Toward a Structural Understanding of Class B GPCR Peptide Binding and Activation.

Class B G protein-coupled receptors (GPCRs) are important therapeutic targets for major diseases. Here, we present structures of peptide and Gs-bound pituitary adenylate cyclase-activating peptide, PAC1 receptor, and corticotropin-releasing factor (CRF), (CRF1) receptor. Together with recently solved structures, these provide coverage of the major class B GPCR subfamilies. Diverse orientations of the extracellular domain to the receptor core in different receptors are at least partially dependent on evolutionary conservation in the structure and nature of peptide interactions. Differences in peptide interactions to the receptor core also influence the interlinked TM2-TM1-TM6/ECL3/TM7 domain, and this is likely important in their diverse signaling. However, common conformational reorganization of ECL2, linked to reorganization of ICL2, modulates G protein contacts. Comparison between receptors reveals ICL2 as a key domain forming dynamic G protein interactions in a receptor- and ligand-specific manner. This work advances our understanding of class B GPCR activation and Gs coupling.

Lipid-Dependent Activation of the Orphan G Protein-Coupled Receptor, GPR3.

The class A orphan G protein-coupled receptor (GPCR), GPR3, has been implicated in a variety of conditions, including Alzheimer's and premature ovarian failure. GPR3 constitutively couples with Gαs, resulting in the production of cAMP in cells. While tool compounds and several putative endogenous ligands have emerged for the receptor, its endogenous ligand, if it exists, remains a mystery. As novel potential drug targets, the structures of orphan GPCRs have been of increasing interest, revealing distinct modes of activation, including autoactivation, presence of constitutively activating mutations, or via cryptic ligands. Here, we present a cryo-electron microscopy (cryo-EM) structure of the orphan GPCR, GPR3 in complex with DNGαs and Gß1γ2. The structure revealed clear density for a lipid-like ligand that bound within an extended hydrophobic groove, suggesting that the observed "constitutive activity" was likely due to activation via a lipid that may be ubiquitously present. Analysis of conformational variance within the cryo-EM data set revealed twisting motions of the GPR3 transmembrane helices that appeared coordinated with changes in the lipid-like density. We propose a mechanism for the binding of a lipid to its putative orthosteric binding pocket linked to the GPR3 dynamics.

Development of a Novel Assay for Direct Assessment of Selective Amylin Receptor Activation Reveals Novel Differences in Behavior of Selective and Nonselective Peptide Agonists.

Dual amylin and calcitonin receptor agonists (DACRAs) show promise as efficacious therapeutics for treatment of metabolic disease, including obesity. However, differences in efficacy in vivo have been observed for individual DACRAs, indicating that detailed understanding of the pharmacology of these agents across target receptors is required for rational drug development. To date, such understanding has been hampered by lack of direct, subtype-selective, functional assays for the amylin receptors (AMYRs). Here, we describe the generation of receptor-specific assays for recruitment of Venus-tagged Gs protein through fusion of luciferase to either the human calcitonin receptor (CTR), human receptor activity-modifying protein (RAMP)-1, RAMP1 (AMY1R), human RAMP2 (AMY2R), or human RAMP3 (AMY3R). These assays revealed a complex pattern of receptor activation by calcitonin, amylin, or DACRA peptides that was distinct at each receptor subtype. Of particular note, although both of the CT-based DACRAs, sCT and AM1784, displayed relatively similar behaviors at CTR and AMY1R, they generated distinct responses at AMY2R and AMY3R. These data aid the rationalization of in vivo differences in response to DACRA peptides in rodent models of obesity. Direct assessment of the pharmacology of novel DACRAs at AMYR subtypes is likely to be important for development of optimized therapeutics for treatment of metabolic diseases. SIGNIFICANCE STATEMENT: Amylin receptors (AMYRs) are important obesity targets. Here we describe a novel assay that allows selective functional assessment of individual amylin receptor subtypes that provides unique insight into the pharmacology of potential therapeutic ligands. Direct assessment of the pharmacology of novel agonists at AMYR subtypes is likely to be important for development of optimized therapeutics for treatment of metabolic diseases.

Phase-plate cryo-EM structure of a class B GPCR-G-protein complex.

Class B G-protein-coupled receptors are major targets for the treatment of chronic diseases, such as osteoporosis, diabetes and obesity. Here we report the structure of a full-length class B receptor, the calcitonin receptor, in complex with peptide ligand and heterotrimeric Gαsßγ protein determined by Volta phase-plate single-particle cryo-electron microscopy. The peptide agonist engages the receptor by binding to an extended hydrophobic pocket facilitated by the large outward movement of the extracellular ends of transmembrane helices 6 and 7. This conformation is accompanied by a 60° kink in helix 6 and a large outward movement of the intracellular end of this helix, opening the bundle to accommodate interactions with the α5-helix of Gαs. Also observed is an extended intracellular helix 8 that contributes to both receptor stability and functional G-protein coupling via an interaction with the Gß subunit. This structure provides a new framework for understanding G-protein-coupled receptor function.

The importance of air quality for underground spaces: An international survey of public attitudes.

Space is a resource that is constantly being depleted, especially in mega-cities. Underground workspaces (UGS) are increasingly being included in urban plans and have emerged as an essential component of vertical cities. While progress had been made on the engineering aspects associated with the development of high-quality UGS, public attitudes toward UGS as work environments (ie, the public's design concerns with UGS) are relatively unknown. Here, we present the first large-scale study examining preferences and attitudes toward UGS, surveying close to 2000 participants from four cities in three continents (Singapore, Shanghai, London, and Montreal). Contrary to previous beliefs, air quality (and not lack of windows) is the major concern of prospective occupants. Windows, temperature, and lighting emerged as additional important building performance aspects for UGS. Early adopters (ie, individuals more willing to accept UGS and thus more likely to be the first occupants) across all cities prioritized air quality. Present results suggest that (perceived) air quality is a key building performance aspect for UGS that needs to be communicated to prospective occupants as this will improve their attitudes and views toward UGS. This study highlights the importance of indoor air quality for the public.

Associations of perceived indoor environmental quality with stress in the workplace.

Indoor environmental quality (IEQ) is a general indicator of the quality of conditions inside a building. We investigated associations of perceived IEQ including air quality, thermal comfort, noise, and light quality with stress at work and the extent to which workplace location modifies these associations. We recruited 464 full-time workers from four companies in Singapore. Data on socio-demographic characteristics, lifestyle/health-related factors, and workplace factors were collected through self-administered questionnaires. Perceived IEQ satisfaction scores of all four factors were collected using the validated OFFICAIR questionnaire. We fitted a logistic regression model to assess associations between each perceived IEQ score and stress at work, adjusting for potential confounders. The odds ratio for stress at work associated with a 1-unit increase in perceived air quality score was 0.88 (0.82-0.94), 0.89 (0.82-0.97) for thermal comfort, 0.93 (0.87-0.98) for noise, and 0.88 (0.82-0.94) for light quality. Significant associations were found in office and control rooms for all four perceived IEQ, except for thermal comfort in office rooms. Higher satisfaction levels of perceived air quality, thermal comfort, noise, and lighting, were significantly associated with a reduction in stress at work. Our findings could potentially provide a useful tool for environmental health impact assessment for buildings.

The multicultural mind as an epistemological test and extension for the thinking through other minds approach.

The multicultural experience (i.e., multicultural individuals and cross-cultural experiences) offers the intriguing possibility for (i) an empirical examination of how free-energy principles explain dynamic cultural behaviors and pragmatic cultural phenomena and (ii) a challenging but decisive test of thinking through other minds (TTOM) predictions. We highlight that TTOM needs to treat individuals as active cultural agents instead of passive learners.

Employee experiences in underground workplaces: a qualitative investigation.

Underground workplaces (UWS) are increasingly being recognised as a sustainable solution to concerns regarding lack of space facing megacities. UWS can multiply available space by reducing urban sprawl thereby improving quality of life in cities. However, developing workplaces that respond to the needs and preferences of occupants will be a crucial factor in determining the success of this concept. We examine the experiences of existing full-time employees of a large underground facility in North America and analyse how these are related to company policies and other organisational factors. From in-depth interviews of 73 participants, three predominant themes emerged from the analyses: environmental effects (e.g. lack of sunlight), design (e.g. the unique working environment), and organisational factors and social dynamics (e.g. policies regarding breaks). We discuss these themes in relation with interventions that may improve employee comfort and retention and suggest that many factors are within organisational control. Practitioner Summary: Underground workplaces are a sustainable solution to lack of urban space. However, developing effective workplaces is crucial to their success. We examine the experiences of existing employees of an underground facility in North America. We suggest that most negative attitudes towards underground spaces can be mitigated through simple organisational interventions. Abbreviations: UWS: underground workplaces; IRB: institutional review board.

Melatonin and health: an umbrella review of health outcomes and biological mechanisms of action.

BACKGROUND: Our aims were to evaluate critically the evidence from systematic reviews as well as narrative reviews of the effects of melatonin (MLT) on health and to identify the potential mechanisms of action involved. METHODS: An umbrella review of the evidence across systematic reviews and narrative reviews of endogenous and exogenous (supplementation) MLT was undertaken. The Oxman checklist for assessing the methodological quality of the included systematic reviews was utilised. The following databases were searched: MEDLINE, EMBASE, Web of Science, CENTRAL, PsycINFO and CINAHL. In addition, reference lists were screened. We included reviews of the effects of MLT on any type of health-related outcome measure. RESULTS: Altogether, 195 reviews met the inclusion criteria. Most were of low methodological quality (mean -4.5, standard deviation 6.7). Of those, 164 did not pool the data and were synthesised narratively (qualitatively) whereas the remaining 31 used meta-analytic techniques and were synthesised quantitatively. Seven meta-analyses were significant with P values less than 0.001 under the random-effects model. These pertained to sleep latency, pre-operative anxiety, prevention of agitation and risk of breast cancer. CONCLUSIONS: There is an abundance of reviews evaluating the effects of exogenous and endogenous MLT on health. In general, MLT has been shown to be associated with a wide variety of health outcomes in clinically and methodologically heterogeneous populations. Many reviews stressed the need for more high-quality randomised clinical trials to reduce the existing uncertainties.

Long-term outcomes with first- vs. second-generation drug-eluting stents in saphenous vein graft lesions.

BACKGROUND: As compared with bare metal stents, first-generation drug-eluting stents (DES) improved post-procedural outcomes in aortocoronary saphenous vein graft (SVG) lesions, but there is limited information on outcomes after use of second-generation DES in SVGs. METHODS: We compared the outcomes of patients who received first- (n = 81) with those who received second-generation (n = 166) DES in SVG lesions at our institution between 2006 and 2013. Major adverse cardiac events (MACE) were defined as the composite of all-cause death, myocardial infarction, and target vessel revascularization. RESULTS: Mean age was 66.0 ± 8.1 years and 97.6% of the patients were men. Mean SVG age was 11.1 ± 0.4 years. First-generation DES were sirolimus-eluting (n = 17) and paclitaxel-eluting (n = 64) stents. Second-generation DES were everolimus-eluting (n = 115) and zotarolimus-eluting (n = 51) stents. Median follow-up was 41 months. At 2-years post-procedure, patients with first- and second-generation DES had similar rates of death (20.91% vs. 20.27%, P = 0.916), target lesion revascularization (16.39% vs. 20.00%, P = 0.572), target vessel revascularization (20.97% vs. 23.16%, P = 0.747), myocardial infarction (26.15% vs. 23.00%, P = 0.644), and MACE (43.5% vs. 40.87%, P = 0.707), respectively. CONCLUSIONS: Outcomes with first- and second-generation DES in SVGs are similar. Novel stent designs are needed to further improve the clinical outcomes in this challenging patient and lesion subgroup. © 2015 Wiley Periodicals, Inc.

Surgical Treatment and Recurrence of Cutaneous Nasal Malignancies: A 26-Year Retrospective Review of 1795 Patients.

Frequent localization of facial malignancies in the nasal area and their required complete surgical extirpation pose a significant challenge to the plastic surgeon, who is called to perform a suitable delicate reconstruction of produced nasal skin defects. The present study was aimed to examine the role of tumor characteristics in the prognosis of patients with nasal skin cancer undergoing surgical management.A retrospective review of 1795 patients operated on for nasal cutaneous neoplasms during a 26-year period is presented in our study. Descriptive statistics were appropriately calculated; multivariate Cox regression analysis was performed regarding the possible risk factors for recurrence. Only those with a complete follow-up were included in the study. The mean age of our study population was 66.7 years with a male majority (52.4%). Basal cell carcinoma appeared as the most common histological type (87.7%), followed by squamous cell carcinoma (7.9%); the latter correlated with poor prognosis.The nasal sidewalls were the most frequent lesion location (29.8%), followed by the alae (27.8%), dorsum (21.7%), and tip (19.3%). The columella was very rarely affected (0.5%) but was associated with increased recurrence [hazard ratio, 4.74; 95% confidence interval (CI), 1.12-20.00; P = 0.034]. Most patients were treated with elliptical excision and direct closure (58.7%). Local flaps (31.0%) and skin grafting (9.0%) proved very reliable surgical options, especially for larger, high-risk lesions. Recurrence transpired in 46 patients (2.6%) and 4 skin cancer-related deaths occurred.Surgical modality of choice should be individualized and carefully adjusted to patients' needs. Moreover, more elective techniques, such as Mohs micrographic surgery or cumulative therapeutic approaches, like irradiation, should be examined as a beneficial aid to confront high-risk malignancies.

With you or against you: social orientation dependent learning signals guide actions made for others.

In social environments, it is crucial that decision-makers take account of the impact of their actions not only for oneself, but also on other social agents. Previous work has identified neural signals in the striatum encoding value-based prediction errors for outcomes to oneself; also, recent work suggests that neural activity in prefrontal cortex may similarly encode value-based prediction errors related to outcomes to others. However, prior work also indicates that social valuations are not isomorphic, with social value orientations of decision-makers ranging on a cooperative to competitive continuum; this variation has not been examined within social learning environments. Here, we combine a computational model of learning with functional neuroimaging to examine how individual differences in orientation impact neural mechanisms underlying 'other-value' learning. Across four experimental conditions, reinforcement learning signals for other-value were identified in medial prefrontal cortex, and were distinct from self-value learning signals identified in striatum. Critically, the magnitude and direction of the other-value learning signal depended strongly on an individual's cooperative or competitive orientation toward others. These data indicate that social decisions are guided by a social orientation-dependent learning system that is computationally similar but anatomically distinct from self-value learning. The sensitivity of the medial prefrontal learning signal to social preferences suggests a mechanism linking such preferences to biases in social actions and highlights the importance of incorporating heterogeneous social predispositions in neurocomputational models of social behavior.

Impact of contrast agent viscosity on coronary balloon deflation times: bench testing results.

OBJECTIVES: To assess the impact of viscosity on angioplasty balloon deflation times. BACKGROUND: Lower contrast viscosity could result in more rapid coronary balloon deflation times. METHODS: We performed a bench comparison of coronary balloon deflation times using 2 contrast agents with different viscosity (ioxaglate and iodixanol), 3 contrast dilutions, and 2 inflation syringe filling volumes. Ten identical pairs of coronary angioplasty balloons were used to conduct each comparison after balloon inflation to 12 atmospheres. Simultaneous deflations were performed under cineangiography. The time to full contrast extraction and the area of contrast remaining after 5 seconds of deflation (quantified by opaque pixel count) were compared between groups. RESULTS: The mean time to full contrast extraction during balloon deflation was 8.3 ± 2.5 seconds for ioxaglate (lower viscosity) versus 10.1 ± 2.9 seconds for iodixanol (higher viscosity) (17.4% decrease, P = 0.005), with a 35.6% (P = 0.004) reduction in contrast area at 5 seconds. Compared to 1:1 ioxaglate-saline mixture, 1:2 and 1:3 ioxaglate/saline mixes resulted in 26.7% (P < 0.001) and 39.0% (P < 0.001) reduction in mean balloon deflation time, respectively, but at the expense of decreased balloon opacity. Filling the inflation syringe with 5 versus 15 ml of contrast/saline solution was associated with 7.5% decrease in balloon deflation time (P = 0.005), but no difference in contrast area at 5 seconds (P = 0.749). CONCLUSIONS: Use of a lower viscosity contrast agent and higher contrast dilution significantly reduced coronary balloon deflation times, whereas use of lower syringe filling volume had a modest effect. Rapid coronary balloon deflation could improve the safety of interventional procedures.

Long-term outcomes of successful chronic total occlusion percutaneous coronary interventions using the antegrade and retrograde approach.

OBJECTIVE: To compare long-term clinical outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI) using the retrograde and antegrade approach. BACKGROUND: There is limited long-term clinical outcomes data on the retrograde approach to CTO PCI. METHODS: We performed a retrospective analysis of the long-term clinical outcomes of 193 consecutive patients who underwent successful CTO PCI at our institution between March 2008 and December 2011. RESULTS: Mean age was 63.6 ± 8.3 years. The target vessel was right coronary artery in 52.6%, left anterior descending artery in 24.5% and circumflex in 21.4% of cases. The retrograde approach was used in 41 patients (21.2%). The mean stent length was longer in the retrograde group (83 ± 32 vs. 64 ± 32 mm, P = 0.001). Two major procedural complications occurred, both in the retrograde group (P = 0.012). During a median follow-up of 2.0 years compared to the antegrade CTO PCI group, patients who underwent retrograde CTO PCI were more likely to undergo target lesion revascularization (TLR) (45.6% vs. 25.7%, P = 0.006). No significant difference was observed in the incidence of all-cause mortality, myocardial infarction, non-target vessel revascularization, or coronary artery bypass graft surgery between the 2 groups. On multivariate analysis, stent length was the only independent predictor of TLR during follow-up. CONCLUSIONS: Retrograde CTO PCI was associated with higher incidence of TLR, but similar incidence of death and myocardial infarction compared to antegrade CTO PCI. These findings likely reflect the higher complexity of CTO lesions treated with the retrograde approach.

Risk-dependent reward value signal in human prefrontal cortex.

When making choices under uncertainty, people usually consider both the expected value and risk of each option, and choose the one with the higher utility. Expected value increases the expected utility of an option for all individuals. Risk increases the utility of an option for risk-seeking individuals, but decreases it for risk averse individuals. In 2 separate experiments, one involving imperative (no-choice), the other choice situations, we investigated how predicted risk and expected value aggregate into a common reward signal in the human brain. Blood oxygen level dependent responses in lateral regions of the prefrontal cortex increased monotonically with increasing reward value in the absence of risk in both experiments. Risk enhanced these responses in risk-seeking participants, but reduced them in risk-averse participants. The aggregate value and risk responses in lateral prefrontal cortex contrasted with pure value signals independent of risk in the striatum. These results demonstrate an aggregate risk and value signal in the prefrontal cortex that would be compatible with basic assumptions underlying the mean-variance approach to utility.

Microsatellite markers within the α-globin gene cluster for robust preimplantation genetic diagnosis of severe α-thalassemia syndromes in Mediterranean populations.

In this study we report the development of a generic protocol for preimplantation genetic diagnosis (PGD) of severe α-thalassemia (α-thal) syndromes in α-thal carrier couples of Mediterranean origin. The in silico identification and design of primers for multiplex analysis of short tandem repeats (STRs), was followed by the optimization of polymerase chain reaction (PCR) conditions for multiplexed STR analysis within the α-globin gene cluster (16p3.3) and subsequent optimization and validation of a single-cell multiplex reaction including the selected STRs. Three simple dinucleotide repeats were selected based on their rate of heterozygosity, multiplex PCR efficiency and product size, and location within the α-globin gene cluster. The multiplex PCR was optimized in single lymphocytes with PCR efficiency ranging from 92.5 to 98% and an allele drop-out (ADO) rate of 0 to 9.0% for the three loci. The optimized method was applied in two clinical PGD cycles and genotypes were achieved in 17 out of 18 blastomeres (94%). Transfer of unaffected embryos led to a singleton pregnancy in one of the two couples. The triplex PCR validated for Greek and Cypriot populations is a robust generic method for α-thal PGD.

Digital Biomarkers for Depression Screening With Wearable Devices: Cross-sectional Study With Machine Learning Modeling.

BACKGROUND: Depression is a prevalent mental disorder that is undiagnosed and untreated in half of all cases. Wearable activity trackers collect fine-grained sensor data characterizing the behavior and physiology of users (ie, digital biomarkers), which could be used for timely, unobtrusive, and scalable depression screening. OBJECTIVE: The aim of this study was to examine the predictive ability of digital biomarkers, based on sensor data from consumer-grade wearables, to detect risk of depression in a working population. METHODS: This was a cross-sectional study of 290 healthy working adults. Participants wore Fitbit Charge 2 devices for 14 consecutive days and completed a health survey, including screening for depressive symptoms using the 9-item Patient Health Questionnaire (PHQ-9), at baseline and 2 weeks later. We extracted a range of known and novel digital biomarkers characterizing physical activity, sleep patterns, and circadian rhythms from wearables using steps, heart rate, energy expenditure, and sleep data. Associations between severity of depressive symptoms and digital biomarkers were examined with Spearman correlation and multiple regression analyses adjusted for potential confounders, including sociodemographic characteristics, alcohol consumption, smoking, self-rated health, subjective sleep characteristics, and loneliness. Supervised machine learning with statistically selected digital biomarkers was used to predict risk of depression (ie, symptom severity and screening status). We used varying cutoff scores from an acceptable PHQ-9 score range to define the depression group and different subsamples for classification, while the set of statistically selected digital biomarkers remained the same. For the performance evaluation, we used k-fold cross-validation and obtained accuracy measures from the holdout folds. RESULTS: A total of 267 participants were included in the analysis. The mean age of the participants was 33 (SD 8.6, range 21-64) years. Out of 267 participants, there was a mild female bias displayed (n=170, 63.7%). The majority of the participants were Chinese (n=211, 79.0%), single (n=163, 61.0%), and had a university degree (n=238, 89.1%). We found that a greater severity of depressive symptoms was robustly associated with greater variation of nighttime heart rate between 2 AM and 4 AM and between 4 AM and 6 AM; it was also associated with lower regularity of weekday circadian rhythms based on steps and estimated with nonparametric measures of interdaily stability and autocorrelation as well as fewer steps-based daily peaks. Despite several reliable associations, our evidence showed limited ability of digital biomarkers to detect depression in the whole sample of working adults. However, in balanced and contrasted subsamples comprised of depressed and healthy participants with no risk of depression (ie, no or minimal depressive symptoms), the model achieved an accuracy of 80%, a sensitivity of 82%, and a specificity of 78% in detecting subjects at high risk of depression. CONCLUSIONS: Digital biomarkers that have been discovered and are based on behavioral and physiological data from consumer wearables could detect increased risk of depression and have the potential to assist in depression screening, yet current evidence shows limited predictive ability. Machine learning models combining these digital biomarkers could discriminate between individuals with a high risk of depression and individuals with no risk.

A Comparative Study of International and Asian Criteria for Overweight or Obesity at Workplaces in Singapore.

To compare the prevalence of and risk factors associated with overweight or obesity between the international (body mass index [BMI] ≥25 kg/m2) and Asian (BMI ≥23 kg/m2) criteria in a working population in Singapore. This was a cross-sectional analysis of a cohort study of 464 employees (aged ≥21 years) conducted at 4 workplaces in Singapore. The prevalence of overweight or obesity was 47.4% and 67.0% with the international and Asian criteria, respectively. With both the criteria, higher age, male sex, Malay ethnicity (vs Chinese), lower white rice intake, and consumption of sugar-sweetened beverages were positively associated with overweight or obesity. Participants with poorer mental health and higher levels of thermal comfort in the workplace were positively associated with overweight or obesity only with the Asian criteria. The use of international criteria alone in this population could have overlooked these risk factors that are highly relevant to the Singapore context.

Neural correlates of value, risk, and risk aversion contributing to decision making under risk.

Decision making under risk is central to human behavior. Economic decision theory suggests that value, risk, and risk aversion influence choice behavior. Although previous studies identified neural correlates of decision parameters, the contribution of these correlates to actual choices is unknown. In two different experiments, participants chose between risky and safe options. We identified discrete blood oxygen level-dependent (BOLD) correlates of value and risk in the ventral striatum and anterior cingulate, respectively. Notably, increasing inferior frontal gyrus activity to low risk and safe options correlated with higher risk aversion. Importantly, the combination of these BOLD responses effectively decoded the behavioral choice. Striatal value and cingulate risk responses increased the probability of a risky choice, whereas inferior frontal gyrus responses showed the inverse relationship. These findings suggest that the BOLD correlates of decision factors are appropriate for an ideal observer to detect behavioral choices. More generally, these biological data contribute to the validity of the theoretical decision parameters for actual decisions under risk.

Fulminant necrotizing fasciitis to the hand in a patient on high-dose steroids: A case report of successful limb salvage.

Glucocorticoids are commonly used in the management of patients with brain Tumour for reducing peritumoral and vasogenic edema. However, they may lead to development of limb and life-threatening conditions such as necrotizing fasciitis (NF). NF is a rare but potentially lethal condition. Early detection and aggressive treatment may lead to decreased mortality and limb salvage. The diagnosis is predominately clinical but may be supported by laboratory and radiological investigations. Chronic steroid use not only predisposes to the development of NF but also may mask early features delaying presentation and diagnosis. Clinicians should have a high index of suspicion especially in patients on chronic steroid therapy as this may aid in early detection and treatment. We present a case report of a successful limb salvage that exemplifies these points.