Delivery or expectant management for prevention of adverse maternal and neonatal outcomes in hypertensive disorders of pregnancy: an individual participant data meta-analysis.

OBJECTIVE: Hypertensive disorders affect 3-10% of pregnancies. Delayed delivery carries maternal risks, while early delivery increases fetal risk, so appropriate timing is important. The aim of this study was to compare immediate delivery with expectant management for prevention of adverse maternal and neonatal outcomes in women with hypertensive disease in pregnancy. METHODS: CENTRAL, PubMed, MEDLINE and ClinicalTrials.gov were searched for randomized controlled trials comparing immediate delivery to expectant management in women presenting with gestational hypertension or pre-eclampsia without severe features from 34 weeks of gestation. The primary neonatal outcome was respiratory distress syndrome (RDS) and the primary maternal outcome was a composite of HELLP syndrome and eclampsia. The PRISMA-IPD guideline was followed and a two-stage meta-analysis approach was used. Relative risks (RR) and numbers needed to treat or harm (NNT/NNH) with 95% CI were calculated to evaluate the effect of the intervention. RESULTS: Main outcomes were available for 1724 eligible women. Compared with expectant management, immediate delivery reduced the composite risk of HELLP syndrome and eclampsia in all women (0.8% vs 2.8%; RR, 0.33 (95% CI, 0.15-0.73); I2  = 0%; NNT, 51 (95% CI, 31.1-139.3)) as well as in the pre-eclampsia subgroup (1.1% vs 3.5%; RR, 0.39 (95% CI, 0.15-0.98); I2  = 0%). Immediate delivery increased RDS risk (3.4% vs 1.6%; RR, 1.94 (95% CI 1.05-3.6); I2  = 24%; NNH, 58 (95% CI, 31.1-363.1)), but depended upon gestational age. Immediate delivery in the 35th week of gestation increased RDS risk (5.1% vs 0.6%; RR, 5.5 (95% CI, 1.0-29.6); I2  = 0%), but immediate delivery in the 36th week did not (1.5% vs 0.4%; RR, 3.4 (95% CI, 0.4-30.3); I2 not applicable). CONCLUSION: In women with hypertension in pregnancy, immediate delivery reduces the risk of maternal complications, whilst the effect on the neonate depends on gestational age. Specifically, women with a-priori higher risk of progression to HELLP, such as those already presenting with pre-eclampsia instead of gestational hypertension, were shown to benefit from earlier delivery. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Assessing the Quality of Models of the Ambient Solar Wind.

In this paper we present an assessment of the status of models of the global Solar Wind in the inner heliosphere. We limit our discussion to the class of models designed to provide solar wind forecasts, excluding those designed for the purpose of testing physical processes in idealized configurations. In addition, we limit our discussion to modeling of the 'ambient' wind in the absence of coronal mass ejections. In this assessment we cover use of the models both in forecast mode and as tools for scientific research. We present a brief history of the development of these models, discussing the range of physical approximations in use. We discuss the limitations of the data inputs available to these models and its impact on their quality. We also discuss current model development trends.

Probabilistic Solar Wind and Geomagnetic Forecasting Using an Analogue Ensemble or "Similar Day" Approach.

Effective space-weather prediction and mitigation requires accurate forecasting of near-Earth solar-wind conditions. Numerical magnetohydrodynamic models of the solar wind, driven by remote solar observations, are gaining skill at forecasting the large-scale solar-wind features that give rise to near-Earth variations over days and weeks. There remains a need for accurate short-term (hours to days) solar-wind forecasts, however. In this study we investigate the analogue ensemble (AnEn), or "similar day", approach that was developed for atmospheric weather forecasting. The central premise of the AnEn is that past variations that are analogous or similar to current conditions can be used to provide a good estimate of future variations. By considering an ensemble of past analogues, the AnEn forecast is inherently probabilistic and provides a measure of the forecast uncertainty. We show that forecasts of solar-wind speed can be improved by considering both speed and density when determining past analogues, whereas forecasts of the out-of-ecliptic magnetic field [ B N ] are improved by also considering the in-ecliptic magnetic-field components. In general, the best forecasts are found by considering only the previous 6 - 12 hours of observations. Using these parameters, the AnEn provides a valuable probabilistic forecast for solar-wind speed, density, and in-ecliptic magnetic field over lead times from a few hours to around four days. For B N , which is central to space-weather disturbance, the AnEn only provides a valuable forecast out to around six to seven hours. As the inherent predictability of this parameter is low, this is still likely a marked improvement over other forecast methods. We also investigate the use of the AnEn in forecasting geomagnetic indices Dst and Kp. The AnEn provides a valuable probabilistic forecast of both indices out to around four days. We outline a number of future improvements to AnEn forecasts of near-Earth solar-wind and geomagnetic conditions.

Ensemble downscaling in coupled solar wind-magnetosphere modeling for space weather forecasting.

Advanced forecasting of space weather requires simulation of the whole Sun-to-Earth system, which necessitates driving magnetospheric models with the outputs from solar wind models. This presents a fundamental difficulty, as the magnetosphere is sensitive to both large-scale solar wind structures, which can be captured by solar wind models, and small-scale solar wind "noise," which is far below typical solar wind model resolution and results primarily from stochastic processes. Following similar approaches in terrestrial climate modeling, we propose statistical "downscaling" of solar wind model results prior to their use as input to a magnetospheric model. As magnetospheric response can be highly nonlinear, this is preferable to downscaling the results of magnetospheric modeling. To demonstrate the benefit of this approach, we first approximate solar wind model output by smoothing solar wind observations with an 8 h filter, then add small-scale structure back in through the addition of random noise with the observed spectral characteristics. Here we use a very simple parameterization of noise based upon the observed probability distribution functions of solar wind parameters, but more sophisticated methods will be developed in the future. An ensemble of results from the simple downscaling scheme are tested using a model-independent method and shown to add value to the magnetospheric forecast, both improving the best estimate and quantifying the uncertainty. We suggest a number of features desirable in an operational solar wind downscaling scheme. KEY POINTS: Solar wind models must be downscaled in order to drive magnetospheric models Ensemble downscaling is more effective than deterministic downscaling The magnetosphere responds nonlinearly to small-scale solar wind fluctuations.

Patient knowledge of peripheral vascular disease in an outpatient setting: an Achilles heel?

Peripheral vascular disease (PVD) has numerous modifiable risk factors. This study aimed to establish patients' awareness of risk factors and causes of PVD and their understanding of mechanisms of secondary prevention. A prospective survey of awareness of PVD among patients attending a tertiary vascular clinic for management of peripheral vascular disease was undertaken. Institutional review board approval was granted. Statistical analysis was performed using SPSS version 18.0 software. There was a 100% response rate, with 97 participants (53 male). Seventeen patients (19%) reported an interval of greater than six months from the onset of symptoms to first seeking medical attention with their General Practitioner. Only 19 (20%) could correctly identify 3 or more risk factors for peripheral vascular disease. Patients have limited awareness of PVD and its consequences. Educational initiatives are needed to encourage patients to seek early medical attention and raise awareness of modifiable risk factors in the community.

Length of stay and medical stability for spinal cord-injured patients on admission to an inpatient rehabilitation hospital: a comparison between a model SCI trauma center and non-SCI trauma center.

STUDY DESIGN: Retrospective database review. OBJECTIVE: To compare lengths of stay (LOS), pressure ulcers and readmissions to the acute care hospital of patients admitted to the inpatient rehabilitation facility (IRF) from a model spinal cord injury (SCI) trauma center or from a non-SCI acute hospital. BACKGROUND: Only sparse data exist comparing the status of patients admitted to IRF from a model SCI trauma center or from a non-SCI acute hospital. METHODS: Acute care, IRF and total LOS were compared between patients transferred to IRF from the SCI center (n=78) and from non-SCI centers (n=131). The percentages of pressure ulcers on admission to IRF and transfer back to acute care were also compared. RESULTS: Patients admitted to IRF from the SCI trauma center (SCI TC) had significantly shorter (P=0.01) acute care LOS and total LOS compared with patients admitted from non-SCI TCs. By neurological category, acute-care LOS was less for all groups admitted from the SCI center, but statistically significant only for tetraplegia. There was no significant difference in the incidence of readmissions to acute care from IRF. More patients from non-SCI centers (34%) than SCI centers (12%) had pressure ulcers (P<0.001). CONCLUSION: Acute care in organized SCI TCs before transfer to IRF can significantly lower acute-care LOS or total LOS and incidence of pressure ulcers compared with non-SCI TCs. Patients admitted to IRF from SCI TCs are no more likely to be sent back to an acute hospital than those from non-SCI TCs.

A systematic review of laparoscopic port site hernias in gastrointestinal surgery.

INTRODUCTION: Port site hernia is an important yet under-recognised complication of laparoscopic surgery, which carries a high risk of strangulation due to the small size of the defect involved. The purpose of this study was to examine the incidence, classification, and pathogenesis of this complication, and to evaluate strategies to prevent and treat it. METHODS: Medline was searched using the words "port site hernia", "laparoscopic port hernia" "laparoscopic complications" and "trocar site hernias". The search was limited to articles on cholecystectomy, colorectal, bariatric or anti-reflux surgery published in English. A total of 42 articles were analysed and of these 35 were deemed eligible for review. Inclusion criteria were laparoscopic gastrointestinal surgery in English only with reported incidence of port site herniation. Studies were excluded if insufficient data was provided. Eligible studies were also cross-referenced. RESULTS: Analysis of 11,699 patients undergoing laparoscopic gastrointestinal procedures demonstrated an incidence of port site hernias of 0.74% with a mean follow-up of 23.9 months. The lowest incidence of port site herniation was for bariatric surgery with 0.57% in 2644 patients with a mean follow-up of 67.4 months while the highest incidence was for laparoscopic colorectal surgery with an incidence of 1.47% in 477 patients with a mean follow-up of 71.5 months. CONCLUSION: All fascial defects larger than or equal to 10mm should be closed with peritoneum, while smaller defects may require closure in certain circumstances to prevent herniation. Laparoscopic port site herniation is a completely preventable cause of morbidity that requires a second surgical procedure to repair.

Baseline brain function in the preadolescents of the ABCD Study.

The Adolescent Brain Cognitive Development (ABCD) Study® is a 10-year longitudinal study of children recruited at ages 9 and 10. A battery of neuroimaging tasks are administered biennially to track neurodevelopment and identify individual differences in brain function. This study reports activation patterns from functional MRI (fMRI) tasks completed at baseline, which were designed to measure cognitive impulse control with a stop signal task (SST; N = 5,547), reward anticipation and receipt with a monetary incentive delay (MID) task (N = 6,657) and working memory and emotion reactivity with an emotional N-back (EN-back) task (N = 6,009). Further, we report the spatial reproducibility of activation patterns by assessing between-group vertex/voxelwise correlations of blood oxygen level-dependent (BOLD) activation. Analyses reveal robust brain activations that are consistent with the published literature, vary across fMRI tasks/contrasts and slightly correlate with individual behavioral performance on the tasks. These results establish the preadolescent brain function baseline, guide interpretation of cross-sectional analyses and will enable the investigation of longitudinal changes during adolescent development.

Continuous expression of corticotropin-releasing factor in the central nucleus of the amygdala emulates the dysregulation of the stress and reproductive axes.

An increase in corticotropin-releasing factor (CRF) is a putative factor in the pathophysiology of stress-related disorders. As CRF expression in the central nucleus of the amygdala (CeA) is important in adaptation to chronic stress, we hypothesized that unrestrained synthesis of CRF in CeA would mimic the consequences of chronic stress exposure and cause dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, increase emotionality and disrupt reproduction. To test this hypothesis, we used a lentiviral vector to increase CRF-expression site specifically in CeA of female rats. Increased synthesis of CRF in CeA amplified CRF and arginine vasopressin peptide concentration in the paraventricular nucleus of the hypothalamus, and decreased glucocorticoid negative feedback, both markers associated with the pathophysiology of depression. In addition, continuous expression of CRF in CeA also increased the acoustic startle response and depressive-like behavior in the forced swim test. Protein levels of gonadotropin-releasing hormone in the medial preoptic area were significantly reduced by continuous expression of CRF in CeA and this was associated with a lengthening of estrous cycles. Finally, sexual motivation but not sexual receptivity was significantly attenuated by continuous CRF synthesis in ovariectomized estradiol-progesterone-primed females. These data indicate that unrestrained CRF synthesis in CeA produces a dysregulation of the HPA axis, as well as many of the behavioral, physiological and reproductive consequences associated with stress-related disorders.Molecular Psychiatry (2009) 14, 37-50; doi:10.1038/mp.2008.91; published online 12 August 2008.

Mediastinal surgery in connective tissue tunnels using flexible endoscopy.

BACKGROUND: Mediastinal surgery most often is performed via a transthoracic or transabdominal approach; however, the pre- and paratracheal mediastinum can be readily accessed with a transcervical approach. The purpose of this study was to evaluate the feasibility, safety, and success rate of using a transcervical approach and flexible endoscopes to perform mediastinal surgery also in the retro- and paraesophageal mediastinum. METHODS: Mediastinal operations on four live pigs and one human cadaver were performed using standard endoscopes through a small cervical incision. The procedure involved marking of four mediastinal lymph nodes using endoscopic ultrasound (EUS). The esophagus was dissected to the phrenoesophageal junction by creating connective tissue tunnels with balloon dilatation and low-pressure CO(2) insufflation. Heller myotomy was performed followed by sequential identification and removal of the marked nodes. Success rate of esophageal dissection to the diaphragm, Heller myotomy, directed mediastinal lymph node harvest, and complication rates were evaluated. RESULTS: Dissection of the esophagus to the diaphragm was achieved in 100% of attempts. Distal esophageal myotomy was performed in all cases. Harvest of marked lymph nodes (ln) was successful in 100% of animals (16/16 ln) and cadavers (2/2 ln). One major complication was recorded in the pig group (tension pneumomediastinum). CONCLUSIONS: The entire visceral mediastinum can be successfully accessed through a transcervical incision using flexible endoscopes. Directed lymph node harvest and esophageal myotomy is feasible with a high success rate. Connective tissue tunnels are safe, atraumatic, and a promising concept for targeted mediastinal exploration. With refinement in technology, this approach may be useful for a variety of mediastinal surgeries.

An analysis of the utilisation and expenditure of medicines dispensed for the management of severe asthma.

There are approximately 6,300 people in Ireland with a diagnosis of Chronic Obstructive Pulmonary Disease (COPD) and with a fast growing elderly population the incidence of COPD is likely to increase. This study examines the prescribing patterns of medicines dispensed for the management Asthma/COPD in patients over the age of 35 years using the HSE-Primary Care Reimbursement Services (PCRS) prescribing databases. The HSE-PCRS pharmacy claims data, which covers all those over 70 years of age and means tested for those less than 70 years, was analysed for the years 2005/2006. Approximately 26,548 (17.9%) of patients who were prescribed a respiratory drug received inhaled short-acting beta2 agonists in combination with a regular standard-dose inhaled corticosteroid. A further 5,044 (3.4%) were also prescribed a regular inhaled long-acting beta2 agonist (salmeterol or formoterol). A total of 2506 patients (6.2%) on combination therapy were co-prescribed four different anti-asthmatic treatments inclusive of oral prednisolone. A small proportion of the patients prescribed a respiratory drug were co-prescribed nicotine replacement therapy (n = 5177, 3.5%). In total there were 9,728 (6.2%) patients prescribed a mucolytic drug in combination with a respiratory drug and the rate of co-prescribing with antibiotics was 22%. COPD is a debilitating disease that is primarily caused by smoking and is therefore largely preventable. The HSE-PCRS pharmacy claims data is a valuable tool for helping to assess the burden of this disease in the Irish context.

Nocturnal transpiration in riparian Tamarix thickets authenticated by sap flux, eddy covariance and leaf gas exchange measurements.

Tamarix chinensis Lour., which is common throughout the southwestern USA, is a phreatophytic riparian tree capable of high water use. We investigated temporal congruence between daily total evapotranspiration (E) estimated from stem sap flux (J(s)) measurements (E(sf)) and eddy covariance (E(cv)), both seasonally and immediately following rain events, and used measurements of leaf-level gas exchange, stem water content and diurnal changes in leaf water potential to track drivers of transpiration. In one study, conducted near the end of the growing season in a pure T. chinensis stand adjacent to the Rio Grande River in central New Mexico, nighttime E(sf) as a proportion of daily E(sf) increased with water availability to a peak of 36.6%. High nighttime E(sf) was associated with underestimates of nighttime E(cv). A second study, conducted in west Texas, beside the Pecos River, investigated the relationships between nighttime J(s) and stem tissue rehydration, on the one hand, and nighttime E, on the other hand. Leaf gas exchange measurements and stomatal impressions suggested that nighttime J(s) was primarily attributed to concurrent transpiration, although there were small overnight changes in stem water content. Both vapor pressure deficit and soil water availability were positively related to nighttime J(s), especially following rainfall events. Thus, both studies indicate that T. chinensis can transpire large amounts at night, a fact that must be considered when attempting to quantify E either by eddy covariance or sap flux methods.

Participatory action research into implementing open access in musculoskeletal X-ray: Management and staff perspectives.

INTRODUCTION: Neighbouring Trusts have implemented open access (walk-in) services to shorten waiting times in x-ray. Despite this, staff perceptions of their effectiveness have not yet been studied. This study forms the initial baseline evaluation phase of wider participatory action research investigating the implementation of an open access service for general practitioner musculoskeletal x-ray referrals. Staff perceptions regarding effectiveness of the current service were gathered, including their opinions regarding the effectiveness of open access services. METHODS: Qualitative data were obtained via three semi-structured interviews with radiology management and two (cross-site) staff focus groups over a 2 month period. Template analysis was used to interpret the data with the aid of NVIVO 11 to facilitate analysis. RESULTS: Template analysis uncovered several drivers for changing the current service including waiting times, external pressures, patient choice and administrative delays. 'Flexibility' was the key theme to arise during discussion regarding the effectiveness of the current service. Potential for improved access was highlighted as a major benefit to the implementation of open access, however 'workload', 'staffing' and 'communication' were all identified as potential barriers to its implementation. CONCLUSION: Although several staff members were satisfied with current service several drivers for change were identified that need to be addressed in order to truly deliver a service that fulfils the patients' needs. Results will inform the wider participatory action research that will investigate the barriers to implementing an open access service and identify whether this is indeed a suitable method of addressing the drivers for change.

Global solar wind variations over the last four centuries.

The most recent "grand minimum" of solar activity, the Maunder minimum (MM, 1650-1710), is of great interest both for understanding the solar dynamo and providing insight into possible future heliospheric conditions. Here, we use nearly 30 years of output from a data-constrained magnetohydrodynamic model of the solar corona to calibrate heliospheric reconstructions based solely on sunspot observations. Using these empirical relations, we produce the first quantitative estimate of global solar wind variations over the last 400 years. Relative to the modern era, the MM shows a factor 2 reduction in near-Earth heliospheric magnetic field strength and solar wind speed, and up to a factor 4 increase in solar wind Mach number. Thus solar wind energy input into the Earth's magnetosphere was reduced, resulting in a more Jupiter-like system, in agreement with the dearth of auroral reports from the time. The global heliosphere was both smaller and more symmetric under MM conditions, which has implications for the interpretation of cosmogenic radionuclide data and resulting total solar irradiance estimates during grand minima.

Coronal mass ejections are not coherent magnetohydrodynamic structures.

Coronal mass ejections (CMEs) are episodic eruptions of solar plasma and magnetic flux that travel out through the solar system, driving extreme space weather. Interpretation of CME observations and their interaction with the solar wind typically assumes CMEs are coherent, almost solid-like objects. We show that supersonic radial propagation of CMEs away from the Sun results in geometric expansion of CME plasma parcels at a speed faster than the local wave speed. Thus information cannot propagate across the CME. Comparing our results with observed properties of over 400 CMEs, we show that CMEs cease to be coherent magnetohydrodynamic structures within 0.3 AU of the Sun. This suggests Earth-directed CMEs are less like billiard balls and more like dust clouds, with apparent coherence only due to similar initial conditions and quasi homogeneity of the medium through which they travel. The incoherence of CMEs suggests interpretation of CME observations requires accurate reconstruction of the ambient solar wind with which they interact, and that simple assumptions about the shape of the CMEs are likely to be invalid when significant spatial/temporal gradients in ambient solar wind conditions are present.

Immune functions characteristic of SJL/J mice and their association with age and spontaneous reticulum cell sarcoma.

Spontaneous reticulum cell sarcoma in SJL/J mice has been proposed as an animal tumor model for Hodgkin's lymphoma. The relationship of tumor progression and immune function is not clear, however, and has prompted a systematic evaluation of SJL/J immune competence. It was found that the ability to generate cell-mediated immunity and antibody response to allografts was not impaired in 2- to 12-month-old mice, regardless of their tumor status. All animals were capable of generating in vivo cytotoxic effector T-cells and both IgG and IgM classes of cytotoxic antibody to a tumor allograft. In addition to being able to respond, older mice showed an unexpected hyperresponsiveness to alloantigens, which suggested that escape from feedback control might be a characteristic of SJL/J mice. Loss of immune regulation was further indicated by the failure to induce tolerance to human gamma-globulin in mice 4 months and older, while 3-week-old SJL/J mice could be rendered unresponsive. Coincident with this apparent loss of regulation, circulating antibodies to synthetic double-stranded RNA, polyinosinis - polycytidylic acid, were first detected in unimmunized mice at 4 months of age, and titers remained elevated regardless of tumor status. It is suggested that tumor development as well as autoimmunity may result from an effective amplification of the immune response.

Initiation and characterization of cultured tumor lines from spontaneous reticulum cell sarcoma of SJL/J mice.

Three reticulum cell sarcoma lines (LA1, LA6, and LA8) have been established from SJL/J spontaneous "Hodgkin's-like" reticulum cell sarcoma. All cultures are lymphoid with blast-like morphology by light and electron microscopy and produce the type B neoplasm (Dunn classification) when injected into young SJL/J mice. Identification of these tumors as lymphocytic and monocytic was investigated by surface markers, histochemical staining, and phagocytic function. LA6 and LA8 bear receptors for the Fc portion of immunoglobulin complement receptors; Thy 1.2 antigens and surface immunoglobulin were not detected on any of the three lines. No lines were able to synthesize immunoglobulin or phagocytose Degalon beads. Histochemical staining was presumptive of lymphocytes or lymphoblasts with slight differences between the lines. Although a T- or B-cell classification cannot definitively be made for these tumors lines because of their lack of specific markers, the results are consistent with an immature B-cell origin for the SJL/J reticulum cell sarcoma.

Evaluation of a modeling system for S-phase estimation in breast cancer by flow cytometry.

Using software programs provided by Coulter Electronics, we have developed an analysis system that would address problems encountered in DNA flow cytometric analysis of heterogeneous solid tumor populations, especially where the G2-M phase of the diploid population contaminates the S-phase of the aneuploid population, causing an overestimation of cells in S phase. We used the PARA 1 and PARA 2 programs in concert and developed three analysis models: (a) for euploid tumors; (b) for hyperdiploid tumors with overlapping populations; and (c) for near-diploid aneuploid tumors. Our purpose in this paper is to determine the limits and reproducibility of this analysis system with an emphasis on tumors with overlapping populations. Aliquots of frozen, pulverized breast tumor tissue (50 to 100 mg), routinely used in the steroid receptor assay, were used for routine flow cytometric measurement of the DNA index and S-phase fraction. To determine the accuracy of the analysis when overlapping populations were present, we mixed an aneuploid breast cancer cell line with human blood lymphocytes in varying ratios. A 10% mixture of aneuploid cells, the lowest mixture tested, still allowed analysis results within 95% confidence limits. Reproducibility of the system was assessed on frozen breast tumor tissue by intra- and interassay variation studies measuring cell cycle parameters and coefficient of variation of the G0-G1 peak width. Within any sample the amount of variation (+/- 2 SD) for the G0-G1 value was +/- 4.40 for intraassay and +/- 4.60 for interassay, and the amount of variation for S phase was +/- 3.0 and +/- 3.2 for intraassay and interassay, respectively. There was no difference in the variation of estimates for G2-M (+/- 2.6 for both intra- and interassay). In this study, the coefficient of variation of the G0-G1 peak greater than 5% was defined as unacceptable for accurate analysis, with the conclusion that S-phase fractions in aneuploid tumors can be routinely analyzed in human breast tumor biopsies despite tumor cell heterogeneity.

Chronic administration of the triazolobenzodiazepine alprazolam produces opposite effects on corticotropin-releasing factor and urocortin neuronal systems.

In view of the substantial preclinical evidence that supports a seminal role of central corticotropin-releasing factor (CRF) neuronal systems in the physiology and pathophysiology of stress and anxiety, it is reasonable to suggest that the anxiolytic properties of benzodiazepines are mediated, at least in part, via regulation of CRFergic function. To begin to test this complex hypothesis, we examined the effects of acute and chronic administration of the triazolobenzodiazepine agonist alprazolam on CRF peptide concentrations, receptor-binding density, and mRNA expression in the CNS. Additionally, we measured mRNA expression for urocortin, a recently discovered neuropeptide that is generally considered to be a second endogenous ligand for CRF receptors. Both acute and chronic alprazolam administration was found to decrease CRF concentrations within the locus coeruleus. Furthermore, chronic alprazolam decreased basal activity of the hypothalamic-pituitary-adrenal axis, CRF mRNA expression in the central nucleus of the amygdala, and CRF(1) mRNA expression and receptor binding in the basolateral amygdala. In marked contrast, urocortin mRNA expression in the Edinger-Westphal nucleus and CRF(2A) receptor binding in the lateral septum and ventromedial hypothalamus were increased. Similar findings of an inverse relationship between the CRF(1) and CRF(2A) receptor systems have been reported in an anxiety model based on adverse early-life experience, suggesting the intriguing possibility that CRF neuronal systems may be comprised of two separate, but interrelated, subdivisions that can be coordinately and inversely regulated by stress, anxiety, or anxiolytic drugs.