Adrenal crises: perspectives and research directions

Adrenal crises (AC) are life-threatening complications of adrenal insufficiency (AI). These events have an estimated incidence of between 5 and 10 ACs/100 patient years (PY) and are responsible for some of the increased morbidity and excess mortality experienced by patients with AI. Treatment involves urgent administration of IV/IM hydrocortisone and IV fluids. Patient education regarding preventive measures, such as increasing the dose of replacement therapy (“stress dosing”) when sick, using parenteral hydrocortisone as necessary and accessing medical assistance promptly, is still considered the best approach to averting the onset of an AC at times of physiological stress, most commonly an infection. However, recent evidence has demonstrated that patient education does not prevent many AC events and the reasons for this are not fully understood. Furthermore, there is no widely accepted definition of AC. Without a validated AC definition it is difficult to interpret variations in the incidence of AC and determine the effectiveness of preventive measures. This article aims to review the clinical aspects of AC events; to explore the epidemiology; and to offer a definition for an AC and to offer a perspective on future directions for research into AC prevention

Counterfactual Choice and Learning in a Neural Network Centered on Human Lateral Frontopolar Cortex

Decision making and learning in a real-world context require organisms to track not only the choices they make and the outcomes that follow but also other untaken, or counterfactual, choices and their outcomes. Although the neural system responsible for tracking the value of choices actually taken is increasingly well understood, whether a neural system tracks counterfactual information is currently unclear. Using a three-alternative decision-making task, a Bayesian reinforcement-learning algorithm, and fMRI, we investigated the coding of counterfactual choices and prediction errors in the human brain. Rather than representing evidence favoring multiple counterfactual choices, lateral frontal polar cortex (lFPC), dorsomedial frontal cortex (DMFC), and posteromedial cortex (PMC) encode the reward-based evidence favoring the best counterfactual option at future decisions. In addition to encoding counterfactual reward expectations, the network carries a signal for learning about counterfactual options when feedback is available—a counterfactual prediction error. Unlike other brain regions that have been associated with the processing of counterfactual outcomes, counterfactual prediction errors within the identified network cannot be related to regret theory. Furthermore, individual variation in counterfactual choice-related activity and prediction error-related activity, respectively, predicts variation in the propensity to switch to profitable choices in the future and the ability to learn from hypothetical feedback. Taken together, these data provide both neural and behavioral evidence to support the existence of a previously unidentified neural system responsible for tracking both counterfactual choice options and their outcomes

Ventromedial Prefrontal and Anterior Cingulate Cortex Adopt Choice and Default Reference Frames during Sequential Multi-Alternative Choice

Although damage to the medial frontal cortex causes profound decision-making impairments, it has been difficult to pinpoint the relative contributions of key anatomical subdivisions. Here we use function magnetic resonance imaging to examine the contributions of human ventromedial prefrontal cortex (vmPFC) and dorsal anterior cingulate cortex (dACC) during sequential choices between multiple alternatives— two key features of choices made in ecological settings. By carefully constructing options whose current value at any given decision was dissociable from their longer term value, we were able to examine choices in current and long-term frames of reference. We present evidence showing that activity at choice and feedback in vmPFC and dACC was tied to the current choice and the best long-term option, respectively. vmPFC, mid-cingulate, and posterior cingulate cortex encoded the relative value between the chosen and next best option at each sequential decision, whereas dACC encoded the relative value of adapting choices from the option with the highest value in the longer term. Furthermore, at feedback we identify temporally dissociable effects that predict repetition of the current choice and adaptation away from the long-term best option in vmPFC and dACC, respectively. These functional dissociations at choice and feedback suggest that sequential choices are subject to competing cortical mechanisms

A descriptive study of adrenal crises in adults with adrenal insufficiency: increased risk with age and in those with bacterial infections

BACKGROUND: An adrenal crisis (AC) is a major cause of morbidity in hypoadrenal patients. However, there is little information available on the incidence and underlying causes of AC. METHODS: The aim of the present study was to describe the incidence of AC in New South Wales (NSW), Australia. Using a health department database, we selected de-identified data on all adults aged 20 years and over who were treated in any hospital in NSW between July1, 2000-June 30, 2011, with either a principal or secondary diagnosis of an AC. AC admission rates were calculated overall and within age categories. Frequencies of co-morbid diagnoses were analysed by age and sex groups. Poisson regression was used to assess the significance of the observed change in AC related admissions with age, while controlling for any secular trends by including year in the model. Chi sq tests were used to assess the differences in frequencies of categorical variables between groups. RESULTS: 824 patients received treatment for an AC in hospital, corresponding to 74.9 admissions/year. The majority (62.5%) of the patients were women and 52.8% were aged 60 years and over. Admission rates were significantly associated with increasing age (p < 0.0001). Patients in the 60-69, 70-79 and 80+ age groups had the highest average admission rates (24.3, 35.2 and 45.8 per million/year). A principal or secondary diagnosis of an infection was reported in 317 (38.5%) patients and infection was significantly associated with age (p < 0.0001) with older patients having the highest proportion of cases. The most frequent infections were pneumonia/lower respiratory tract infection in 85 (10.3%) cases and urinary tract infection (UTI) in 82 (10.0%) patients. Women experienced 78.0% of the reported UTIs. There were 125 patients (15.2%) with an AC and a record of gastroenteritis. Twenty-six (3.2%) patients died in hospital but, of these, only 4 deaths (0.9%) were recorded among the 467 patients with a principal diagnosis of an AC. CONCLUSIONS: The incidence of AC increases with age. Infections, especially bacterial infections, are associated with the incidence of ACs and this increases with age.R Louise Rushworth, and David J Torp

Access to medicines in remote and rural areas: a survey of residents in the Scottish Highlands and Western Isles.

Objectives: Sparsely populated areas are potentially predisposed to health inequalities due to limited access to services. This study aimed to explore and describe issues of access to medicines and related advice experienced by residents of the Scottish Highlands and Western Isles. Study design: Cross-sectional cohort study. Methods: Anonymized questionnaires were mailed to a random sample of 6000 residents aged ≥18 years identified from the electoral register. The questionnaire contained items on: access to medicines; interactions with health care services; and perceptions of the services. Results were analysed using descriptive, inferential and spatial statistics. Results: Adjusted response rate was 49.5% (2913/5889). Almost two thirds (63.4%, 1847) were prescribed medicines regularly, 88.5% (1634) of whom considered the source convenient. Pharmacy (73.8%, 1364) or dispensing GP (24.0%, 443) were the most accessed sources. Prescription medicine advice was mainly obtained from the GP (55.7%, 1029). Respondents ≥80 years old were significantly (P0.0001) more likely to live alone (45.3%, 92) compared with those 80 (15.8%, 424). Almost a fifth (16.5%, 31) of those 80 years living alone disagreed that they obtained prescribed medicines from a convenient source. The majority of respondents who felt they did not have a convenient medicines source, regardless of urban/rural classification, lived within five miles of a pharmacy or GP practice. Conclusions: Respondents accessed medicines and advice from a variety of sources. While most considered their access to medicines convenient, there were issues for those over 80 years and living alone. Perceived convenience would not appear to be solely based on geographical proximity to supply source. This requires further exploration given that these individuals are likely to have long-term conditions and be prescribed medicines on a chronic basis

NRF2-driven miR-125B1 and miR-29B1 transcriptional regulation controls a novel anti-apoptotic miRNA regulatory network for AML survival

Transcription factor NRF2 is an important regulator of oxidative stress. It is involved in cancer progression, and has abnormal constitutive expression in acute myeloid leukaemia (AML). Posttranscriptional regulation by microRNAs (miRNAs) can affect the malignant phenotype of AML cells. In this study, we identified and characterised NRF2-regulated miRNAs in AML. An miRNA array identified miRNA expression level changes in response to NRF2 knockdown in AML cells. Further analysis of miRNAs concomitantly regulated by knockdown of the NRF2 inhibitor KEAP1 revealed the major candidate NRF2-mediated miRNAs in AML. We identified miR-125B to be upregulated and miR-29B to be downregulated by NRF2 in AML. Subsequent bioinformatic analysis identified putative NRF2 binding sites upstream of the miR-125B1 coding region and downstream of the mir-29B1 coding region. Chromatin immunoprecipitation analyses showed that NRF2 binds to these antioxidant response elements (AREs) located in the 5′ untranslated regions of miR-125B and miR-29B. Finally, primary AML samples transfected with anti-miR-125B antagomiR or miR-29B mimic showed increased cell death responsiveness either alone or co-treated with standard AML chemotherapy. In summary, we find that NRF2 regulation of miR-125B and miR-29B acts to promote leukaemic cell survival, and their manipulation enhances AML responsiveness towards cytotoxic chemotherapeutics

Causal role of a neural system for separating and selecting multidimensional social cognitive information

People are multi-faceted, typically good at some things but bad at others, and a critical aspect of social judgement is the ability to focus on those traits relevant for the task at hand. However, it remains unknown how the brain supports such context-dependent social judgement. Here, we examine how people represent multidimensional individuals, and how the brain extracts relevant information and filters out irrelevant information when comparing individuals within a specific dimension. Using human fMRI, we identify distinct neural representations in dorsomedial prefrontal cortex (dmPFC) and anterior insula (AI) supporting separation and selection of information for context-dependent social judgement. Causal evaluation using non-invasive brain stimulation shows that AI disruption alters the impact of relevant information on social comparison, whereas dmPFC disruption only affects the impact of irrelevant information. This neural circuit is distinct from the one supporting integration across, as opposed to separation of, different features of a multidimensional cognitive space

The representation of abstract task rules in the human prefrontal cortex

We have previously reported sustained activation in the ventral prefrontal cortex while participants prepared to perform 1 of 2 tasks as instructed. But there are studies that have reported activation reflecting task rules elsewhere in prefrontal cortex, and this is true in particular when it was left to the participants to decide which rule to obey. The aim of the present experiment was to use functional magnetic resonance imaging (fMRI) to find whether there was activation in common, irrespective of the way that the task rules were established. On each trial, we presented a word after a variable delay, and participants had to decide either whether the word was abstract or concrete or whether it had 2 syllables. The participants either decided before the delay which task they would perform or were instructed by written cues. Comparing the self-generated with the instructed trials, there was early task set activation during the delay in the middle frontal gyrus. On the other hand, a conjunction analysis revealed sustained activation in the ventral prefrontal and polar cortex for both conditions. We argue that the ventral prefrontal cortex is specialized for handling conditional rules regardless of how the task rules were established