Search

The analysis of an 11-year (2008–2018) seismic catalogue of the Azores suggests the existence of secondary cyclic influences on the seismicity rate of the oceanic region, with more earthquakes observed during the summer months, from May to August, than in winter. Statistical testing based on Monte-Carlo simulations and a Jack-Knife methodology indicate that the seasonal modulation affects earthquakes with magnitudes M3.3–4.5, well above the magnitude of completeness. Here, we investigate the seasonal variations of earthquake rate considering both the whole Azores oceanic domain and four separate sub-regions, corresponding to four regional clusters identified by previous authors. The analysis shows that the seasonal modulation is particularly observed near the Triple Junction region between the Faial Island and the Mid-Atlantic Ridge. To identify possible mechanisms driving the seasonal modulation, we apply Singular Spectral Analysis to the seismicity rate and to time-series of plausible external triggers, in order to investigate possible common periodicities. We find significant correlations between the earthquake rate, sea level anomaly rate, GRACE satellite anomalies and ocean bottom pressure, suggesting that water load may modulate the Azores oceanic seismicity.

Studying a large number of volcanic eruptions is a way to decipher general characteristics related to volcano dynamics but also on external forcing influencing it, such as solid Earth and ocean tides. Many studies have tackled this tidal influence on the onset of volcanic eruptions and more generally, on volcanic activity. However, the interplay between this quasi-permanent forcing and volcanic systems is still poorly understood. With the present study, we propose to consider a global viewpoint to address this interaction. We analyzed the number of monthly volcanic eruptions and the global mean sea level between 1880 and 2009 using the Singular Spectrum Analysis time-series analysis technique to evaluate the existence of common periodicities. We found multi-decadal components of similar periodicities present in both time-series which we link to those already recognized in the polar motion. Its multi-decadal variations result in a mass reorganization in the oceans whose associated stress changes may impact processes generating volcanic eruptions worldwide. Our results show the influence of global processes on volcanic activity and open many questions to further investigate these multi-scale interactions.

Volcano dynamics results from an interplay between internal and external processes spanning different time scales. Unravelling how such processes interact may provide key insights into the mechanisms that may lead to the destabilization of the volcanoes and eruption, a critical information to forecast hazards. Studies dealing with tidal influence on volcanoes fall within this context, yet the cause-effect relationship between tides and eruptions is still poorly understood. In the present study, we investigate the tidal influence on two nearby volcanoes, Ischia and Campi Flegrei (Italy), characterized by intense hydrothermal activity. We analyze the seismic tremor of hydrothermal origin recorded by four seismic stations between January and June 2020 by using Singular Spectrum Analysis. We detect up to five long term tidal periodicities ranging from ∼5 to ∼29 days. The results indicate that the seismic tremor is modulated by Earth tides at both volcanoes. In addition, differences in phase and amplitude modulation between the response of both hydrothermal systems to tidal forcing reveal specific features related to the tremor source and to properties of the surrounding medium. These phenomena indicate an interplay between solid Earth and the dynamics of these two volcanoes. Similar approaches on hydrothermal systems at volcanoes would contribute to better characterize the hydrothermal circulation and their evolving conditions that may represent a precursor of a new phase of activity.

Large-volume volcanic eruptions can occur despite only limited precursory activity. Here the authors show that modelling the combined effects of buoyant magma, viscoelastic earth behaviour, and sustained magma channels can explain such behaviour of volcanoes and gives an estimate of pressure evolution in magma bodies.

Abstract A 3 day exercise simulating unrest and a large explosive eruption at Katla volcano, Iceland, was conducted in January 2016. A large volume of simulated data based on a complex, but realistic eruption scenario was compiled in advance and then transmitted to exercise participants in near-real time over the course of the exercise. The scenario was designed to test the expertise and procedures of the local institutions in charge of warning and responding to volcanic hazards, namely the volcano observatory, national civil protection, and the local university-science sector, as well as their interactions with the European science community and the London Volcanic Ash Advisory Centre. This exercise was the first of this magnitude and scope in Iceland and has revealed many successful developments introduced since the 2010 Eyjafjallajökull and 2011 Grímsvötn eruptions. Following the exercise, 90% of participants said that they felt better prepared for a future eruption. As with any exercise, it also identified areas where further development is required and improvements can be made to procedures. Seven key recommendations are made to further develop capability and enhance the collaboration between the volcano observatory, volcano research institutions and civil protection authorities. These recommendations cover topics including notification of responders, authoritative messaging, data sharing and media interaction, and are more broadly applicable to volcanic institutions elsewhere. Lessons and suggestions for how to run a large-scale volcanic exercise are given and could be adopted by those planning to rehearse their own response procedures.

We report how data from satellite and aerial synthetic aperture radar (SAR) observations were integrated into monitoring of the 2014–2015 Holuhraun eruption in the Bárðarbunga volcanic system, the largest effusive eruption in Iceland since the 1783–84 Laki eruption. A lava field formed in one of the most remote areas in Iceland, after the propagation of a ∼50 km-long dyke beneath the Vatnajökull ice cap, where the Bárðarbunga caldera is located. Due to the 6 month duration of the eruption, mainly in wintertime, daily monitoring was particularly challenging. During the eruption, the European volcanological project FutureVolc was ongoing, allowing collaboration of many European experts on volcano monitoring activities. Icelandic volcanoes are also a permanent Supersite within the Geohazard Supersites and Natural Laboratories (GSNL) initiative, with support from the Committee on Earth Observation Satellite (CEOS) in the form of a large collection of SAR images. SAR data were acquired by Cosmo-SkyMed (CSK) and TerraSAR-X (TSX) satellites and complemented by aerial SAR images. The large set of SAR satellite data significantly contributed to the daily monitoring during the unrest at Bárðarbunga caldera, the Holuhraun eruption and the year following the eruption. Detection of surface changes using both SAR amplitude and phase information was conducted throughout the whole duration of the volcano-tectonic event, and in the following months, to quantify and track the evolution of volcanic processes at Holuhraun and geothermal activity at Bárðarbunga volcano. Combination of SAR data with other data sets, e.g., satellite optical images and geodetic Global Positioning System (GPS) measurements, was essential for the evaluation of the volcanic hazard in the whole area. International collaboration within the FutureVolc project formed the basis for successful analyses and interpretation of the large SAR data set. Information was provided at Scientific Advisory Board meetings of the Icelandic Civil Protection and used in decision-making, as well as for supporting field-deployment and air-based surveys.

Following publication of the original article Witham et al., 2020, it was noticed a mistake of copyright holder name.

The cerebellum contains a circadian clock, generating internal temporal signals. The daily oscillations of cerebellar proteins were investigated in mice using a large-scale two-dimensional difference in gel electrophoresis (2D-DIGE). Analysis of 2D-DIGE gels highlighted the rhythmic variation in the intensity of 27/588 protein spots (5%) over 24 h based on cosinor regression. Notably, the rhythmic expression of most abundant cerebellar proteins was clustered in two main phases (i.e., midday and midnight), leading to bimodal distribution. Only six proteins identified here to be rhythmic in the cerebellum are also known to oscillate in the suprachiasmatic nuclei, including two proteins involved in the synapse activity (Synapsin 2 [SYN2] and vesicle-fusing ATPase [NSF]), two others participating in carbohydrate metabolism (triosephosphate isomerase (TPI1] and alpha-enolase [ENO1]), Glutamine synthetase (GLUL), as well as Tubulin alpha (TUBA4A). Most oscillating cerebellar proteins were not previously identified in circadian proteomic analyses of any tissue. Strikingly, the daily accumulation of mitochondrial proteins was clustered to the mid-resting phase, as previously observed for distinct mitochondrial proteins in the liver. Moreover, a number of rhythmic proteins, such as SYN2, NSF and TPI1, were associated with non-rhythmic mRNAs, indicating widespread post-transcriptional control in cerebellar oscillations. Thus, this study highlights extensive rhythmic aspects of the cerebellar proteome.

Vicente Huidobro, dé-constructeur d’ordres et de langage, est le poète de l’utopie inaugurale par excellence. La production huidobrienne, des œuvres primitives jusqu’au grand Altazor de 1931, s’inscrit dans un acte cohérent et répété de rupture, d’innovation dans les modes d’élaboration du poème. Un parcours parmi les étapes clefs de cette démarche fondatrice nous mène jusqu’à l’aboutissement du double projet de déconstruction/reconstruction qui trouve sa pleine expression au sein même de la figure du « désastre » qu’est le personnage altazorien.

Ultra-deep sequencing (UDS) of amplicons is a major application for next-generation sequencing tech nologies, even more so for the 454 Genome Sequencer FLX. Especially for this application, errors that might be introduced during any of the sample processing or data analysis steps should be avoided or at least recognized, as they might lead to aberrant sequence variant calling. Since 454 pyrosequencing relies on PCR-driven target amplification, it is key to differentiate errors introduced during the amplification step from genuine minority variants. Thereto, optimal primer design is imperative because primer selection, primer dimer formation, and nonspecific binding may all affect the quality and outcome of amplicon-based deep sequencing. Also, other intrinsic PCR characteristics including amplification drift and the formation of secondary structures may influence sequencing data quality. We illustrate these phenomena using real life case studies and propose experimental and analytical evidence-based solutions for effective practice. Furthermore, because accuracy of the DNA polymerase is vital for reliable UDS results, a comparative analysis of error profiles from seven different DNA polymerases was performed and experimentally as-sessed in parallel by 454 sequencing. Finally, intra and interrun variability evaluation of the 454 sequencing protocol revealed highly reproducible results in amplicon-based UDS.

The 2014–2015 Bárðarbunga fissure eruption at Holuhraun in central Iceland was distinguished by the high emission of gases, in total 9.6 Mt SO2, with almost no tephra. This work collates all ground-based measurements of this extraordinary eruption cloud made under particularly challenging conditions: remote location, optically dense cloud with high SO2 column amounts, low UV intensity, frequent clouds and precipitation, an extensive and hot lava field, developing ramparts, and high-latitude winter conditions. Semi-continuous measurements of SO2 flux with three scanning DOAS instruments were augmented by car traverses along the ring-road and along the lava. The ratios of other gases/SO2 were measured by OP-FTIR, MultiGAS, and filter packs. Ratios of SO2/HCl = 30–110 and SO2/HF = 30–130 show a halogen-poor eruption cloud. Scientists on-site reported extremely minor tephra production during the eruption. OPC and filter packs showed low particle concentrations similar to non-eruption cloud conditions. Three weather radars detected a droplet-rich eruption cloud. Top of eruption cloud heights of 0.3–5.5 km agl were measured with ground- and aircraft-based visual observations, web camera and NicAIR II infrared images, triangulation of scanning DOAS instruments, and the location of SO2 peaks measured by DOAS traverses. Cloud height and emission rate measurements were critical for initializing gas dispersal simulations for hazard forecasting.

When food availability is restricted, animals adjust their behavior according to the timing of food access. Most rodents, such as rats and mice, and a wide number of other animals express before timed food access a bout of activity, defined as food-anticipatory activity (FAA). One notable exception amongst rodents is the Syrian hamster, a photoperiodic species that is not prone to express FAA. The present study was designed to understand the reasons for the low FAA in that species. First, we used both wheel-running activity and general cage activity to assess locomotor behavior. Second, the possible effects of photoperiod was tested by challenging hamsters with restricted feeding under long (LP) or short (SP) photoperiods. Third, because daytime light may inhibit voluntary activity, hamsters were also exposed to successive steps of full and skeleton photoperiods (two 1-h light pulses simulating dawn and dusk). When hamsters were exposed to skeleton photoperiods, not full photoperiod, they expressed FAA in the wheel independently of daylength, indicating that FAA in the wheel is masked by daytime light under full photoperiods. During FAA under skeleton photoperiods, c-Fos expression was increased in the arcuate nuclei independently of the photoperiod, but differentially increased in the ventromedial and dorsomedial hypothalamic nuclei according to the photoperiod. FAA in general activity was hardly modulated by daytime light, but was reduced under SP. Together, these findings show that food-restricted Syrian hamsters are not prone to display FAA under common laboratory conditions, because of the presence of light during daytime that suppresses FAA expression in the wheel.

Based on a reading of the early poetry collections of Chilean poet Vicente Huidobro, this article aims to show the coherence of Huidobro’s poetic practice in the founding works of his œuvre. Successive early works (1912-1925) see the steady development of Huidobro’s writing strategies and the genesis of a series of figures of the poet as disproportionately grandiose as the writing project which they represent. The “creationist” ambition of these works, an ambition which was a feature of the poet’s many manifestos of the period, is the guiding principal governing their semantic and structural architecture. This imaginary beginning or genesis is particularly embodied by the figure of Adán (Adán, 1916), the first incarnation of the Poet as creator of worlds, and precursor of the later figure, Altazor (Altazor, 1931). These early works can thus be read as a kind history, or pre-history of Huidobro’s later poetic myth.

Abstract We investigated whether linoleic acid (LA) supplementation could modulate emotional behavior and microglia-related neuroinflammation. For that, male mice of C57BL/6J genetic background fed either a high-fat diet (HFD) or a standard diet (STD) for 12 weeks, were treated with a vehicle or LA solution for 5 weeks before being evaluated for emotional behavior using a battery of behavioral tests. The animals were subsequently sacrificed and their brains collected and processed for immunofluorescence staining, targeting microglia-specific calcium-binding proteins (IBA-1). Neuroinflammation severity was assessed in multiple hypothalamic, cortical and subcortical brain regions. We show an anxio-depressive-like effect of sustained HFD feeding that was neither alleviated nor worsened with LA supplementation. However, increased IBA-1 expression and microgliosis in the HFD group were largely attenuated by LA supplementation. These observations demonstrate that the anti-neuroinflammatory properties of LA are not restricted to hypothalamic areas but are also evident at the cortical and subcortical levels. This study discloses that neuroinflammation plays a role in the genesis of neuropsychiatric disorders in the context of obesity, and that LA supplementation is a useful dietary strategy to alleviate the impact of obesity-related neuroinflammation.

ObjectiveTo identify the key coding genes underlying the biomarkers and pathways associated with giant cell arteritis (GCA), we performed an in situ spatial profiling of molecules involved in the temporal arteries of GCA patients and controls. Furthermore, we performed pharmacogenomic network analysis to identify potential treatment targets.MethodsUsing human formalin-fixed paraffin-embedded temporal artery biopsy samples (GCA, n = 9; controls, n = 7), we performed a whole transcriptome analysis using the NanoString GeoMx Digital Spatial Profiler. In total, 59 regions of interest were selected in the intima, media, adventitia, and perivascular adipose tissue (PVAT). Differentially expressed genes (DEGs) (fold-change > 2 or < −2, p-adjusted < 0.01) were compared across each layer to build a spatial and pharmacogenomic network and to explore the pathophysiological mechanisms of GCA.ResultsMost of the transcriptome (12,076 genes) was upregulated in GCA arteries, compared to control arteries. Among the screened genes, 282, 227, 40, and 5 DEGs were identified in the intima, media, adventitia, and PVAT, respectively. Genes involved in the immune process and vascular remodeling were upregulated within GCA temporal arteries but differed across the arterial layers. The immune-related functions and vascular remodeling were limited to the intima and media.ConclusionThis study is the first to perform an in situ spatial profiling characterization of the molecules involved in GCA. The pharmacogenomic network analysis identified potential target genes for approved and novel immunotherapies.

Abstract Transcranial direct current stimulation (tDCS) is an emerging noninvasive brain neuromodulation technique aimed at relieving symptoms associated with psychiatric disorders, including addiction. The goal of the present study was to better identify which phase of alcohol-related behavior (hedonic effect, behavioral sensitization, self-administration, or motivation to obtain the drug) might be modulated by repeated anodal tDCS over the frontal cortex (0.2 mA, 20 min, twice a day for 5 consecutive days), using female mice as a model. Our data showed that tDCS did not modulate the hedonic effects of ethanol as assessed by a conditioned place preference test (CPP) or the expression of ethanol-induced behavioral sensitization. Interestingly, tDCS robustly reduced reacquisition of ethanol consumption (50% decrease) following extinction of self-administration in an operant paradigm. Furthermore, tDCS significantly decreased motivation to drink ethanol on a progressive ratio schedule (30% decrease). Taken together, our results show a dissociation between the effects of tDCS on “liking” (hedonic aspect; no effect in the CPP) and “wanting” (motivation; decreased consumption on a progressive ratio schedule). Our tDCS procedure in rodents will allow us to better understand its mechanisms of action in order to accelerate its use as a complementary and innovative tool to help alcohol-dependent patients maintain abstinence or reduce ethanol intake.

Repeated anodal transcranial direct current stimulation (RA-tDCS) is a neuromodulatory technique consisting of stimulating the cerebral cortex with a weak electric anodal current in a non-invasive manner. RA-tDCS over the dorsolateral prefrontal cortex has antidepressant-like properties and improves memory both in humans and laboratory animals. However, the mechanisms of action of RA-tDCS remain poorly understood. Since adult hippocampal neurogenesis is thought to be involved in the pathophysiology of depression and memory functioning, the purpose of this work was to evaluate the impact of RA-tDCS on hippocampal neurogenesis levels in mice. RA-tDCS was applied for 20 min per day for five consecutive days over the left frontal cortex of young adult (2-month-old, high basal level of neurogenesis) and middle-aged (10-month-old, low basal level of neurogenesis) female mice. Mice received three intraperitoneal injections of bromodeoxyuridine (BrdU) on the final day of RA-tDCS. The brains were collected either 1 day or 3 weeks after the BrdU injections to quantify cell proliferation and cell survival, respectively. RA-tDCS increased hippocampal cell proliferation in young adult female mice, preferentially (but not exclusively) in the dorsal part of the dentate gyrus. However, the number of cells that survived after 3 weeks was the same in both the Sham and the tDCS groups. This was due to a lower survival rate in the tDCS group, which suppressed the beneficial effects of tDCS on cell proliferation. No modulation of cell proliferation or survival was observed in middle-aged animals. Our RA-tDCS protocol may, therefore, influence the behavior of naïve female mice, as we previously described, but its effect on the hippocampus is only transient in young adult animals. Future studies using animal models for depression in male and female mice should provide further insights into RA-tDCS detailed age- and sex-dependent effects on hippocampal neurogenesis.

Abstract Background Abdominal symptoms in patients with primary Sjögren syndrome (pSS) are poorly documented. The objective of the study was to describe the abdominal symptoms of patients with pSS and to assess their association with characteristics of the disease. Methods One hundred and fifty patients with pSS were evaluated using a composite global symptom score for abdominal symptoms and their severity. Data concerning the clinical and biological characteristics of pSS and abdominal disorders were also collected. Results Of the patients with pSS, 95% suffered from abdominal symptoms (median global symptom score 7.5 ± 5.5 points out of 30). More than half of the patients experienced abdominal tension (68%), upper abdominal pain (54%), abdominal discomfort (58%) and/or constipation (54%). Regarding the pSS activity, in relation to European League Against Rheumatism (EULAR) Sjögren syndrome disease activity index score items, general and central nervous system involvement wereassociated with a high global symptom score. The EULAR Sjogren Syndrome Patient Reported Index (ESSPRI) symptom score was positively correlated with the global symptom score (p

Non-invasive neuromodulatory techniques, including transcranial direct current stimulation (tDCS), have been shown to modulate neuronal function and are used both in cognitive neuroscience and to treat neuropsychiatric conditions. In this context, animal models provide a powerful tool to identify the neurobiological mechanisms of action of tDCS. However, finding a current generator that is easily usable and which allows a wide range of stimulation parameters can be difficult and/or expensive. Here, we introduce the Open-tES device, a project under a Creative Commons License (CC BY, SA 4.0) shared on the collaborative platform Git-Hub. This current generator allows tDCS (and other kinds of stimulations) to be realized, is suitable for rodents, is easy to use, and is low-cost. Characterization has been performed to measure the precision and accuracy of the current delivered. We also aimed to compare its effects with a commercial stimulator used in clinical trials (DC-Stimulator Plus, NeuroConn, Germany). To achieve this, a behavioral study was conducted to evaluate its efficacy for decreasing depression related-behavior in mice. The stimulator precision and accuracy were better than 250 nA and 25 nA, respectively. The behavioral evaluation performed in mice in the present study did not reveal any significant differences between the commercial stimulator used in clinical trials and the Open-tES device. Accuracy and precision of the stimulator ensure high repeatability of the stimulations. This current generator constitutes a reliable and inexpensive tool that is useful for preclinical studies in the field of non-invasive electrical brain stimulation.

Fluorodesoxyglucose Positron Emission Tomography (PET/CT) has never been compared to Chest-Abdomen-Pelvis CT (CAPCT) in patients with a fever of unknown origin (FUO), inflammation of unknown origin (IUO) and episodic fever of unknown origin (EFUO) through a prospective and multicentre study. In this study, we investigated the diagnostic value of PET/CT compared to CAPCT in these patients. The trial was performed between 1 May 2008 through 28 February 2013 with 7 French University Hospital centres. Patients who fulfilled the FUO, IUO or EFUO criteria were included. Diagnostic orientation (DO), diagnostic contribution (DC) and time for diagnosis of both imaging resources were evaluated. One hundred and three patients were included with 35 FUO, 35 IUO and 33 EFUO patients. PET/CT showed both a higher DO (28.2% vs. 7.8%, p < 0.001) and DC (19.4% vs. 5.8%, p < 0.001) than CAPCT and reduced the time for diagnosis in patients (3.8 vs. 17.6 months, p = 0.02). Arthralgia (OR 4.90, p = 0.0012), DO of PET/CT (OR 4.09, p = 0.016), CRP > 30 mg/L (OR 3.70, p = 0.033), and chills (OR 3.06, p = 0.0248) were associated with the achievement of a diagnosis (Se: 89.1%, Sp: 56.8%). PET/CT both orients and contributes to diagnoses at a higher rate than CAPCT, especially in patients with FUO and IUO, and reduces the time for diagnosis.

While the diagnosis of adult-onset Still’s disease (AOSD) involves the exclusion of differential diagnoses, the characteristics and value of 18F-Fluorodeoxyglucose (18F-FDG) Positron Emission Tomography coupled with CT (PET/CT) in the management of AOSD remain poorly known. Our retrospective study included patients from four centers, fulfilling Yamaguchi or Fautrel criteria, who underwent a PET/CT during an active AOSD. Thirty-five patients were included. At the time of PET/CT, the Yamaguchi criteria were met in 23 of 29 evaluable cases. PET/CT showed bone marrow (74.3%), lymph node (74.3%), and splenic (48.6%) FDG uptake. Despite arthralgia or arthritis in most patients, joints were rarely the sites of 18F-FDG accumulation. The spatial distribution of 18F-FDG uptake was nonspecific, and its intensity could be similar to malignant disease. Lymph node or bone marrow biopsy was performed after PET/CT in 20 patients (57.1%). The intensity of bone marrow; splenic and lymph node hypermetabolism appeared to be correlated with disease activity. Abnormal PET/CT in the cervical lymph nodes and age ≥ 60 years seemed to be predictive factors for monocyclic evolution. The clinical value of PET/CT is not in direct diagnosis; but as an aid in excluding differential diagnoses by searching for their scintigraphic features and guiding biopsy.

BackgroundNeurotrophins play a central role in the development and maintenance of the nervous system. However, neurotrophins can also modulate B and T cell proliferation and activation, especially via autocrine loops. We hypothesized that both serum and lymphocytic neurotrophin levels may be deregulated in systemic Lupus erythematosus (SLE) and may reflect clinical symptoms of the disease.MethodsNeurotrophins in the serum (ELISA tests) and lymphocytes (flow cytometry) were measured in 26 SLE patients and 26 control subjects. Th1 (interferon-γ) and Th2 (IL-10) profiles and serum concentration of BAFF were assessed by ELISA in the SLE and control subjects.FindingsWe have demonstrated that both NGF and BDNF serum levels are higher in SLE patients than healthy controls (p=0.003 and pConclusionThis study demonstrates that serum and B cell levels of both NGF and BDNF are increased in SLE, suggesting that the neurotrophin production pathway is deregulated in this disease. These results must be confirmed in a larger study with naive SLE patients, in order to avoid the potential confounding influence of prior immune-modulating treatments on neurotrophin levels.

OBJECTIVES: Giant cell arteritis (GCA) is a chronic systemic vasculitis of large and medium-sized arteries, for which long-term glucocorticoid (GC) treatment is needed. During GC withdrawal patients can suffer adrenal insufficiency. We sought to determine the time until recovery of adrenal function after long-term GC therapy, and to assess the prevalence and predictors for secondary adrenal insufficiency. SUBJECTS AND DESIGN: 150 patients meeting the ACR criteria for GCA between 1984 and 2012 were analyzed. All received the same GC treatment protocol. The low-dose ACTH stimulation test was repeated annually until adrenal recovery. Biographical, clinical and laboratory data were collected prospectively and compared. RESULTS: At the first ACTH test, 74 (49%) patients were non-responders: of these, the mean time until recovery of adrenal function was 14 months (max: 51 months). A normal test response occurred within 36 months in 85% of patients. However, adrenal function never recovered in 5% of patients. GC of >15 mg/day at 6 months, GC of >9.5 mg/day at 12 months, treatment duration of >19 months, a cumulative GC dose of >8.5 g, and a basal cortisol concentration of