respondents to the questionnaire, 48 children with spina bifida and 50 controls. The average age of respondents was 7.88 years (3–16 years). Of those with Spina Bifida, 33 (69%) were on retrograde rectal irrigations, [19 (58%) Peristeen® system, 11 (33%) tube rectal irrigations, and 3 (9%) Willis system], 6 (12%) were on laxatives, and 9 (19%) were on no treatment. The median NBDS for Spina Bifida patients was significantly higher 13.5 (2–32) compared to the control group 2 (0–26, p

Objectives To evaluate, through the investigation of an administrative database, the cost of patients affected by diabetes. Our dataset allows to map the progress of the disease so as to evaluate the impact on costs of co-pathologies.

Aim: Few retrospective studies have evaluated infants with hypertrophic pyloric stenosis (HPS) for associated urological anomalies. They have led to contradictory conclusions. The aim of this study was to evaluate the incidence of urinary tract anomalies in infants with HPS and to establish the clinical significance of this association. Methods: One hundred and twenty-two infants (100 boys) who underwent pyloromyotomy between 1992 and 2002 were prospectively evaluated. Screening ultrasound (Us) of the urinary tract was performed in 107 infants, while 15 did not attend their ultrasound appointment. Results: Renal ultrasound was abnormal in 4 (4%) of 107 screened patients with HPS. Three patients were found to have mild hydronephrosis and, in one patient, a small, normal kidney was detected. Two patients with hydronephrosis had Us follow-up and the third patient underwent Tc-99 mercaptoacetyl triglycine (MAG 3) scan. In all three patients, the hydronephrosis resolved completely on follow-up scan. Conclusion: The incidence of abnormal renal ultrasound in children with HPS is similar to the reported incidence of 3–6% determined with routine ultrasound screening of healthy newborns. The abnormalities detected were not clinically relevant and did not require surgical intervention. We do not recommend screening of the urinary tract in infants with HPS.

Little is known about genes that govern the development of the definitive endoderm in mammals; this germ layer gives rise to the intestinal epithelium and various other cell types, such as hepatocytes, derived from the gut. The discovery that the rat hepatocyte transcription factor HNF3 is similar to the Drosophila forkhead gene, which plays a critical role in gut development in the fly, led us to isolate genes containing the HNF3/forkhead (HFH) domain that are expressed in mouse endoderm develop ment. We recovered mouse HNF3β from an embryo cDNA library and found that the gene is first expressed in the anterior portion of the primitive streak at the onset of gastrulation, in a region where definitive endoderm first arises. Its expression persists in axial structures derived from the mouse equivalent of Hensen’s node, namely definitive endoderm and notochord, and in the ventral region of the developing neural tube. Expression of the highly related gene, HNF3α, appears to initiate later than HNF3P and is first seen in midline endoderm cells. Expression. subsequently appears in notochord, ventral neural tube, and gut endoderm in patterns similar to HNF3β. Microscale DNA binding assays show that HNF3 proteins are detectable in the midgut at 9.5 days p.c. At later stages HNF3 mRNAs and protein are expressed strongly in endoderm-derived tissues such as the liver. HNF3 is also the only known hepatocyte enriched transcription factor present in a highly de-dif ferentiated liver cell line that retains the capacity to re differentiate to the hepatic phenotype. Taken together, these studies suggest that HNF3α and HNF3β are involved in both the initiation and maintenance of the endodermal lineage. We also discovered a novel HFH containing gene, HFH-ES.1, that is expressed transiently in posterior ectoderm and mesoderm at the primitive streak stage, and later predominantly in the neural tube. HFH-ES.1 is highly similar in structure and expression profile to the Drosophila HFH gene FD4, suggesting that HFH family members have different, evolutionarily conserved roles in development.

We have used streptozotocin (STZ)-induced diabetes in rats to determine whether this represents a sustained stimulus to the adrenocortical system and whether STZ-diabetic rats are able to mount an acute stress response. Furthermore, we compared pituitary responsiveness to CRF and/or arginine vasopressin, and adrenal responsiveness to ACTH in STZ- vs. vehicle-treated rats. We also compared the efficacy of dexamethasone inhibitory feedback in STZ-diabetic and control rats. Our results show that STZ-treated rats chronically hypersecrete corticosterone (B) as evidenced by their decreased thymus weights, their increased urinary B excretion, and their elevated mean plasma B levels during the light hours of the day. Despite the evidence for sustained hypersecretion of B, STZ-treated rats showed greater and more prolonged ACTH and B responses to the acute stress of histamine injection. However, when tested separately, neither pituitary nor adrenal responsiveness to their secretagogues were increased in STZ-diabetic compared to control rats. Dexamethasone inhibition of stress-induced B secretion was tested using two different paradigms: pentobarbital-anesthetized rats were given iv injections of acid saline, and awake rats were given ip injections of histamine. In both experiments the STZ-treated rats were relatively resistant to glucocorticoid inhibition of stress responses. This finding, taken together with the exaggerated ACTH and B responses to stress, strongly suggests that the facilitatory effects of chronic STZ-diabetes are a consequence of changes in sensitivity of central neural components of the adrenocortical system to stimulatory and/or inhibitory inputs, in conjunction with changes in glucocorticoid feedback sensitivity.

The mechanisms involved in the physiology of the secretion of ACTH are reviewed. The secretion is regulated by the biological consequences of the occupancy of high affinity mineralocorticoid (MR) and lower affinity glucocorticoid receptors (GR) for corticosterone at specific sites of the rat brain. The regulation by this mechanism of basal secretion during the circadian rhythm, the effect of adrenalectomy and of corticosterone replacement is discussed. Experiments with RU486, a specific glucocorticoid antagonist, suggest that occupancy of both MR and GR is required for normal control of ACTH at the time of peak activity. The occupancy of the GR for a few hours per day apparently suffices to maintain steady levels of the products of GR-responsive genes throughout the body.

The authors report the preliminary data of the case studies of the new National Protocol TGC91 and examine the role of surgery in the treatment of these neoplasms

Pervasive developmental disorder, not otherwise specified (PDD, NOS), a developmental-neurologic spectrum disorder, occurs in 10 to 12 of every 10,000 children. PDD, NOS is characterized by a spectrum of significant problems that may vary substantially in range and expression. These may include visual/spatial, kinesthetic, verbal/linguistic, and musical/rhythmic problems. Social skill deficits are also common, as are restricted, repetitive patterns of behavior, interests, and activities. Symptoms of PDD, NOS are often expressed differently among children with the disorder and can be mistakenly attributed to other problems such as attention deficits, oppositional behavior, or stress reactions. Clinicians may encounter children in their practice who exhibit symptoms of PDD, NOS and must be familiar with this disorder so that appropriate diagnosis and treatment can be provided. Families also need ongoing, anticipatory guidance to help them cope with the behavioral aspects of the disorder.

We have determined the effects of bilateral electrolytic lesions of the ventromedial hypothalamus (VMH) on activity in the hypothalamo-pituitary-adrenal (HPA) system. Acutely, during the first 5 days, lesions of the anterior-medial VMH caused loss of the diurnal rhythms in food intake and plasma corticosterone (B) levels. Plasma B concentrations were elevated during the time of the normal trough of the basal diurnal rhythm in HPA axis activity and the diurnal rhythm in food intake was abolished, in agreement with the results of others. Consistent with hyperactivity in the HPA axis, lesioned rats had increased adrenal weight, decreased thymus and body weights and decreased plasma transcortin concentrations. To determine how lesions of the VMH provoke these increases in activity of the HPA system, the sensitivity of ACTH in adrenalectomized, lesioned rats to replacement with exogenous B was determined under basal conditions during the trough (morning-AM) and peak (evening-PM) of the diurnal rhythm in HPA axis activity. ACTH in lesioned rats in the AM was insensitive to feedback over the very low range of plasma B of 1-4 micrograms/dl, whereas sham-lesioned controls exhibited the normal, high sensitivity of ACTH to B at this time of day. There was no difference between the sensitivity of ACTH to this low range of B in the PM in VMH- and sham-lesioned rats. Two to 5 weeks after VMH lesions, as found by others, mean daily plasma B levels did not differ from sham-lesioned controls; however, plasma B during the AM was still mildly elevated in these rats. Inhibition of plasma B in the PM by dexamethasone was less effective in lesioned rats. Although HPA system responses to hypoglycemia, corticotropin-releasing factor and ACTH were normal, the lesioned rats exhibited obesity, hyperinsulinemia, hyperglycemia, hypertension and tachycardia, all signs consistent with mild hyperactivity of the PHA axis. Occupancy of type I, high-affinity corticosteroid receptors is known to control basal activity of the HPA system during the trough of the diurnal rhythm and to interact with glucocorticoid receptors to affect basal activity during the peak of the diurnal rhythm and during AM stress. We conclude that VMH lesions disrupt transmission of inhibitory signals, mediated by occupancy of type I corticosteroid receptors, that are initiated by a B feed-back site.

The enhancement of critical-thinking skills empowers students to participate in the building of healthy environments in a variety of settings. The authors describe the development and implementation of unique classroom strategies emphasizing the use of critical thinking by students, the forging of faculty-student partnerships in community health nursing, and the potential impact of these strategies on the expanding horizons of practice.

Gli Autori evidsenziano le caratteristiche clinice e terapeutiche del Neuroblastoma.

La Terapia Chirurgica dei tumori benigni del testicolo si basa sulla orchiectomia radicale inguinale. Tale criterio è stato messo in discussioneda alcuni Autori e per tale motivo sono stati valutati i risultati di una casistica nazionale multicentrica retrospettiva di 10 anni allo scopo di valutare la possibilità di una exeresi radicale conservativa di queste neoplasie

Previous studies with embryonic tissue explants showed that cellular interactions with mesenchyme are required for endodermal cells to differentiate into hepatocytes. However, these studies assayed hepatocyte characteristics that were evident after days of culture, leaving open the question of whether the primary inductive interactions initiated hepatocyte differentiation, or whether subsequent steps, such as may occur during cell aggregation to form the liver, were necessary. Using the technique of in situ hybridization, we find that serum albumin mRNA, a liver-specific gene product, is first detected in hepatic precursor cells of the endoderm as early as 9.5 days of mouse embryo development, a full day prior to cell aggregation and liver formation. The endodermal cells express albumin mRNA upon migration into strands of connective tissue matrix within mesenchyme. Thus, the onset of differentiation of the endoderm is coincident with its interaction with mesenchyme. Early albumin transcripts are initiated at the same site of the albumin promoter as in adult hepatocytes, suggesting that at least a subset of the transcription factors that control albumin transcription in the adult may be involved in executing the early steps of hepatic determination. We also observe a sharp increase in albumin mRNA levels shortly after the definitive formation of the liver, apparently reflecting cell interactions that enhance hepatocyte differentiation. Hepatocyte differentiation is therefore similar in several respects to pancreatic exocrine cell development, and may represent a general pattern for gut-derived tissues. For both cell types, early interactions with mesenchyme are coincident with the initial expression of differentiated gene products at a low level in proliferating endoderm, and the initial pattern of expression is amplified upon organ formation.

The responsiveness of the neonatal hypothalamus-pituitary-adrenal (HPA) axis to stress has been thought to be impaired or diminished during the first 2 weeks of life. Although we previously found full responsiveness of the hypothalamus-pituitary unit to adrenalectomy in young rats [days (d) 5-10], we failed to measure a significant increase in ACTH 10 min after ether administration until d14 of age. These studies were, therefore, designed to test the functional activation of the HPA axis after a single or repeated exposures to stress. Both qualitative (time-course, stressor-specific, circadian) and quantitative changes in the ACTH and corticosterone (B) responses to various stressors were tested during the first 10 days of life. Exposure to 3 min of ether vapor increased ACTH and B secretion (P less than 0.05-0.01) in 1-, 5-, and 10-d-old rats, with an increasing amplitude of both ACTH and B responses as a function of age. Peak secretion of ACTH occurred 5 min after the onset of stress (122 +/- 3.8 to 359 +/- 54 pg/ml on d1-10), while the time of maximal B increased as a function of age. Other stressors, such as maternal separation (12 h), cold (4 C; 60 min), or histamine injection (4 mg/kg BW, ip), provoked significant and stressor-specific ACTH and B responses in 10-d old rats. Histamine administration increased ACTH secretion above that of vehicle-injected rats, with a peak of secretion 15 min after drug injection (272 +/- 29 vs. 127 +/- 8 pg/ml; P less than 0.01). Histamine-induced B secretion peaked at 60 min (3.7 +/- 0.5 micrograms/dl). In contrast to early responses observed after ether, separation, or histamine stress, cold stress in 10-d-old pups caused a large ACTH and B release 4 h after the onset of cold compared to that in maternally deprived pups [ACTH: cold, 457 +/- 61 pg/ml; separated, 150 +/- 14 (P less than 0.01); B: cold, 3.3 +/- 0.4 micrograms/dl; separated, 1.8 +/- 0.2 (P less than 0.05)]. We did not detect morning-evening (AM-PM) differences in either the pattern or the magnitude of the ACTH or B response to maternal separation or cold stress. Suppression of cold-induced ACTH release by B injection (1 mg/kg BW) 2 h before stress was observed until 4 h after stress in the AM and PM, whereas when given after cold, B was less effective in the PM than in the AM at preventing the rise in ACTH levels observed at 4 h.(ABSTRACT TRUNCATED AT 400 WORDS)

To test whether the diurnal rhythm in stress responsiveness is dependent on corticosterone (B)-mediated negative feedback, the responses of intact (SHAM) and adrenalectomized (ADX) rats to restraint for 3-90 minutes or ip injection with saline in the morning (AM) and the evening (PM) were compared. In both SHAM and ADX rats, ACTH responses to restraint stress were larger in the AM. In intact rats, this could have resulted from both fast negative feedback, due to the rate of rise of B during the stress in the PM, and delayed negative feedback, due to the high basal concentrations of B before the stress in the PM. However, this diurnal pattern of stress responsiveness was not dependent on B, as the same relative responses to restraint and ip injection were found in ADX rats. To determine whether the lack of response of ADX rats in the PM to stress was due to a loss of sensitivity to endogenous secretagogues, ADX rats were given CRF + arginine vasopressin (AVP) while anesthetized with ether after 30 min of restraint. In both the AM and the PM, the pituitaries were able to respond to exogenous secretagogues. A second novel finding was that in the PM, but not the AM, plasma ACTH concentrations in the ADX rats decreased substantially during the period of restraint, despite the lack of B-mediated negative feedback. In the AM and the PM, ADX rats were restrained for 30 min and then stressed with ether for 6 min. The ACTH concentrations were not different before and after ether, suggesting that, although the pituitaries of ADX rats are able to respond to exogenous CRF + AVP after stress, an additional stress of ether exposure no longer stimulates endogenous CRF and AVP release after 30 min of restraint at either time of day. After 90 min of restraint in the AM and the PM, the relationship between ACTH and B was positive, not negative, providing no evidence of ongoing B-mediated negative feedback in the SHAM rats. Therefore, the same mechanism responsible for the decrease in ACTH secretion in ADX rats may occur in SHAM rats as well. From these results, we conclude that the diurnal rhythm in stress responsiveness and, in the PM in the ADX rats, the decrease in plasma ACTH during stress, are largely independent of B.

Pervasive developmental disorder, not otherwise specified (PDD, NOS), a developmental-neurologic spectrum disorder, occurs in 10 to 12 of every 10,000 children. PDD, NOS is characterized by a spectrum of significant problems that may vary substantially in range and expression. These may include visual/spatial, kinesthetic, verbal/linguistic, and musical/rhythmic problems. Social skill deficits are also common, as are restricted, repetitive patterns of behavior, interests, and activities. Symptoms of PDD, NOS are often expressed differently among children with the disorder and can be mistakenly attributed to other problems such as attention deficits, oppositional behavior, or stress reactions. Clinicians may encounter children in their practice who exhibit symptoms of PDD, NOS and must be familiar with this disorder so that appropriate diagnosis and treatment can be provided. Families also need ongoing, anticipatory guidance to help them cope with the behavioral aspects of the disorder.

[3H]Tryptamine binds to rat brain cortex. The binding is saturable and of high affinity. Drug displacement studies indicate that the binding site has a high degree of specificity for tryptamine and that the site is distinct from serotonin receptor binding sites.

We report the case of a possible hepatotoxic reaction in a patient receiving the investigational macrolide antibiotic, rosaramicin. The patient presented with complaints attributable to an acute cholestatic reaction with a maculopapular skin rash. Serum enzymes indicative of hepatic function were initially markedly elevated but returned to normal after withdrawal of the drug. Because of the close chemical structural similarity of rosaramicin to other macrolide antibiotics known to produce similar hepatotoxic reactions, careful surveillance of patients receiving this drug is suggested.

The role of alpha-adrenergic mechanism in the acute effects of morphine in the hypothalamo-pituitary-adrenocortical (HPA) and cardiovascular (CV) systems, and the interrelationship between the HPA and CV responses to alpha-adrenoceptor antagonists and/or morphine were studied by peripheral administration of prazosin, a selective alpha 1-adrenoceptor antagonist, and yohimbine, a selective alpha 2-adrenoceptor antagonist, in conscious, unstressed or ether-stressed rats. The test substances were administered intravenously or intraperitoneally in chronically cannulated or noncannulated rats. In the i.v. experiment, morphine (1 mg/100 g BW) rapidly induced a pronounced bradycardia and a short-lasting fall in blood pressure (BP), followed by a rise in BP, and increased plasma corticosterone concentration. Prazosin (0.5 mg/kg BW) induced a rapid fall in BP and tachycardia, and increased plasma corticosterone concentration. Pretreatment with prazosin did not block the effect of morphine on the CV system, but abolished the morphine-induced increment in plasma corticosterone concentration. Yohimbine (0.5 mg/kg BW) induced a rapid and a subsequent slowly developing rise in BP and tachycardia, and increased plasma corticosterone concentration. Pretreatment with yohimbine did not block the effect of morphine on the CV system nor alter the stimulatory effect of morphine on the secretion of corticosterone. In the intraperitoneal experiment, morphine (2 mg/100 g BW) stimulated the secretion of adrenocorticotropic hormone (ACTH) and corticosterone and prazosin (1 mg/kg BW) stimulated the secretion of corticosterone, but pretreatment with prazosin reduced the morphine-induced increment in plasma corticosterone concentration in unstressed rats. In stressed rats, morphine reduced the stress-induced increment in plasma ACTH and corticosterone concentrations and prazosin also reduced the stress-induced increment in plasma corticosterone concentration. Pretreatment with prazosin did not alter the inhibitory effect of morphine...

After removal of corticosteroid feedback by surgical or pharmacological adrenalectomy, plasma ACTH increases more rapidly than can be explained by changes in receptor-mediated gene expression. In aminoglutethimide-treated rats, plasma ACTH increased only at doses much higher than those inhibiting plasma corticosterone, suggesting that adrenal enzyme blockers may themselves be stressful. To determine the adrenocortical system response to stressless corticosterone removal, adrenalectomized rats maintained for 5 days on corticosterone in the drinking water were switched to steroid-free fluid (-B) or again given steroid (+B); additional rats were adrenalectomized (ADX). Plasma ACTH did not differ between -B and +B rats until 18-24 h after steroid removal, regardless of whether steroid was withdrawn at the circadian maximum or minimum. Plasma ACTH was similar between -B and ADX rats 0.5-14 days after corticosterone removal, although morning plasma ACTH was more stable in -B rats at 4-7 days. Evening plasma ACTH increased significantly after day 3 in ADX and -B rats. Unlike ADX rats, -B rats did not exhibit pituitary ACTH depletion at 12 and 24 h, but both -B and ADX groups had significantly elevated pituitary ACTH by 6.5 days. We conclude that 1) rapid increases in ACTH secretion after surgical or pharmacological adrenalectomy result from interaction between stress and loss of corticosteroid feedback; 2) no immediate interaction occurs between loss of feedback and circadian stimuli; and 3) the effects of steroid withdrawal may require at least 3 days to be stably expressed.

There is evidence in man and rats that higher circulating levels of glucocorticoids are required to normalize basal unstimulated ACTH levels at the peak of the circadian rhythm than at the trough. To explore this phenomenon, we tested the inhibitory effect of constant levels of corticosterone on plasma ACTH in the morning (AM) and evening (PM) in young male rats implanted with fused pellets of corticosterone-cholesterol at the time of adrenalectomy (ADX+B) and studied 5 days later. There was a marked shift of the plasma corticosterone-ACTH inhibition curve to the right between AM and PM, demonstrating that the efficacy of corticosterone feedback inhibition of ACTH is less in the PM. Comparison of plasma ACTH and corticosterone levels during 24 h in sham-adrenalectomized rats (SHAM-ADX), adrenalectomized rats (ADX), and ADX+B revealed constantly low ACTH in SHAM-ADX, constantly high ACTH in ADX, and biphasic ACTH levels in ADX+B. Corticosterone levels were biphasic in SHAM-ADX and were constant in the other two groups. These results again showed a shift in corticosterone feedback efficacy as a function of the time of day and also suggested that basal ACTH secretion is maintained in the low normal range in intact rats because of the marked diurnal rhythm in corticosterone. The sensitivity of the pituitary ACTH response to exogenous CRF did not change between AM and PM in either intact or ADX+B showing that the shift in feedback sensitivity to corticosterone does not reside in the pituitary. The response of the entire adrenocortical system to histamine stress was shown to be equivalent in both the AM and PM, suggesting that feedback sensitivity of the entire system to corticosterone does not change as a function of the time of day. We conclude from these results that there is an apparent diurnal change in ACTH sensitivity to corticosterone feedback that can be defined operationally as reset. We believe that the site of feedback being tested shifts solely from the pituitary in the AM (at the nadir of the rhythm) to the brain and the pituitary in the PM (at the peak of the rhythm). The lack of the normally high transients of corticosterone that occur in SHAM-ADX rats results in increased brain drive of the pituitary in ADX+B.

The results summarized here have established the temporal and regional activation of three kinds of Xenopus actin genes. The cardiac and skeletal muscle actin genes are among the first cell-type-specific genes to be expressed in early development. The first transcripts to be synthesized by these genes appear to be correctly initiated, spliced, and at once translated into proteins. Both cardiac and skeletal actin genes are strongly transcribed in the axial skeletal muscle of embryos. The mechanism by which the cardiac actin gene is first transcribed in only the somite region of an embryo depends, at least in part, on materials already localized in the subequatorial region of a fertilized but uncleaved egg. Cells which acquire this material seem able to activate their cardiac actin genes without requiring normal contact with other cells.

The effect of bilateral lesions of the suprachiasmatic nuclei (SCN) on the circadian rhythm in ACTH was studied in rats that were adrenalectomized and implanted with a subcutaneous corticosterone (B) pellet. Rats were chronically cannulated to allow for repeated blood sampling. In rats with B pellets, bilateral lesions of the SCN eliminated the circadian rise in plasma ACTH seen in sham-lesioned animals. This is consistent with the idea that the SCN stimulate ACTH secretion in the evening.

The affinities of four tetrahydro-beta-carbolines at [3H]tryptamine, [3H]5-HT (5-HT1), and [3H]spiperone (5-HT2) binding sites in rat cerebral cortex were investigated. The unsubstituted tetrahydro-beta-carboline was the most potent of the four compounds at all three binding sites, but was 200-400 times more potent at the tryptamine site than at either of the serotonin sites.

There are different methods for recording physiologic electrical signals cutaneously. Monopolar recording has been used, by us and by others, to record the basic electrical rhythm of the stomach. In an effort to improve our ability to routinely obtain a recording of the basic electrical rhythm of the stomach, using cutaneous electrodes (electrogastrography), we have investigated different electrode recording techniques, and compared them with monopolar recording. We studied 10 healthy asymptomatic volunteers who were fasting, using each of the techniques while simultaneously monitoring a monopolar electrogastrogram. Three different recording techniques were studied: a Wilson central terminal, comparing alternative placements of the reference electrodes; a Wilson central terminal with a single placement of the reference electrodes, but alternative placements of the active exploratory electrode; and, last, a differential recording technique. We found all of the studied techniques to be superior to monopolar recording in the amount of time a recognizable three/min basic electrical rhythm could be recorded. However, the differential recording arrangement yielded an improvement in percent of recording time so significant that the electrogastrographic signal could be visually discerned to greater than 80%, compared with 37%, of the monopolar recording. Thus, the differential recording technique is far superior for recording the electrogastrogram.

ACTH secretion appears to be under fairly tight negative feedback control by corticosteroids secreted from the adrenal cortex. In these studies we determined the circulating levels of a constant corticosterone signal that best restored body weight gain, thymus weight and ACTH levels to normal in bilaterally adrenalectomized rats given saline to drink. Young male rats were treated at the time of adrenalectomy with subcutaneously implanted pellets of wax or various ratios of corticosterone-cholesterol. Sham-adrenalectomized rats and adrenalectomized rats given corticosterone in the drinking fluid served as comparison groups. Rats were killed 3, 7, or 14 days after adrenalectomy. There was no difference in levels of plasma corticosterone in the morning and in the evening in pellet-implanted rats in contrast to the diurnal variation in the reference groups. Circulating corticosterone levels that best restored body weight, thymus weight, and resting and stress-induced ACTH levels to normal ranged between 4.5 and 7.4 micrograms/dl. Plasma corticosterone levels of 8-11 micrograms/dl were excessive and levels of 2-4 micrograms/dl were not adequate. We conclude that there is a very narrow range of plasma corticosterone compatible with normal growth rate, thymus mass and ACTH secretion. These results reveal the necessity for strict negative feedback regulation of ACTH secretion by corticosteroids.

Publisher Summary This chapter discusses the regulation of function in the adrenocortical system. There are three major characteristics that describe most changes in activity of the system: (1) the circadian rhythm in basal activity, (2) stress-induced activation, and (3) corticosteroid feedback regulation. The first two may occur on very different timescales, and it is probably a consequence of the differing temporal demands that the third, corticosteroid feedback inhibition, is exerted by a variety of mechanisms over time. At any time of the day, the adrenocortical system can be activated by application of stressors. These include alteration of the value of a regulated variable or may be invoked by subjecting an animal to sudden disturbances of its environment, for example, noise, flashing lights, handling, strange environment, mild heat or cold. The adrenocortical system may be activated by traumatic stimuli or by psychological stimuli—in man, examinations, or mental arithmetic, or medical school admissions exams; in rats, unexpected decreases in food rewards.

The incubation of Xenopus embryo fragments in cycloheximide at 5 or 10μgml−1 rapidly inhibits protein synthesis to 10 % or less of control levels. In most batches of embryos, treatment with cycloheximide for up to 1 h causes no obvious cellular damage and protein synthesis is fully restored to normal levels 5h later. Transcript analysis with RNA probes shows that the inhibition of protein synthesis at late blastula or early gastrula stages completely suppresses the normal initiation of actin gene transcription at the mid-late gastrula stage. This applies to muscle-specific actin genes, whose transcription is initiated by induction, as well as to cytoskeletal actin genes not activated by induction. Two-dimensional gel protein analysis shows that cycloheximide irreversibly inhibits only 10 % of all genes normally expressed at a postneurula stage and that all of these are genes whose expression is normally initiated during or soon after gastrulation. Cycloheximide treatment causes a limited reduction of DNA synthesis, and no reduction of overall RNA synthesis. We conclude that the initiation of new gene transcription during gastrulation in Xenopus is dependent on the immediately preceding synthesis of certain proteins.

The effects of chronic administration of electroconvulsive shock and antidepressant drugs on rat brain serotonin-2 (5-HT2) receptors were investigated. Electroconbulsive shock increases the density and antidepressant drugs decrease the density of 5-HT2 receptors labelled by [3H]spiperone.

The results summarized here have established the temporal and regional activation of three kinds of Xenopus actin genes. The cardiac and skeletal muscle actin genes are among the first cell-type-specific genes to be expressed in early development. The first transcripts to be synthesized by these genes appear to be correctly initiated, spliced, and at once translated into proteins. Both cardiac and skeletal actin genes are strongly transcribed in the axial skeletal muscle of embryos. The mechanism by which the cardiac actin gene is first transcribed in only the somite region of an embryo depends, at least in part, on materials already localized in the subequatorial region of a fertilized but uncleaved egg. Cells which acquire this material seem able to activate their cardiac actin genes without requiring normal contact with other cells.

To characterize further the effects of providing a constant corticosterone signal after bilateral adrenalectomy, we have compared the effects of bilateral adrenalectomy with no replacement (ADX) and with replacement with a corticosterone pellet implanted sc at surgery (B-PELLET) to those of sham-adrenalectomy (SHAM) on pituitary and plasma ACTH concentrations during the first 3 postoperative days. In ADX rats, plasma ACTH concentrations were elevated at all times compared to those in the SHAM group; pituitary ACTH content decreased during the first 12 h, then increased and was not different from that in the SHAM group thereafter. Replacement of corticosterone at the time of adrenal surgery in B-PELLET rats resulted in no differences in pituitary and plasma ACTH concentrations from SHAM values, suggesting that immediate steroid replacement prevents the major adrenalectomy-induced changes in central regulatory components governing basal activity of the adrenocortical system. Although B-PELLET rats had normal basal morning ACTH concentrations 5 days after surgery, they exhibited augmented and sustained ACTH responses to five different ACTH-releasing stimuli (injection, restraint, chlorpromazine, and, under pentobarbital anesthesia, morphine or sham adrenalectomy). The circulating corticosterone concentrations were maintained at relatively constant, low levels (3-6 micrograms/dl). Because these concentrations appear to restore basal morning ACTH concentrations to normal, but do not restore the ACTH response to stress to normal, we conclude that a different corticosterone signal is required to normalize stress-induced ACTH responses.

Electroconvulsive shock (ECS) administered once daily for up to 14 days decreases beta-adrenergic receptor binding in the cortex and hippocampus in a time-dependent manner. The decrease in binding in the cortex lasts at least 1 week after the last shock. In the striatum, hypothalamus, or cerebellum, 14 days of ECS did not produce significant changes in beta-adrenergic receptor binding. The brain regional pattern of beta-adrenergic receptor changes suggests that repeated ECS affects beta 1-adrenergic receptors in brain regions that receive a noradrenergic innervation activated by ECS. The effects of ECS on neurotransmitter receptor binding appear to be highly selective. Of five receptors in the cortex and three receptors in the hippocampus measured, only beta-adrenergic receptor binding is decreased. Chronic footshock stress does not alter beta-adrenergic receptor binding sites in the cortex, indicating that the effects of ECS are not due to stress alone. The effects of ECS on reserpine-induced alterations in beta-adrenergic receptor binding sites were also examined. Ten days of ECS following chronic reserpine injections reverses the increased binding of beta-adrenergic receptors.

Adrenalectomy-induced increases in ACTH secretion in rats are returned to normal by an action of corticosterone on the brain, not on the pituitary. Five days after adrenalectomy with constant steroid replacement, the concentration of free corticosterone in plasma which reduces plasma ACTH by 50% is approximately 0.8 nM. By contrast, the concentration of free plasma corticosterone required for 50% reduction of thymus wet weight or plasma transcortin concentration (both targets for glucocorticoid action) is about 4.5 nM. These results suggested that the inhibition of ACTH by corticosterone might be mediated by association of the steroid with high affinity, type I corticosteroid receptors, whereas the inhibition of thymus weight and transcortin might be mediated by association of the steroid with lower affinity, type II receptors. The results of studies comparing the ability of corticosterone, dexamethasone and aldosterone to inhibit adrenalectomy-induced ACTH secretion support the hypothesis that basal ACTH secretion in rats is mediated by association of corticosterone with type I receptors.

[ 3 H]Tryptamine binds with high affinity to sites on rat brain membranes. The sites have the characteristics of tryptamine receptor recognition sites. These sites are widely distributed among rat brain regions with the highest density occurring in the cerebral cortex, striatum and hippocampus. The site is also found in human cerebral cortex. The binding site is localized mainly to the synaptosomal fraction. Drug competition studies indicate that the [ 3 H]tryptamine binding site is distinct from serotonin receptors. Drugs that are potent inhibitors of [ 3 H]tryptamine binding include tetrahydro-β-carboline, quipazine, phenylethylamine, amphetamine, p-chloroamphetamine and methamphetamine.

[3H]Tryptamine binding sites were measured in 4 areas of rat brain following treatment with either pargyline or reserpine for 12 days, or 5 days and 30 days following intraventricular injections of 6-hydroxydopamine or 5,7-dihydroxytryptamine. Pargyline treatment decreased [3H]tryptamine binding in cerebral cortex, hippocampus, striatum and hypothalamus. Reserpine treatment increased binding in the cerebral cortex and hippocampus, but not in the striatum or hypothalamus. Neither 6-hydroxydopamine nor 5,7-dihydroxytryptamine altered [3H]tryptamine binding in any of the 4 brain areas. These results indicate that [3H]tryptamine binding sites in brain may be modified by drugs that can potentially affect tryptamine metabolism, and that the sites are not located on catecholamine or serotonin axons.

The effects of long-term lithium administration on pre- and postsynaptic processes involved in serotonergic neurotransmission were measured in rat hippocampus and cerebral cortex. Long-term lithium administration increased both basal and potassium chloride-stimulated release of endogenous serotonin from the hippocampus but not from the cortex. Serotonergic receptor binding was reduced in the hippocampus but not in the cortex. These results suggest a mechanism by which lithium may stabilize serotonin neurotransmission.

These studies were performed to determine pharmacologically the corticosteroid receptor type that mediates the effects of corticosterone (B) on ACTH secretion in adrenalectomized rats. We have compared the effects of treating young male rats at the time of adrenalectomy and throughout the next 5 days with B, dexamethasone (DEX), or aldosterone (ALDO) in doses that elevated plasma levels to concentrations in the range between 0.2-30 nM. Plasma ACTH, corticosteroid-binding globulin (CBG), and thymus weight were measured in the morning or evening, and these steroid-sensitive end points were related to the circulating concentrations of B (total B - CBG-bound B), total DEX, and total ALDO. For the inhibition of ACTH the rank order of potency of the three steroids was B greater than DEX greater than or equal to ALDO in the morning (estimated IC50, 0.7 +/- 0.1, 2.3 +/- 0.5, and 4.9 +/- 1.6 nM for B, DEX, and ALDO, respectively). There was a significant shift to the right in steroid efficacy between morning and evening (estimated IC50 in the evening, 3.9 +/- 0.2 and 9.3 +/- 0.8 nM for B and DEX; ALDO at the concentrations achieved was ineffective). The rightward shift in efficacy may result from the circadian increase in drive to ACTH secretion. The rank order of potency for B and DEX on ACTH and the agreement between the steady state IC50 values achieved for these steroids and the Kd values determined for B and DEX with type I receptors in vitro strongly suggest that feedback control of basal diurnal ACTH by corticosteroids is mediated by association with type I, B-preferring receptors. By contrast, DEX was 3 times more potent than B on CBG (estimated IC50, 1.5 and 4.5 nM, respectively) and tended to be more effective on thymus weight, suggesting that the effects of corticosteroids on these peripheral targets are mediated by association of the steroids with type II glucocorticoid receptors. ALDO coinfused with DEX or B did not alter the inhibitory effects of these on ACTH, suggesting that ALDO does not interfere with these type I, B-preferring receptors in vivo. Because there is little if any evidence for type I corticosteroid receptors in the hypothalamus, these results strongly suggest that the majority of corticosteroid feedback inhibition of basal morning and evening ACTH secretion is mediated transynaptically by the activity of extra-hypothalamic neurons.

MIGRATORY polyarthritis was the predominant presenting manifestation of acute primary histoplasmosis in the following case. Case Report A 23-year-old student first noted pain, swelling and redness of the left ankle. Four days later the right ankle became similarly involved. After 3 days, bilateral ankle pain prevented him from attending classes. He recalled a mild "cold" about 1 week earlier and thereafter had experienced malaise and low-grade fever. On admission the temperature was 38.1°C, and the pulse 100. Both ankles showed diffuse swelling, marked tenderness, calor, and limited painful motion. The remainder of the examination was within normal limits. Fever (temperature . . .