Outcomes after stereotactic radiosurgery of brain metastases in patients with malignant melanoma and validation of the melanoma molGPA

Malignant melanoma is the third most common primary in the diagnosis of brain metastases. Stereotactic radiosurgery (SRS) is a well-established treatment option in limited brain disease. We analyzed outcomes of SRS with a particular focus on the graded prognostic assessment (GPA, melanoma molGPA), prognostic factors, and toxicity. Methods We evaluated 173 brain metastases in 83 patients with malignant melanoma. All were treated with SRS median dose of 20 Gy prescribed to the 80 or 100% isodose line between 2002 and 2019. All patients were followed-up regularly, including contrast‐enhanced brain imaging as well as clinical examination, initially 6 weeks after treatment, then in quarterly follow-up. Results The median age was 61 years (range 27–80); 36 female and 47 male patients were treated. After a median follow-up of 5.7 months, median OS (overall survival) was 9.7 months 95%-KI 4.7–14.7). LC (local control) at 6 months, 12, 24 months was 89%, 86%, and 72%, respectively (median was not reached). Median DBC (distant brain control) was 8.2 months (95%-KI 4.7–11.7). For OS, a KPS ≥ 80%, a positive BRAF mutation status, a small PTV (planning target volume), the absence of extracranial metastases, as well as a GPA and melanoma molGPA > 2 were prognostic factors. In the MVA, a small PTV and a melanoma molGPA > 2 remained significant. Conclusion The present survival outcomes support the use of the disease-specific melanoma molGPA as reliable prognostic score. Favorable outcomes for SRS compared to other studies were observed. In the treatment of brain metastases of malignant melanoma patients, a multidisciplinary approach consisting of surgery, SRS, chemotherapy, and immunotherapy should be considered (AU)

Outcomes after stereotactic radiosurgery of brain metastases in patients with malignant melanoma and validation of the melanoma molGPA.

INTRODUCTION: Malignant melanoma is the third most common primary in the diagnosis of brain metastases. Stereotactic radiosurgery (SRS) is a well-established treatment option in limited brain disease. We analyzed outcomes of SRS with a particular focus on the graded prognostic assessment (GPA, melanoma molGPA), prognostic factors, and toxicity. METHODS: We evaluated 173 brain metastases in 83 patients with malignant melanoma. All were treated with SRS median dose of 20 Gy prescribed to the 80 or 100% isodose line between 2002 and 2019. All patients were followed-up regularly, including contrast-enhanced brain imaging as well as clinical examination, initially 6 weeks after treatment, then in quarterly follow-up. RESULTS: The median age was 61 years (range 27-80); 36 female and 47 male patients were treated. After a median follow-up of 5.7 months, median OS (overall survival) was 9.7 months 95%-KI 4.7-14.7). LC (local control) at 6 months, 12, 24 months was 89%, 86%, and 72%, respectively (median was not reached). Median DBC (distant brain control) was 8.2 months (95%-KI 4.7-11.7). For OS, a KPS ≥ 80%, a positive BRAF mutation status, a small PTV (planning target volume), the absence of extracranial metastases, as well as a GPA and melanoma molGPA > 2 were prognostic factors. In the MVA, a small PTV and a melanoma molGPA > 2 remained significant. CONCLUSION: The present survival outcomes support the use of the disease-specific melanoma molGPA as reliable prognostic score. Favorable outcomes for SRS compared to other studies were observed. In the treatment of brain metastases of malignant melanoma patients, a multidisciplinary approach consisting of surgery, SRS, chemotherapy, and immunotherapy should be considered.

Psychosocial problems in traumatized refugee families: overview of risks and some recommendations for support services.

This article is an abridged version of a report by an advisory council to the German government on the psychosocial problems facing refugee families from war zones who have settled in Germany. It omits the detailed information contained in the report about matters that are specific to the German health system and asylum laws, and includes just those insights and strategies that may be applicable to assisting refugees in other host countries as well. The focus is on understanding the developmental risks faced by refugee children when they or family members are suffering from trauma-related psychological disorders, and on identifying measures that can be taken to address these risks. The following recommendations are made: recognizing the high level of psychosocial problems present in these families, providing family-friendly living accommodations, teaching positive parenting skills, initiating culture-sensitive interventions, establishing training programs to support those who work with refugees, expanding the availability of trained interpreters, facilitating access to education and health care, and identifying intervention requirements through screening and other measures.

Prevention of childhood obesity and food policies in Latin America: from research to practice.

BACKGROUND: Addressing childhood obesity in Latin America requires a package of multisectoral, evidence-based policies that enable environments conducive to healthy lifestyles. OBJECTIVE: Identify and examine key elements to translating research into effective obesity policies in Latin America. METHODS: We examined obesity prevention policies through case studies developed with an expert in the specific policy. Policies were selected based on their level of implementation, visibility and potential impact to reduce childhood obesity. They include: (i) excise taxes on sugar sweetened beverages and energy-dense foods; (ii) front-of-package food label legislation; (iii) trans fatty acids removal from processed foods; and (iv) Ciclovías recreativas or 'open streets'. Case studies were coded to identify components that explained successful implementation and sustainability using the Complex Adaptive Health Systems framework. RESULTS: The analysis identified key elements for effective and sustainable policy, including evidence justifying policy; evidence-based advocacy by civil society; political will; and legislation and skillful negotiations across government, academia, the private sector and civil society. Scientific evidence and evaluation played an important role in achieving tipping points for policies' launch and sustain effective implementation. CONCLUSIONS: Well-coordinated, intersectoral partnerships are needed to successfully implement evidence-based anti-obesity policies. Prospective policy research may be useful for advancing knowledge translation.

Getting personal: Endogenous adenosine receptor signaling in lymphoblastoid cell lines.

Genetic differences between individuals that affect drug action form a challenge in drug therapy. Many drugs target G protein-coupled receptors (GPCRs), and a number of receptor variants have been noted to impact drug efficacy. This, however, has never been addressed in a systematic way, and, hence, we studied real-life genetic variation of receptor function in personalized cell lines. As a showcase we studied adenosine A2A receptor (A2AR) signaling in lymphoblastoid cell lines (LCLs) derived from a family of four from the Netherlands Twin Register (NTR), using a non-invasive label-free cellular assay. The potency of a partial agonist differed significantly for one individual. Genotype comparison revealed differences in two intron SNPs including rs2236624, which has been associated with caffeine-induced sleep disorders. While further validation is needed to confirm genotype-specific effects, this set-up clearly demonstrated that LCLs are a suitable model system to study genetic influences on A2AR response in particular and GPCR responses in general.

From Mice to Men: research models of developmental programming.

Developmental programming can be defined as a response to a specific challenge to the mammalian organism during a critical developmental time window that alters the trajectory of development with persistent effects on offspring phenotype and predisposition to future illness. We focus on the need for studies in relevant, well-characterized animal models in the context of recent research discoveries on the challenges, mechanisms and outcomes of developmental programming. We discuss commonalities and differences in general principles of developmental programming as they apply to several species, including humans. The consequences of these differences are discussed. Obesity, metabolic disorders and cardiovascular diseases are associated with the highest percentage of morbidity and mortality worldwide. Although many of the causes are associated with lifestyle, high-energy diets and lack of physical activity, recent evidence has linked developmental programming to the epidemic of metabolic diseases. A better understanding of comparative systems physiology of mother, fetus and neonate using information provided by rapid advances in molecular biology has the potential to improve the lifetime health of future generations by providing better women's health, diagnostic tools and preventative and therapeutic interventions in individuals exposed during their development to programming influences.

Ventilation rates in large commercial layer hen houses with two-year continuous monitoring.

1. Ventilation controls the indoor environment and is critical for poultry production and welfare. Ventilation is also crucial for assessing aerial pollutant emissions from the poultry industry. Published ventilation data for commercial layer houses have been limited, and are mostly based on short-term studies, mainly because monitoring airflow from large numbers of fans is technically challenging. 2. A two-year continuous ventilation monitoring trial was conducted at two commercial manure belt houses (A and B), each with 250 000 layers and 88 130-cm exhaust fans. All the fans were individually monitored with fan rotational speed sensors or vibration sensors. Differential static pressures across the house walls were also measured. Three fan performance assessment methods were applied periodically to determine fan degradations. Fan models were developed to calculate house ventilations. 3. A total of 693 and 678 complete data days, each containing >16 h of valid ventilation data, were obtained in houses A and B, respectively. The two-year mean ventilation rates of houses A and B were 2·08 and 2·10 m(3) h(-1) hen(-1), corresponding to static pressures of -36·5 and -48·9 Pa, respectively. For monthly mean ventilation, the maximum rates were 4·87 and 5·01 m(3) h(-1) hen(-1) in July 2008, and the minimum were 0·59 and 0·81 m(3) h(-1) hen(-1) in February 2008, for houses A and B, respectively. 4. The two-year mean ventilation rates were similar to those from a survey in Germany and a 6-month study in Indiana, USA, but were much lower than the 8·4 and 6·2 m(3) h(-1) hen(-1) from a study in Italy. The minimum monthly mean ventilation rates were similar to the data obtained in winter in Canada, but were lower than the minimum ventilation suggested in the literature. The lower static pressure in house B required more ventilation energy input. The two houses, although identical, demonstrated differences in indoor environment controls that represented potential to increase ventilation energy efficiency, and reduce carbon footprints and operational costs.

Ion optical design of a collinear laser-negative ion beam apparatus.

An apparatus for photodetachment studies on atomic and molecular negative ions of medium up to heavy mass (M ≃ 500) has been designed and constructed. Laser and ion beams are merged in the apparatus in a collinear geometry and atoms, neutral molecules and negative ions are detected in the forward direction. The ion optical design and the components used to optimize the mass resolution and the transmission through the extended field-free interaction region are described. A 90° sector field magnet with 50 cm bending radius in combination with two slits is used for mass dispersion providing a resolution of M∕ΔM≅800 for molecular ions and M∕ΔM≅400 for atomic ions. The difference in mass resolution for atomic and molecular ions is attributed to different energy distributions of the sputtered ions. With 1 mm slits, transmission from the source through the interaction region to the final ion detector was determined to be about 0.14%.

[Electronically recorded occlusion treatment in amblyopes older than 7 years: acuity gain after more than 4 months of treatment?]. / Elektronisch erfasste Okklusionstherapie bei über 7-jährigen Amblyopen: Visusanstieg noch nach mehr als 4 Monaten?

BACKGROUND: According to the ROTAS study most of the improvement in visual acuity (VA) during amblyopia therapy of children aged 3 to 8 years occurs during the first 6 to 8 weeks . Sattler reported a VA gain in 11-year olds even during the second year of treatment . So far there are no standards concerning the intensity and duration of the treatment of patients older than 7 years of age. After a report on electronic monitoring of occlusion treatment in patients aged 7 to 16 years for 4 months , we now analyse whether this age group benefits from a longer-lasting treatment. MATERIALS AND METHODS: In this pilot study the progression of VA was analysed in 11 patients (age range 7.18 to 15.76 years; median 11.42 years) during 12 months of occlusion therapy (types of amblyopia: 5 anisometropic, 1 strabismic, 5 combined). The daily occlusion times were recorded using the occlusion dose monitor (ODM) . At the beginning of treatment the prescription of the occlusion regime (median) was 6 h/d (range 4 to 7 h/d), the (decimal) VA 0.2 (range 0.02 to 0.63) for single and 0.16 (range 0.02 to 0.8) for crowded optotypes. RESULTS: The recorded occlusion time (median) was 4.4 h/d during the 12 months of treatment, the VA gain (median) was 0.4 log units for single (range 0.2 to 0.7 log units) and 0.3 for crowded optotypes (range--0.1 to 0.6). During the period of 4 to 12 months of treatment (received occlusion 4.12 h/d) the VA gain was 0.1 log units for single and for crowded optotypes. The maximum VA gain during the interval of 4 to 12 months of treatment was 0.2 log units, both single and crowded. The interocular difference for crowded VA (median) decreased from 0.9 to 0.6 log units during treatment, however only one patient achieved an interocular difference of < 0.2 log units. CONCLUSION: The patients presented here were able to integrate daily occlusion lasting several hours and the electronic monitoring of occlusion treatment into their daily routine over a period of 12 months. During this period the VA of all included types of amblyopia improved significantly, both from a clinical and statistical point of view. Further long-term studies using ODMs with larger groups of patients may identify factors for success of treatment, reveal the long-term stability of the improvement and contribute to a standardised treatment in this age group.

Characteristics of ammonia and carbon dioxide releases from layer hen manure.

1. Ammonia (NH(3)) is an important gaseous pollutant generated from manure in commercial poultry farms and has been an environmental, ecological, and health concern. Poultry manure also releases carbon dioxide (CO(2)), which is a greenhouse gas and is often used as a tracer gas to calculate building ventilation. 2. A 38-d laboratory study was conducted to evaluate the characteristics of NH(3) and CO(2) releases from layer hen manure using 4 manure reactors (122 cm tall, 38 cm internal diameter), which were initially filled with 66 cm deep manure followed by weekly additions of 5 cm to simulate manure accumulation in commercial layer houses. 3. The average daily mean (ADM) NH(3) and CO(2) release fluxes for the 4 reactors during the entire study were 1615 +/- 211 microg/s.m(2) (ADM +/- 95% confidence interval) and 100 +/- 03 mg/s.m(2), respectively. The daily mean NH(3) and CO(2) releases in individual reactors varied from 352 to 6791 microg/s.m(2) and from 66 to 205 mg/s.m(2), respectively. 4. The ADM NH(3) release flux was within the range of those obtained in 4 high-rise layer houses by Liang et al. (2005, Transactions of the ASAE, 48). However, the CO(2) release flux in this study was about 10 to 13 times as high as the data reported by Liang et al. (2005). Fresh manure had greater NH(3) release potential than the manure in the reactors under continuous ventilation. Manure with higher contents of moisture, total nitrogen, and ammonium in the 4th weekly addition induced 11 times higher NH(3) and 75% higher CO(2) releases immediately after manure addition compared with pre-addition releases.

Acute abdominal pain as a result of a ruptured hematosalpinx: a rare complication of an unusual müllerian anomaly.

CASE REPORT: A 15-year-old virgin Caucasian female presented to the emergency room with a 40-hour history of acute left lower quadrant abdominal pain and nausea. Evaluation suggested a left pelvic kidney with obstructed ureter being the etiology. Her pain continued to escalate so further workup with laparoscopy was performed. This demonstrated a left pelvic sidewall hemi uterus with ruptured hematosalpinx. This is an unusual clinical presentation of a müllerian anomaly not previously documented. DISCUSSION: The differential diagnosis of acute unilateral abdominal pain in adolescent females should include müllerian anomalies. The incidence of this diagnosis is low but the evaluation and treatment can be performed in an expeditious manner if the diagnosis is considered. The laparoscopic excision of a unilateral noncommunicating uterine horn is a valid and recommended treatment approach of this rare malformation.

A double-blind, randomized trial of 0.05% betamethasone vs. topical catalase/dismutase superoxide in vitiligo.

BACKGROUND: Among all the topical immunomodulators, vitiligo's mainstay therapy includes topical corticosteroids. Many other non-immune theories have also been suggested for vitiligo's pathogenesis, but the role of oxidative stress has gained more importance in recent years. OBJECTIVE: To compare the effect of topical 0.05% betamethasone vs. catalase/dismutase superoxide (C/DSO). STUDY DESIGN: Randomized, matched-paired, double-blind trial. SETTING: Dermatology Section, University of Antioquia, Medellín, Colombia. SUBJECTS: Patients (aged > 18 years or between 12 and 18 years) with parent's informed consent, with stable or active bilateral vitiligo. INTERVENTION: Topical 0.05% betamethasone or C/DSO. METHODS: Two lesions similar to each other in size were chosen. All assessments were made by two blinded investigators, and photographs were subjected to morphometry analysis. MAIN OUTCOME: Skin repigmentation by digital morphometry. RESULTS: Twenty-five patients were enrolled in the study (21 women and 4 men). Mean age of participants was 40 years (range: 12-74 years). One patient on C/DSO experienced a mild local erythematous papular rash that self-resolved. At 4 months of therapy, there was no statistical difference on the percentage of repigmentation between betamethasone and C/DSO (5.63% +/- 27.9 vs. 3.22% +/- 25.8, respectively, P = 0.758). After 10 months of therapy, the percentage of skin repigmentation increased to 18.5 +/- 93.14% with betamethasone and to 12.4 +/- 59% with C/DSO, but again, we found no statistical differences (P = 0.79). DISCUSSION AND CONCLUSIONS: Few studies have described objective methods to evaluate repigmentation among vitiligo patients. Digital morphometry provides an objective assessment of repigmentation in vitiligo. Objective vitiligo repigmentation with topical C/DSO at 10 months is similar to topical 0.05% betamethasone. Although a mild adverse effect was related to the use of C/DSO, such finding was not severe enough to discontinue treatment.

Inhibition of vasopressin V1b receptor translation by upstream open reading frames in the 5'-untranslated region.

The 5'-UTR of the vasopressin V1b receptor (V1bR) mRNA contains small open reading frames (ORF) located upstream (u) of the main ORF encoding the V1bR. The ability of the three proximal uORFs to be translated into peptides and their influence on V1bR translation was examined using fusion constructs of uORFs and V5 epitope, or ATG/ATA uORF mutations in the V1bR cDNA. In vitro translation and western blot analysis after transfection of uORF1-V5 or uORF2-V5 into cells revealed that uORF1 can be translated. As predicted by computer analysis, in vitro translation using a rabbit reticulocyte/canine microsome system, immunohistochemistry and western blot in membranes of transfected cells with uORF1-V5 revealed translocation of the uORF1 peptide into membrane fractions. In vitro translation of V1bR cDNA with mutations of the two uORFs proximal to the initiating methionine, uORFs 1 and 2 (Mut 1-2), or uORF2 (Mut 2) showed significantly increased translation of a 46 kDa band corresponding to the V1bR, compared with wild-type (WT) V1bR, an effect that was attenuated by cotranslation of uORF1-V5. Consistently, VP-induced inositol phosphate formation was higher in Chinese hamster ovay cells transfected with Mut 1-2 than with WT V1bR. Immunohistochemical and western blot analysis, using an antibody against uORF1, revealed peptide immunoreactivity in rat pituitary but not in liver. Pituitary uORF immunoreactivity increased following glucocorticoid administration. The present study shows that uORFs in the 5'-UTR of the V1bR mRNA inhibit V1bR translation, and suggests that translation of a 38-amino acid membrane peptide encoded by uORF1 exerts tonic inhibition of V1bR translation.

Transcriptional and post-transcriptional mechanisms regulating the rat pituitary vasopressin V1b receptor gene.

The number of V1b vasopressin receptors (V1bR) in the anterior pituitary plays an important role during adaptation of the hypothalamic-pituitary-adrenal axis to stress in rats. Regulation of V1bR expression involves transcriptional and translational mechanisms. One of the elements mediating transcriptional activation of the rat V1bR gene is a long stretch of GAGA repeats (GAGA box) in the promoter located near the transcription start point capable of binding a protein complex of 127 kDa present in pituitary nuclear extracts. There is a lack of correlation between changes in V1bR mRNA and the number of VP binding sites, suggesting that V1bR expression depends on the efficiency of V1b R mRNA translation into protein. Two mechanisms by which the 5' untranslated region (5'-UTR) of the rat V1bR mRNA can mediate either inhibition or activation of V1bR mRNA translation have been identified. First, upstream open reading frames (ORF) present in the 5'-UTR repress translation of the major ORF encoding the V1b receptor, and secondly, an internal ribosome entry site (IRES) activates V1bR translation. Stimulation of IRES activity through protein kinase C-mediated pathways results in V1bR mRNA translation increasing V1bR protein levels. The existence of multiple loci of regulation for the V1bR at transcriptional and translational levels provides a mechanism to facilitate plasticity of regulation of the number of pituitary vasopressin receptors according to physiological demand.

Multiple sites of control of type-1 corticotropin releasing hormone receptor levels in the pituitary.

Hypothalamic corticotropin releasing hormone (CRH) stimulates pituitary ACTH secretion through interaction with type 1 CRH receptors (CRH-R1), the number of which varies during alterations of the hypothalamic-pituitary-adrenal (HPA) axis. CRH-R1 are essential for ACTH responses to stress but CRH receptor content in the pituitary does not correlate with corticotroph responsiveness. This indicates that a small number of receptors is sufficient for full ACTH responses probably through post-receptor interaction with vasopressin (VP) signaling. CRH binding and hybridization studies in adrenalectomized, glucocorticoid-treated or stressed rats revealed divergent levels of CRH receptors and CRH-R1 mRNA in the pituitary, with binding reductions but normal or elevated CRH-R1 mRNA levels during alterations of the HPA axis. Western blot analysis of CRH-R1 protein in pituitary membranes from adrenalectomized rats show unchanged CRH-R1 mRNA levels, but reduced CRH binding associated with significant increases in CRH-R1 protein, suggesting that the decrease in binding is due to homologous desensitization and not to reduced receptor synthesis. In contrast, decreased CRH binding following glucocorticoid administration is associated with reduction in CRH-R1 protein suggesting inhibition of CRH-R1 mRNA translation. Regulation of CRH-R1 translation may involve binding of cytosolic proteins, and a minicistron in the 5'UTR of the CRH-R1 mRNA. Post-transcriptional regulatory mechanisms allowing rapid changes in CRH receptor activity are important for adaptation of corticotroph responsiveness to continuous change in physiological demand.

Regulation of pituitary corticotropin releasing hormone receptors.

Corticotropin releasing hormone (CRH) stimulates pituitary ACTH secretion through type-1 CRH (CRH1) receptors. Stimulation of the hypothalamic pituitary adrenal (HPA) axis as well as increased corticotroph responsiveness during stress and adrenalectomy are associated with marked pituitary CRH binding downregulation. The presence of CRH1 receptors in the pituitary are essential to maintain ACTH secretion. Downregulation of CRH binding is associated with normal or elevated levels of CRH1 receptor mRNA and this may contribute to the maintainence of permissive levels of CRH1 receptors in the pituitary. Injection of either CRH or glucocorticoids in rats in vivo induces CRH binding and CRH1 receptor mRNA downregulation, whereas their simultaneous administration causes only transient CRH1 receptor mRNA loss. Vasopressin increases CRH1 receptor mRNA levels. This suggest that interactions between CRH, vasopressin and glucocorticoids accounts for CRH1 receptor mRNA upregulation during stress. The lack of correlation between CRH binding and CRH1 receptor mRNA indicates that the major sites for pituitary CRH1 receptor regulation are at the post-transcriptional level.

Inhibition of corticotropin releasing hormone type-1 receptor translation by an upstream AUG triplet in the 5' untranslated region.

The influence of an upstream open reading frame (ORF) in the 5'-untranslated region (UTR) of the mRNA on corticotropin-releasing hormone receptor type 1 (CRHR1) translation was studied in constructs containing the 5'-UTR of CRHR1, with or without an ATG-to-ATA mutation in the upstream ORF, and the main ORF of luciferase or CRHR1. Upstream mutation in luciferase constructs increased luciferase activity when transfected into COS-7 or AtT20 cells compared with the native 5'-UTR. Transfection of CRHR1 constructs containing the upstream mutation into AtT20 or LVIP2.0zc reporter cells, resulted in higher (125)I-Tyr-oCRH binding and corticotropin-releasing hormone-stimulated cAMP production, without changes in CRHR1 mRNA levels (measured by RNase protection assay). In vitro translation of luciferase or CRHR constructs with or without mutation of the upstream ATG, and Western blot analysis with anti-luciferase and anti-CRHR1 antibodies confirmed that mutation of the upstream ATG increases translation of the main ORF. The mechanism by which the upstream ORF inhibits translation may involve translation of the upstream peptide, because in vitro translation, or transfection into LVIP2.0zc cells of a fusion construct of the upstream ORF and green fluorescent protein (GFP) yielded a band consistent with the molecular size of GFP protein. The study shows that the upstream AUG in 5'-UTR of CRHR1 mRNA inhibits receptor expression by inhibiting mRNA translation and suggests the short open reading frame in the 5'-UTR plays a role in regulating translation of the CRH receptor.

Vasopressinergic regulation of the hypothalamic-pituitary-adrenal axis: implications for stress adaptation.

In addition to its role on water conservation, vasopressin (VP) regulates pituitary ACTH secretion by potentiating the stimulatory effects of corticotropin releasing hormone (CRH). The pituitary actions of VP are mediated by plasma membrane receptors of the V1b subtype, coupled to calcium-phospholipid signaling systems. VP is critical for adaptation of the hypothalamic-pituitary-adrenal (HPA) axis to stress as indicated by preferential expression of VP over CRH in parvocellular neurons of the hypothalamic paraventricular nucleus, and the upregulation of pituitary VP receptors during stress paradigms associated with corticotroph hyperresponsiveness. V1b receptor mRNA levels and coupling of the receptor to phospolipase C are stimulated by glucocorticoids, effects which may contribute to the refractoriness of VP-stimulated ACTH secretion to glucocorticoid feedback. The data suggest that vasopressinergic regulation of the HPA axis is critical for sustaining corticotroph responsiveness in the presence of high circulating glucocorticoid levels during chronic stress.