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The functionality of food-derived nucleotides is revealed when nucleotide components are ingested in emergency situations, such as during stress loading, though it is difficult to elucidate the physiological function of dietary nucleotide supplementation. Using a stress load experimental system utilizing territoriality among male mice, we evaluated whether DNA sodium salt derived from salmon milt (DNA-Na) has stress-relieving effects. It was found that stress was reduced in mice fed a diet containing a 1% concentration of DNA-Na, but this was insignificant for yeast-derived RNA. Next, we attempted to elucidate the anti-stress effects of DNA-Na using another experimental system, in which mice were subjected to chronic crowding stress associated with aging: six mice in a cage were kept until they were 7 months of age, resulting in overcrowding. We compared these older mice with 2-month-old mice that were kept in groups for only one month. The results show that the expression of genes associated with hippocampal inflammation was increased in the older mice, whereas the expression of these genes was suppressed in the DNA-Na-fed group. This suggests that dietary DNA intake may suppress inflammation in the brain caused by stress, which increases with age.

The developmental origins of stress-related mental illnesses are well-established, and early-life stress/adversity (ELA) is an important risk factor. However, it is unclear how ELA impacts the maturation of salient brain circuits, provoking enduring vulnerability to stress and stress-related disorders. Here we find that ELA increases the number and function of excitatory synapses onto stress-sensitive hypothalamic corticotropin-releasing hormone (CRH)-expressing neurons, and implicate disrupted synapse pruning by microglia as a key mechanism. Microglial process dynamics on live imaging, and engulfment of synaptic elements by microglia, were both attenuated in ELA mice, associated with deficient signaling of the microglial phagocytic receptor Mer. Accordingly, selective chemogenetic activation of ELA microglia increased microglial process dynamics and reduced excitatory synapse density to control levels. Selective early-life microglial activation also mitigated the adrenal hypertrophy and prolonged stress responses in adult ELA mice, establishing microglial actions during development as powerful contributors to experience-dependent sculpting of stress-related brain circuits.

Objective: to study the stress-protective and immunomodulatory effects of Semax under conditions of informational stress. Materials and methods. The study deals with stress-protective and immunocorrective effects of Semax (Met-Glu-His-Phe-Pro-Gly-Pro) under conditions of experimental informational stress which was performed on white non-linear male rats. The formation of a stress reaction under the conditions of informational impact was confirmed by the presence of a stress triad, including adrenal hypertrophy, a decrease in the number of eosinophils in the peripheral blood and the presence of erosive-ulcerative lesions of the gastric mucosa. In addition, to assess the reactivity of the organism, the adaptation intensity index according to L.Kh. Garkavi was used as an indicator of the balance of the response of blood cells to the stress factor. Functional activity of the immune system of laboratory animals was assessed on the basis of standard immunopharmacological tests: delayed-type hypersensitivity reaction (DTH), direct agglutination test (DAT), latex test for studying the phagocytic activity of peripheral blood neutrophils, evaluation of changes in the leukocyte formula. Results. It has been established that under conditions of information stress, changes in the immune response are multidirectional that confirms the theory of “immune imbalance” under the action of stress factors. As a result of studying the influence of Semax under conditions of informational stress, it was found that the drug manifested itself as an effective stress protector and immunocorrector, reducing stress-reactive manifestations, restoring cellular and humoral immunogenesis, as well as neutrophil phagocytic activity. Conclusion. This study expands the scientific research base in the field of immune reaction under stress-induced conditions, with the aim of further developing a pharmacological strategy for correcting the revealed violations by means of substances of a neuropeptide structure.

Chronic psychosocial stress is known to affect the behavioural, physiological and inflammatory status of the organism and represents an accepted risk factor for the development and aggravation of affective and somatic diseases. Besides, chronic psychosocial stress is able to change the intestinal microbiota composition. Given that stress-related affective or gastrointestinal diseases are often accompanied by an altered intestinal microbiota composition and that the intestinal microbiome is able to influence the behaviour and physiology of an organism, it is very likely that chronic psychosocial stress mediates the vulnerability to develop chronic stress-induced diseases by changing the intestinal microbiota composition. If this hypothesis is true, a promising therapeutical approach to treat or to prevent chronic stress-induced changes in the intestinal microbiota composition and the associated consequences for the organism might be the transplantation of a healthy intestinal microbiota composition. An ideal model to address this hypothesis is the so called “chronic subordinate colony housing” (CSC) paradigm, as it induces chronic psychosocial stress in male mice and has repeatedly shown to alter the anxiety-related behaviour, physiological and inflammatory parameters and the intestinal microbiota composition. Therefore, to address the above mentioned hypothesis, it was the main aim of my thesis to examine i) if transplantations of feces from non-stressed single-housed control (SHC) mice into chronically stressed CSC mice can prevent CSC-induced alterations and ii) if transplantations of a “stressed” microbiome from CSC-donor mice can transfer CSC-induced effects into SHC mice. Besides, the study aimed to generally test if fecal transplantation (FT) via the rectal route instead of the commonly used oral route and without an antibiotic pre-treatment can affect stress-induced parameters in recipient mice. To do so, SHC- and CSC-recipient mice received repeated rectal infusions of SHC-donor feces on days 4 and 11 of the CSC paradigm. Anxiety-related behaviour was tested on day 19 and physiological and local colonic inflammatory parameters were assessed after sacrificing the mice in the morning of day 20. The same procedure was done with another set of SHC- and CSC-recipient mice that received CSC-donor feces. To see if rectal infusions per se have any effects on the assessed parameters, a set of SHC and CSC control mice received saline infusions at the respective days. The results of my thesis reveal that transplantations of SHC-donor feces had slightly stress-protective effects, indicated by the reduction of CSC-induced anxiety-related behaviour and by the prevention of CSC-induced thymus atrophy. However, transplantations of SHC-donor feces had no effects on CSC-induced adrenal enlargement. Moreover, the results of my study show that transplantations of CSC-donor feces did not transfer CSC-induced anxiety-related behaviour and physiological alterations to SHC-recipients. Moreover, the results of my study indicate that FT via the rectal route and without an antibiotic pre-treatment can affect certain chronic stress-induced parameters of the recipients as shown in the above-mentioned effects of SHC-donor feces on the behaviour and physiology of recipient CSC mice. Besides, my results show that local colonic inflammatory parameters were neither increased in saline nor in SHC- and CSC-recipient mice, indicating that the procedure of rectal infusions does not cause colonic inflammation in the recipients. Therefore, the rectal route can be regarded as an appropriate type of application for FT. In conclusion, the results of my study in combination with the recently published paper about this study (with me as second author) show that rectal transplantations of an “unstressed” microbiome can treat and/or prevent certain consequences of chronic psychosocial stress in the recipients. Therefore, in the future, transplantations of a “healthy” microbiome might be used as a therapeutical application for humans to treat and/or prevent negative consequences of chronic stress and to reduce the vulnerability to develop chronic stress-related diseases. Besides, the results of the published paper about this experiment reveal that some chronic stress-induced effects can be transferred to the recipient via FT, indicating that FT can also have undesirable side effects. Therefore, therapeutic approaches that use FT need to intensely screen fecal donors for present or previous chronic stress exposure.

Chronic ACTH exposure is associated with adrenal hypertrophy and steroidogenesis. The underlying molecular processes in mice have been analysed by microarray, histological and immunohistochemical techniques. Synacthen infused for 2 weeks markedly increased adrenal mass and plasma corticosterone levels. Microarray analysis found greater than 2-fold changes in expression of 928 genes (P Scarb1, Sqle, Apoa1) and disposal (Cyp27a1, Cyp7b1). Oil red O staining showed lipid depletion consistent with reduced expression of genes involved in lipid synthesis. Genes involved in steroidogenesis (Star, Cyp11a1, Cyp11b1) were modestly affected (P Ki67, Ccna2, Ccnb2 and Tk1 expression complemented immunohistochemical evidence of a 3-fold change in cell proliferation. Growth arrest genes, Cdkn1a and Cdkn1c, which are known to be active in hypertrophied cells, were increased >4-fold and cross-sectional area of fasciculata cells was 2-fold greater. In contrast, genes associated with apoptosis (eg Casp12, Clu,) were downregulated and apoptotic cells (Tunel staining) were fewer (P

The stress-reducing effect of matcha, a high-quality fine-powdered green tea, has recently been clarified by animal experiments and clinical trials. However, the effect of matcha added to confectioneries is not clear. One aim of this study was to evaluate the relationship between matcha components and their stress-reducing effect in mice that were loaded with territorially-based stress. Adrenal hypertrophy, a marker of stress, was significantly suppressed in stress-loaded mice that had ingested matcha components, displaying a caffeine and epigallocatechin gallate to theanine and arginine (CE/TA) ratio of 2 or less. Another aim was to evaluate, in humans, the stress-reducing effect of matcha in cookies using test-matcha (CE/TA = 1.79) or placebo-matcha (CE/TA = 10.64). Participants, who were fifth year pharmacy college students, consumed 4.5 g of matcha in three pieces of cookie daily for 15 days. Salivary α-amylase activity, a stress marker, was significantly lower in the test-matcha group than in the placebo group. These results indicate that the CE/TA ratio of tea components is a key indicator for the suppression of stress. Moreover, matcha with a CE/TA ratio of 2 or less displays a stress-reducing effect, even if it is included in confectionery products. Such products may also benefit individuals who have no habit of drinking matcha as a beverage.

Tea, including green tea made from the leaves of the Camellia senenisis plant, is the second most consumed beverage worldwide after water, and is consumed by more than two-thirds of the world population [...]

Cushing’s disease is most commonly the result of a microadenoma derived from pituitary corticotrophic cells that secretes excess adrenocorticotropic hormone (ACTH). ACTH is an important modulator of steroidal hormone synthesis and secretion from the adrenal gland and its selective activity at the melanocortin type 2 receptor (MC2) dictates the synthesis and secretion of cortisol (corticosterone in rats). The resulting hypercortisolemia in Cushing’s patients presents in a myriad of symptoms that include growth of fat pads, excessive sweating, dilation of capillaries, thinning of the skin, muscle weakness, hirsutism, depression/anxiety, hypertension, osteoporosis, insulin resistance, hyperglycemia, and heart disease, among others that result in high morbidity. We hypothesize that blocking ACTH action directly via a selective MC2 receptor antagonist may provide an important new therapeutic mechanism to help better manage Cushing’s disease in patients. To test this hypothesis, we launched an iterative medicinal chemistry program to identify potent and selective nonpeptide MC2 receptor antagonists with pharmaceutical and safety characteristics suitable for evaluation in human clinical trials. Unlike most other G protein coupled receptors, MC2 requires the presence of an accessory protein (MRAP) for cell surface expression and recognition of ACTH and our effort led to small molecule nonpeptides with antagonist activity in CHO-K cells stably expressing the MC2-MRAP complex. Iterative optimization led rapidly to the discovery of multiple chemical classes of highly potent, nonpeptide MC2 selective antagonist leads, which were then further optimized for drug-like characteristics. We have identified multiple compounds that exhibit high potency for human and rat MC2 receptors (hMC2 Kb

Objectives Adrenal gland hypertrophy can be related to acute stress with abnormal adrenal function tests. It may not always need treatment. Material and methods An acute presentation of adrenal gland hypertrophy following an abdominal emergency, with subsequent hypoadrenalism was investigated. Results Adrenal medullary and cortical function fully recovered without treatment. Conclusions We postulate that the adrenal glands became enlarged and hypertrophied during an acute stress event, possibly caused by acute adrenal medullary hypersecretion and subsequent cortical hyposecretion. A wait and watch policy should be followed if no other clinical symptoms and signs of adrenal disease are present. CT scan remains an important diagnostic tool. LEARNING POINTS Abnormal adrenocortical function tests and hypertrophy can occur in an acutely ill patient as a stress response. It is possible to have both hypersecretion and hyposecretion of adrenal hormones. A wait and watch policy should be followed if no other clinical symptoms and signs of adrenal disease are present in an acutely ill patient.

Theanine, a major amino acid in green tea, exhibits a stress-reducing effect in mice and humans. Matcha, which is essentially theanine-rich powdered green tea, is abundant in caffeine. Caffeine has a strong antagonistic effect against theanine. The stress-reducing effect of matcha was examined with an animal experiment and a clinical trial. The stress-reducing effect of matcha marketed in Japan and abroad was assessed based on its composition. The stress-reducing effect of matcha in mice was evaluated as suppressed adrenal hypertrophy using territorially-based loaded stress. High contents of theanine and arginine in matcha exhibited a high stress-reducing effect. However, an effective stress-reducing outcome was only possible when the molar ratio of caffeine and epigallocatechin gallate (EGCG) to theanine and arginine was less than two. Participants (n = 39) consumed test-matcha, which was expected to have a stress-reducing effect, or placebo-matcha, where no effect was expected. Anxiety, a reaction to stress, was significantly lower in the test-matcha group than in the placebo group. To predict mental function of each matcha, both the quantity of theanine and the ratios of caffeine, EGCG, and arginine against theanine need to be verified.

Although adrenocorticotropic hormone is generally considered to play a major role in the regulation of adrenal glucocorticoid secretion, several reports have suggested that other pituitary hormones (e.g., prolactin) also play a significant role in the regulation of adrenal function. The aim of the present study was to measure the adrenocortical cell area and to determine the effects of the transition from the prepubertal to the postpubertal period on the hyperprolactinemic state induced by domperidone (4.0 mg kg-1 day-1, sc). In hyperprolactinemic adult and young rats, the adrenals were heavier, as determined at necropsy, than in the respective controls: adults (30 days: 0.16 +/- 0.008 and 0.11 +/- 0.007; 46 days: 0.17 +/- 0.006 and 0.12 +/- 0.008, and 61 days: 0.17 +/- 0.008 and 0.10 +/- 0.004 mg for treated and control animals, respectively; P0.05), and young rats (30 days: 0.19 +/- 0.003 and 0.16 +/- 0.007, and 60 days: 0.16 +/- 0.006 and 0.13 +/- 0.009 mg; P0.05). We selected randomly a circular area in which we counted the nuclei of adrenocortical cells. The area of zona fasciculata cells was increased in hyperprolactinemic adult and young rats compared to controls: adults: (61 days: 524.90 +/- 47.85 and 244.84 +/- 9.03 microm2 for treated and control animals, respectively; P0.05), and young rats: (15 days: 462.30 +/- 16.24 and 414.28 +/- 18.19; 60 days: 640.51 +/- 12.91 and 480.24 +/- 22.79 microm2 ; P0.05). Based on these data we conclude that the increase in adrenal weight observed in the hyperprolactinemic animals may be due to prolactin-induced adrenocortical cell hypertrophy.

Hans Selye has a historic role in the development of the stress concept. Before his short article in Nature in 1936, the neuroendocrine response to nonspecific injury was thought to be restricted to the release of catecholamines, as recognized by Cannon. Selye was the first to appreciate the crucial role of the adrenal cortex/hypophysis axis in the stress response. He also insisted on the nonspecificity of this neuroendocrine response, and he named the stress-causing agent "stressors". His last major contribution was the distinction between negative, that is, distress, and positive, that is, eustress reactions. The "triad of stress" (adrenal hypertrophy, gastrointestinal ulcers, thymolymphatic atrophy) was also first described by Selye, who was fascinated by the fact that in stressed rodents only gastric and not duodenal ulcers would develop. It was not until the recognition of duodenal ulcerogenic properties of propionitrile and cysteamine as well as the subsequent quantitative structure-activity studies predicting the duodenal ulcerogenic action of complex molecules that pathogenetic investigations allowed a molecular and mechanistic approach for studying the etiology and pathogenesis of duodenal ulceration. Recent studies on the role of sulfhydryls, TRH, ET, and growth factors provide new insights into central and peripheral pre-ulcer pathways. We were surprised to learn that an organ-specific ET-1 release may play a role both in ulcer induction and healing, which seems to start with the expression of immediate early genes such as egr-1 and stimulation of the local synthesis of growth factors such as bFGF and PDGF. Thus, a historic review originating with Hans Selye and extending through the next 60 years allows a cellular and molecular approach to the better understanding of stress-related disorders such as gastroduodenal ulceration.

It is shown in rats that the structures of brain stem (medial and lateral nuclei) are involved in the mechanisms of individual resistance to emotional stress (immobilization and cutaneous electrostimulation). Bilateral destruction of brain stem structures reduces this resistance, which manifests itself as behavioral changes in the open field test (the behavior of rats resistant to stress resembles that of rats prone to it), increased adrenal hypertrophy, thymic involution, and high mortality under conditions of emotional stress.

Seventy-seven wild otters found dead in south-west England between 1988 and 1996 were examined postmortem. Road traffic accidents were responsible for 64 of the deaths and there were marked seasonal peaks. Bite wounds were present in 12 animals and five were considered to have died from their injuries. The animals' general nutritional state was good, but the males were in overall poorer condition than the females. There was little evidence of infectious disease and the results suggested a young, generally healthy population. Adrenal hypertrophy was observed in males dying of bite wounds and in lactating or pregnant females. Convoluted, modular uteri were observed in three females.

Previous experiments demonstrated consistent individual behavioral differences in pigs. Some showed a more active behavioral response (so-called A/R pigs), others a more passive behavioral response (so-called NA/NR pigs). In the present study we selected 32 A/R and 32 NA/NR individuals and tested them individually in an open field at 3 (OF1) and 8 weeks of age (OF2). Individual response patterns were remarkably consistent between OF1 and OF2. While more A/R than NA/NR pigs made escape attempts, the A/R ones vocalized less, and were less inhibited to approach novel objects in OF1 and OF2, although they spent less time in exploring these objects than NA/NR pigs. Cortisol (CS) level after OF1 increased in A/R pigs but did not change in NA/NR ones, while CS level in OF2 remained constant in A/R pigs but decreased in NA/NR pigs. CS response to ACTH1–39 was measured at 3 and 8 weeks of age but did not differ between types. Basal CS level was higher in NA/NR than in A/R pigs and accompanied by adrenal hypertrophy. Mean heart rate (HR) was higher of A/R pigs compared to NA/NR ones in two backtests. HR of A/R pigs substantially increased (23.9 bpm = 15.5%) in reaction to the novel object in OF2, while HR of NA/NR ones only slightly increased (4.5 bpm = 2.9%), or even decreased (bradycardia). A/R pigs had more often heart deviations than NA/NR ones. The present study demonstrates that the two behavioral strategies of pigs are characterized by consistent differences in behavioral, physiological, and endocrine responses to conflict situations.

weeks postoperation, 22-26% thymus involution was observed in the animals with marked autotomy. Adrenal hypertrophy was found 2-6 weeks postoperation in the rats with severe autotomy, 7-8 weeks postoperation in the rats with severe and mild autotomies, and in the animals with repeated autotomies. Thus, the model of DPS caused by transection of the sciatic nerve showed the onset of autotomies in all the operated rats by the 5th month postoperation. It was established that DPS is a constant process, the course of autotomy being wavelike or continuous. The microcirculatory disorders observed two weeks to six months after sciatic nerve transection were shown to be the result of the development of DPS. These disturbances were found in the animals with marked autotomies and did not depend upon whether these were primary or repeated. The healing of the self-mutilated extremities correlated with the normalization of the microcirculation. The microcirculatory disorders observed in the group of animals with continuous autotomy were comparable to those observed during the repeated autotomies; however, in the latter case the number of microvessels with stasis rose significantly and degranulation of the mast cells increased.

This report describes studies of delta-sleep-inducing peptide in the mechanism of compensating emotional behavior following disruption of a number of structures of the limbic complex (the septum and amygdala). Studies were performed in male Wistar rats. Peptide was given i.p. at a dose of 60 nmol/kg. The individual/typological characteristics of the rats' behavior and their resistance to stress was predicted using an open field test. Emotional stress was modeled by immobilizing the animals and applying electric shocks to the skin. Stress was assessed in terms of survival, adrenal hypertrophy, and thymic involution in stress conditions. Bilateral lesioning to brain structures was carried out by anodic polarization. The results obtained showed that the septum and amygdala play a significant role in the mechanisms of resistance to emotional stress. Bilateral disruption of these structures significantly decreased the animals' resistance to emotional stress, producing alterations in behavior in the open field test, increasing the lethality of acute emotional stress, and inducing changes in stress marker organs (the adrenals and thymus) in stress conditions, as compared to controls. Administration of peptide to animals with lesions to the septum or amygdala increased their resistance to emotional stress, as indicated by open field test behavior, survival, and adrenal and thymus weight in stress conditions. Thus, doses of delta-sleep-inducing peptide partially reverse reductions in stress resistance in animals with lesions to structures of the limbic complex.

In the early classic period it was suggested by Heracleitus that a static unchanged state was not the natural condition, but rather that the capacity to undergo constant change was intrinsic to all living things. After that, Empedoeles, circa 500 BC, proposed that for living organisms to survive they require a harmonious mixture of elements. Hippocrates, around 400 BC, developed this concept further by suggesting that health is a state of harmonious balance of these elements, equating disease to a state of disharmony and introducing the concept that nature heals disease (Noysvn Fyseiw/atrui). Soon after, Epicurus extended these ideas to include among these healing forces, the mind, writing that imperturbability of mind is desirable. Claude Bernard introduced the concept of the milieu interieur or the internal physiologic environment, describing its constancy as essential in an external environment typified by its variability. Walter Cannon described Bernard's constancy as Homeostasis and identified the "fight or flight reflex," linking the adaptive response and catecholamine secretion, with extreme levels of activation-producing pathology. Selye outlined four stages of the stress response: 1) the "alarm reaction" characterized by an immediate activation of the sympathetic-adrenomedullary axis (SA); 2) a "resistance phase" characterized by hypothalamic pituitary-adrenal axis (HPA) activation; 3) a stage of adrenal hypertrophy, gastrointestinal ulceration, along with thymic and lymphoid atrophy; and 4) an exhaustion phase and finally death (1).

1. It is known that, in rats, hypoxia stimulates adrenal steroidogenesis, but our understanding of the hypoxic effect on the glandular parameters remains incomplete. 2. Adrenals were collected and analysed from rats that had been exposed to hypoxic conditions for 3 weeks. 3. The results reveal increased adrenal concentrations of corticosterone, free cholesterol and total cholesterol without a change in glandular weight and protein concentration. The increased total cholesterol is primarily associated with enriched cholesteryl adrenate (CE22: 4), cholesteryl arachidonate (CE20: 4) and cholesteryl oleate (CE18: 1).

Ten repeated daily interactions (20 min each) of the same pairs of isolated male mice produced a clear distinction between attacking (dominant) and defeated (subordinate) animals. The fighting level remained fairly constant over the 10 days. One hr after the end of the 10th session, the increase in serum NGF levels described previously (2) was significantly more marked in subordinate than in dominant mice. The mean level of serum NGF was correlated with the number of fighting episodes, particularly in the case of dominant individuals. Moreover, within-pair differences in NGF values were correlated with differences in locomotor activity between dominants and subordinates; this makes it possible that stimuli other than those produced by fighting per se may be responsible for the increase in circulating NGF. As is well known, the adrenal hypertrophy produced by fighting stress is more marked in subordinate than in dominant mice, while previous work has shown that stress of a nonpsychosocial kind does not elevate serum NGF levels. Therefore, the present data support the hypothesis that NGF release contributes to the modulation of adrenal function in a situation-specific fashion.

An adrenal gland hypertrophy is observed in 25 % of non hodgkin's lymphomas. An exclusive localization of the lymphoma to both adrenal gland is exceptional. We report an unusual case in which bilateral adrenal hypertrophy and adrenal insuffisancy were finaly related to centroblastic malignant lymphoma.

The response to ACTH 1–39 of adrenal cells from fetal sheep, monkeys and guinea pigs were compared with that of cells from adult glands. Although the cortisol production rate was lower from the fetal cells they responded to physiological rises in ACTH concentration by large increases in output. The proportional increase in cortisol production was of the same order in the fetal and adult tissue. The in vitro responses of fetal tissue contrasts with the data available on in vivo function. Analysis of ACTH in fetal plasma and pituitary show it to be present in high-molecular-weight peptides and ACTH 1–39 At the time of adrenal hypertrophy and increase cortisol secretion prior to birth the concentration ratio in plasma of ACTH 1–39 /“big” peptides increases markedly. The big peptides inhibit the response to ACTH 1–39 of the fetal adrenal cells. These peptides may be responsible for suppressing the fetal adrenal in vivo and the fall in their relative contribution, late in gestation, to the total ACTH pool may be one of the factors initiating parturition.

Maternal adrenalectomy on days 14 and 15 of gestation did not alter the fetal adrenal weight 2 days later. The same operation on day 16 caused a significant increase in the adrenal weight with a hypertrophy of the cortical cells. Nevertheless, the operation on days 17 and 18 induced no change in the fetal adrenals. Subsequently on days 19 and 20, the operation resulted in a significant hypertrophy of the fetal adrenals. Fetal unilateral adrenalectomy on day 18 caused, 2 days later, significant hypertrophy of the contralateral adrenal, in contrast with no significant change after maternal adrenalectomy. This is perhaps due to the difference in the amount of fetal plasma corticoids, as evidenced by the previous reports of high concentrations of fetal plasma corticosterone on days 19 and 20. The overall results suggest that the fetal pituitary-adrenal feedback mechanism begins to appear between days 16 and 18 of gestation.

Adrenal hypertrophy and steroidogenesis in vitro by dissociated adrenocortical cells from normal intact rats and from rats pretreated for 3–30 days with pharmacologic doses of thyroxine and/or unilate

SUMMARY Adult genetically obese (ob/ob) mice which are characterized by adrenal hypertrophy and increased secretion of corticosteroids have considerably increased levels of ACTH in the pituitary gland. At 5 weeks of age there is no difference in the pituitary ACTH content of lean and obese animals and dietary restriction, sufficient to maintain body weight at normal values, reduces the pituitary ACTH content of adult obese mice from 14 times the level found in lean litter-mate controls to almost normal values. Using an in-vitro perifusion system, the release of ACTH from isolated pituitary glands was studied. Pituitaries from lean and obese mice responded similarly to stimulation with a crude extract of hypothalamic tissue containing corticotrophin releasing factor (CRF). The CRF content of the hypothalamus in both groups appears to be similar. In contrast with the high pituitary content, plasma values for ACTH in unstressed obese mice are not increased. The results are discussed in relation to other evidence for a hypothalamic disorder in ob/ob mice.

Male Pekin ducks adapted to seawater and maintained under sheltered conditions (27 degrees C) in the laboratory may consume considerable volumes of petroleum without showing overt symptoms of distress. Under these conditions, birds consuming petroleum-contaminated food have shown a persistent hyperphagia; this was most apparent among those given food contaminated with South Louisiana crude oil, least apparent among birds given No. 2 fuel oil, and intermediate among those that consumed food contaminated with Kuwait crude oil. When maintained at 27 degrees C, some mortality occurred among the birds given South Louisiana crude oil (22.2%) and No. 2 fuel oil (35.7%), whereas none of the freshwater- and seawater-maintained birds given uncontaminated food and none of the birds given Kuwait crude oil died during this period. Following their exposure to chronic mild cold stress (3 degrees C), mortality occurred in all groups of birds; the birds that had consumed petroleum-contaminated food tended to die earlier and in larger numbers than either the seawater- or freshwater-maintained control birds. These effects suggest that the mortality in all groups of birds was due primarily to the additive effects of a series of nonspecific stressors. Thus, at autopsy, birds that had succumbed to the effects of these stressors frequently showed adrenal hypertrophy and severe involution of the lymphoepithelial tissues. The consumption of petroleum-contaminated food seemed to constitute only one of a series of environmental stressors, and, among birds that were already exposed to stressors such as hypertonic drinking water and persistent cold, the ingestion of petroleum seemed to render them more vulnerable and death frequently ensued.

Chicks, aged two weeks, were injected with either adrenaline (300 μg/kg) or saline daily for seven days. One day after the seventh injection it was found that the birds treated with adrenaline had become hypo-lipacidaemic and hypocholesteraemic and that there had been adrenal hypertrophy and an increase in the adrenal store of cholesterol. Plasma concentrations of glucose and corticosterone were within the normal range. The two groups (adrenaline- or saline-treated) were further subdivided each into two subgroups and were now injected with either adrenaline or saline, and their responses measured over a 120 min period. A significantly shorter period of hyperglycaemia was found in the birds pretreated with adrenaline and given a further injection of the hormone. These birds also showed an enhanced lipacidaemic response but the corticosterone response was not altered.

This is apparently the first attempt to elucidate the relationship between drug dependence and the osmotic fragility of erythrocyte membrane. The osmotic fragility was measured using a coil planet centrifuge (CPC) system. Utilizing the drug-admixed food (DAF) method, rats were made drug-dependent. The osmotic fragility of morphine-dependent rats was significantly enhanced, compared with that of naive rats. By withdrawing or treating the rats with levallorphan, the osmotic fragility was enhanced more than in the morphine-dependent state. When the morphine-withdrawal rats were again given the morphine-admixed food, the osmotic fragility recovered to the morphine-dependent level. The osmotic fragility of phenobarbital-dependent rats was significantly decreased, compared with that of naive rats. On the contrary, in the phenobarbital-withdrawal rats, the osmotic fragility was significantly enhanced, compared with that of the phenobarbital-dependent rats. With re-treatment of phenobarbital-admixed food, the osmotic fragility was recovered to the levels seen in the phenobarbital-dependent rats. Abstinence signs including weight loss, decrease in food and water intake, adrenal hypertrophy etc., were observed during morphine or phenobarbital withdrawal. The effects of food or water deprivation and application of ACTH on the osmotic fragility were then studied and we found that the osmotic fragility was enhanced with these treatments. These results suggest that enhancement of osmotic fragility during withdrawal of these drugs is partly influenced by these treatments.

Computed tomography (CT) has been shown to detect both adrenal glands in 88.5% of upper abdominal examinations and can visualize at least one gland in 96.5% of patients. However, in examinations carried out specifically to visualize the adrenals, the glands were located in 98% of cases. This technique was used in 18 patients with primary aldosteronism to localize aldosterone-secreting adrenal tumours and to distinguish these from non-adenomas (bilateral adrenal hyperplasia). The results were compared with quadric analysis, a statistical technique used to predict the likely surgical outcome. In seven patients the CT results were verified by operation (six adenomas, one adrenal hypertrophy). However, in one further patient a large adenoma (20 mm in diameter) which had not been predicted by CT scanning was found at operation. In the remaining ten patients who have been medically treated, results concordant with quadric analysis were obtained in eight cases. We would suggest that CT scanning should be the initial investigation for the pre-operative localization of adenomas but further comparative studies are required.

Glucocorticoids were injected sc into rat foetuses through the uterine wall on day 19 of intrauterine development; two days later the foetuses were removed and their adrenal glands were weighed. Some betamethasone derivatives produced marked adrenal hypertrophy in the foetuses. Structural characteristics of the effective compounds were 17α-esterification and 16β-methylation. 9α-Halogenation and 21-esterification of glucocorticoids were not essential for producing the hypertrophy. Propionic acid at the C-17 position was more effective than valeric and acetic acids in producing the hypertrophy. The effect of betamethasone 17, 21-dipropionate was dose-responsive and prevented by simultaneous administration of betamethasone 21-disodium phosphate. Results obtained with decapitated or encephalectomized foetuses suggested that the hypertrophy produced was not due to a direct action of the glucocorticoids on the adrenal gland, but mediated by the hypothalamo-pituitary system.