The primary prevention of pancreatic fistula using a vascularised rectus abdominis muscle flap - A porcine model.

Background: A pancreatic fistula is one of the most devastating complications following a Whipple's procedure. Fistula rates remain high despite various modifications to surgical techniques. We propose the use of a vascularised muscle flap in the primary prevention of pancreatic fistulas. Method: A distal pancreatectomy was performed on 5 pigs in our porcine model. A pancreaticojejunal (PJ) anastomotic leak was simulated. The pigs were divided into treatment (4 pigs) and control groups (1 pig). A left pedicled rectus abdominis flap was wrapped around the PJ anastomosis for the treatment group and omitted for the control group. Serum and drain amylase levels were recorded. The PJ-rectus abdominis flap complex was evaluated histologically. Results: There was no biochemical evidence of anastomotic leak in the treatment group. The drain-serum amylase ratio was less than 1.5 in the treatment group (p=0.006). Microscopically, the muscle adjacent to the anastomotic leak showed mild necrotic changes with an affected muscle depth of less than 10%. Conclusion: The vascularised rectus abdominis muscle is a durable flap to withstand proteolytic pancreatic enzymes. It is able to provide a water-tight seal around the PJ anastomosis and mitigate intraperitoneal haemorrhage and infection caused by erosion from the pancreatic fistula.

MRI for Cushing Disease: A Systematic Review.

BACKGROUND: MR imaging is key in the diagnostic work-up of Cushing disease. The sensitivity of MR imaging in Cushing disease is not known nor is the prognostic significance of "MR imaging-negative" disease. PURPOSE: Our aim was to determine the overall sensitivity and prognostic significance of MR imaging localization of Cushing disease. DATA SOURCES: We performed a systematic review of the MEDLINE and PubMed databases for cohort studies reporting the sensitivity of MR imaging for the detection of adenomas in Cushing disease. STUDY SELECTION: This study included 57 studies, comprising 5651 patients. DATA ANALYSIS: Risk of bias was assessed using the methodological index for non-randomized studies criteria. Meta-analysis of proportions and pooled subgroup analysis were performed. DATA SYNTHESIS: Overall sensitivity was 73.4% (95% CI, 68.8%-77.7%), and the sensitivity for microadenomas was 70.6% (66.2%-74.6%). There was a trend toward greater sensitivity in more recent studies and with the use of higher-field-strength scanners. Thinner-section acquisitions and gadolinium-enhanced imaging, particularly dynamic sequences, also increased the sensitivity. The use of FLAIR and newer 3D spoiled gradient-echo and FSE sequences, such as spoiled gradient-echo sequences and sampling perfection with application-optimized contrasts by using different flip angle evolutions, may further increase the sensitivity but appear complementary to standard 2D spin-echo sequences. MR imaging detection conferred a 2.63-fold (95% CI, 2.06-3.35-fold) increase in remission for microadenomas compared with MR imaging-negative Cushing disease. LIMITATIONS: Pooled analysis is limited by heterogeneity among studies. We could not account for variation in image interpretation and tumor characteristics. CONCLUSIONS: Detection on MR imaging improves the chances of curative resection of adenomas in Cushing disease. The evolution of MR imaging technology has improved the sensitivity for adenoma detection. Given the prognostic importance of MR imaging localization, further effort should be made to improve MR imaging protocols for Cushing disease.

Frontal sinus obliteration with beta-tricalcium phosphate putty: case series with long-term radiological follow up.

OBJECTIVES: Frontal sinus obliteration is often performed using fat, autologous bone or a range of synthetic materials. This paper reports the long-term clinical and radiological outcomes of frontal sinus obliteration using beta-tricalcium phosphate putty. METHODS: A retrospective audit was performed of patients who underwent frontal sinus obliteration with beta-tricalcium phosphate putty. Patient-, disease- and procedure-related data were collected. Pre- and post-operative computed tomography scans were reviewed to assess bone integration. RESULTS: Four patients underwent frontal sinus obliteration using beta-tricalcium phosphate putty for treatment of a cerebrospinal leak, mucocele and recalcitrant frontal sinusitis. All patients had disease resolution, with no intra- or post-operative complications reported in the 16.5-month follow up. Post-operative computed tomography scans confirmed native bone obliteration of the frontonasal ducts in all patients. CONCLUSION: Beta-tricalcium phosphate putty is a safe and effective option for bone obliteration of the frontal sinus in a range of pathologies, including cerebrospinal fluid leak.

Differential relationships between thought dimensions and momentary affect in daily life.

Commonly used to characterize mind wandering, task-unrelated thought has long been associated with negative affective outcomes. However, less is known about how other thought dimensions including intentionality and freedom of movement interact with task-unrelated thought to modulate momentary affect in everyday life. To address this, we used ecological momentary assessments to prompt participants to report their thought patterns and affective valence five times a day for seven consecutive days. Each assessment asked participants to report on their affective valence as well as several thought dimensions including their task-relatedness, intentionality and freedom of movement. We examined the latter two thought dimensions alone as well as how they interacted with the commonly examined dimension of task-relatedness with respect to their relationship to momentary affect. We replicated the well-established negative relationship between task-unrelated thought and momentary affect. Furthermore, unintentional task-unrelated thought was associated with more negative affect than intentional thought. This pattern was also observed more broadly in thoughts regardless of their task relevance. In contrast, freely moving thought was positively related to momentary affect in general. A significant interaction between task-relatedness and freedom of movement of thought revealed that the commonly reported negative relationship between task-unrelated thought and more negative affect is mitigated by freely moving thought. In summary, our findings indicate that these various thought dimensions have unique relationships with momentary affect, highlighting the importance of accounting for thought dimensions in establishing its affective and possibly other functional consequences.

Electrophysiological markers of mind wandering: A systematic review.

The ability to mentally wander away from the external environment is a remarkable feature of the human mind. Although recent years have witnessed a surge of interest in examining mind wandering using EEG, there is no comprehensive review that summarizes and accounts for the variable findings. Accordingly, we conducted a systematic review that synthesizes evidence from EEG studies that examined the electrophysiological measures of mind wandering. Our search yielded 42 studies that met eligibility criteria. The reviewed literature converges on a reduction in the amplitude of canonical ERP components (i.e., P1, N1 and P3) as the most reliable markers of mind wandering. Spectral findings were less robust, but point towards greater activity in lower frequency bands, (i.e., delta, theta, and alpha), as well as a decrease in beta band activity, during mind wandering compared to on-task states. The variability in these findings appears to be modulated by the task context. To integrate these findings, we propose an electrophysiological account of mind wandering that explains how the brain supports this inner experience. Conclusions drawn from this work will inform future endeavours in basic science to map out electrophysiological patterns underlying mind wandering and in translational science using EEG to predict the occurrence of this phenomenon.

68Ga-PSMA PET/CT vs. mpMRI for locoregional prostate cancer staging: correlation with final histopathology.

BACKGROUND: Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) can be used to locate lesions based on PSMA avidity, however guidelines on its use are limited by its infancy. We aimed to compare multiparametric magnetic resonance imaging (mpMRI) and PSMA PET/CT to prostatectomy histopathology. METHODS: We conducted a chart review from February 2015 to January 2017 of 50 male patients staged for prostate cancer using PSMA PET/CT and mpMRI who then underwent radical prostatectomy. Pre-operative PSMA PET/CT and mpMRI were paired with corresponding histopathology. Correlations, sensitivity, and specificity were used for comparisons. RESULTS: A total of 81 lesions were confirmed by histopathology. Fifty index lesions were detected by histopathology, all of which were detected by PSMA PET/CT (100% detection), and 47 by mpMRI (94% detection). Thirty-one histologically confirmed secondary lesions were detected, 29 of which were detected by PSMA PET/CT (93.5% detection), and 16 by mpMRI (51.6% detection). PSMA had better sensitivity for index lesion localization than mpMRI (81.1 vs. 64.8%). Specificity was similar for PSMA PET/CT and mpMRI (84.6 vs. 82.7%). SUVmax of index lesions ranged from 2.9 to 39.6 (M = 9.27 ± 6.41). Index lesion SUVmax was positively correlated with PSA (rho = 0.48, p < 0.001) and ISUP grade (rho = 0.51, p < 0.001). CONCLUSIONS: PSMA-PET/CT provided superior detection of prostate cancer lesions with better sensitivity than mpMRI. PSMA-PET/CT can be used to enhance locoregional mpMRI to provide improved detection and characterization of lesions.

Adding a PECS II block for proximal arm arteriovenous access - a randomised study.

BACKGROUND: Brachial plexus block is often utilised for proximal arm arteriovenous access creation. However, the medial upper arm and axilla are often inadequately anaesthetised, requiring repeated, intraoperative local anaesthetic supplementation, or conversion into general anaesthesia. We hypothesised that the addition of a PECS II block would improve anaesthesia and analgesia for proximal arm arteriovenous access surgery. METHODS: In this prospective, double-blinded, randomised proof-of-concept study, 36 consenting adults with end-stage renal disease aged between 21 and 90 years received either a combined supraclavicular and PECS II block (Group PECS, n = 18), or combined supraclavicular and sham block (Group SCB, n = 18) for proximal arm arteriovenous access surgery. Primary outcome was whether patients required intraoperative local anaesthetic supplementation by the surgeon. RESULTS: In Group PECS, 33.3% (6/18) needed local anaesthetic supplementation vs. 100% (18/18) in Group SCB. Group SCB had three times (RR 3.0, 95% CI 1.6-5.8; P < 0.001) the risk of requiring intraoperative local anaesthetic supplementation. Group PECS required lower volume of supplemental local anaesthetic compared to Group SCB (0.0 ml, IQR 0.0-6.3 ml vs. 15.0 ml, IQR 7.4-17.8 ml; P < 0.001). Group SCB had twice [RR 2.2, 95% CI 1.1-4.4; (P = 0.019)] the risk of needing additional sedation or analgesia. There were no significant differences between the groups with respect to postoperative visual analogue scale pain scores, time to first rescue analgesia or patient satisfaction. CONCLUSION: The results suggest that adding a PECS II block to a supraclavicular block improves regional anaesthesia for patients with end-stage renal disease undergoing proximal arm arteriovenous access surgery.

Effect of aerobic exercise on cancer-associated cognitive impairment: A proof-of-concept RCT.

BACKGROUND: Change in cognitive ability is a commonly reported adverse effect by breast cancer survivors. The underlying etiology of cognitive complaints is unclear and to date, there is limited evidence for effective intervention strategies. Exercise has been shown to improve cognitive function in older adults and animal models treated with chemotherapy. This proof-of-concept randomized controlled trial tested the effect of aerobic exercise versus usual lifestyle on cognitive function in postmenopausal breast cancer survivors. METHODS: Women, aged 40 to 65 years, postmenopausal, stages I to IIIA breast cancer, and who self-reported cognitive dysfunction following chemotherapy treatment, were recruited and randomized to a 24-week aerobic exercise intervention (EX; n = 10) or usual lifestyle control (CON; n = 9). Participants completed self-report measures of the impact of cognitive issues on quality of life (Functional Assessment of Cancer Therapy-Cognitive version 3), objective neuropsychological testing, and functional magnetic resonance imaging at baseline and 24 weeks. RESULTS: Compared to CON, EX had a reduced time to complete a processing speed test (trail making test-A) (-14.2 seconds, P < .01; effect size 0.35). Compared to CON, there was no improvement in self-reported cognitive function and effect sizes were small. Interestingly, lack of between-group differences in Stroop behavioral performance was accompanied by functional changes in several brain regions of interest in EX compared to CON at 24 weeks. CONCLUSION: These findings provide preliminary proof-of-concept results for the potential of aerobic exercise to improve cancer-related cognitive impairment and will serve to inform the development of future trials.

Differential Sources for 2 Neural Signatures of Target Detection: An Electrocorticography Study.

Electrophysiology and neuroimaging provide conflicting evidence for the neural contributions to target detection. Scalp electroencephalography (EEG) studies localize the P3b event-related potential component mainly to parietal cortex, whereas neuroimaging studies report activations in both frontal and parietal cortices. We addressed this discrepancy by examining the sources that generate the target-detection process using electrocorticography (ECoG). We recorded ECoG activity from cortex in 14 patients undergoing epilepsy monitoring, as they performed an auditory or visual target-detection task. We examined target-related responses in 2 domains: high frequency band (HFB) activity and the P3b. Across tasks, we observed a greater proportion of electrodes that showed target-specific HFB power relative to P3b over frontal cortex, but their proportions over parietal cortex were comparable. Notably, there was minimal overlap in the electrodes that showed target-specific HFB and P3b activity. These results revealed that the target-detection process is characterized by at least 2 different neural markers with distinct cortical distributions. Our findings suggest that separate neural mechanisms are driving the differential patterns of activity observed in scalp EEG and neuroimaging studies, with the P3b reflecting EEG findings and HFB activity reflecting neuroimaging findings, highlighting the notion that target detection is not a unitary phenomenon.

ClariVein® - Early results from a large single-centre series of mechanochemical endovenous ablation for varicose veins.

Objectives This study assessed the effectiveness and patient experience of the ClariVein® endovenous occlusion catheter for varicose veins from a large single-centre series in the UK. Methods A total of 300 patients (371 legs) underwent ClariVein® treatment for their varicose veins; 184 for great saphenous vein (GSV) incompetence, 62 bilateral GSV, 23 short saphenous vein (SSV), 6 bilateral SSV and 25 combined unilateral great saphenous vein and SSV. Patients were reviewed at an interval of two months post procedure and underwent Duplex ultrasound assessment. Postoperative complications were recorded along with patient satisfaction. Results All 393 procedures were completed successfully under local anaesthetic. Complete occlusion of the treated vein was initially achieved in all the patients, but at eight weeks' follow-up, there was only partial obliteration in 13/393 (3.3%) veins. These were all successfully treated with ultrasound-guided foam sclerotherapy. Procedures were well tolerated with a mean pain score of 0.8 (0-10). No significant complications were reported. Conclusions ClariVein® can be used to ablate long and short saphenous varicose veins on a walk-in-walk-out basis. Bilateral procedures can be successfully performed, and these are well tolerated as can multiple veins in the same leg. Early results are promising but further evaluation and longer term follow-up are required.

Do we need transbronchial lung biopsy if we have bronchoalveolar lavage Xpert® MTB/RIF?

BACKGROUND: Studies evaluating the role of transbronchial lung biopsy (TBLB) in diagnosing pulmonary tuberculosis (PTB) date back decades and have shaped current practice. However, with the recent advent of bronchoalveolar lavage (BAL) Xpert® MTB/RIF, it is time to re-evaluate the role of TBLB. OBJECTIVE: To assess the impact of BAL and TBLB with the addition of BAL Xpert on diagnostic PTB yields and time to treatment initiation in sputum-scarce or acid-fast bacilli (AFB) smear-negative PTB patients. METHODS: We retrospectively reviewed all sputum-scarce or AFB smear-negative patients who underwent both BAL and TBLB for suspected PTB between March 2011 and October 2013. Xpert was performed on all BAL specimens. RESULTS: Of 158 patients included in our analysis, 44 were culture-proven PTB. Ninety-four per cent of the patients had AFB smear-negative BAL samples. The sensitivity and specificity of Xpert in AFB smear-negative BAL samples were respectively 60% and 98%. The addition of BAL Xpert expedited the institution of PTB treatment while having diagnostic yields comparable to those of conventional BAL with TBLB. CONCLUSIONS: The use of BAL Xpert may obviate the need for TBLB in increasing the diagnostic yield of PTB in sputum-scarce or AFB smear-negative patients.

Sustained attention abnormalities in breast cancer survivors with cognitive deficits post chemotherapy: An electrophysiological study.

OBJECTIVE: Many breast cancer survivors (BCS) report cognitive problems following chemotherapy, yet controversy remains concerning which cognitive domains are affected. This study investigated a domain crucial to daily function: the ability to maintain attention over time. METHODS: We examined whether BCS who self-reported cognitive problems up to 3 years following cancer treatment (n=19) performed differently from healthy controls (HC, n=12) in a task that required sustained attention. Participants performed a target detection task while periodically being asked to report their attentional state. Electroencephalogram was recorded during this task and at rest. RESULTS: BCS were less likely to maintain sustained attention during the task compared to HC. Further, the P3 event-related potential component elicited by visual targets during the task was smaller in BCS relative to HC. BCS also displayed greater neural activity at rest. CONCLUSIONS: BCS demonstrated an abnormal pattern of sustained attention and resource allocation compared to HC, suggesting that attentional deficits can be objectively observed in breast cancer survivors who self-report concentration problems. SIGNIFICANCE: These data underscore the value of EEG combined with a less traditional measure of sustained attention, or attentional states, as objective laboratory tools that are sensitive to subjective complaints of chemotherapy-related attentional impairments.

Acute Neurological Illness in a Kidney Transplant Recipient Following Infection With Enterovirus-D68: An Emerging Infection?

We report the first case of enterovirus-D68 infection in an adult living-donor kidney transplant recipient who developed rapidly progressive bulbar weakness and acute flaccid limb paralysis following an upper respiratory infection. We present a 45-year-old gentleman who underwent pre-emptive living-donor kidney transplantation for IgA nephropathy. Eight weeks following transplantation, he developed an acute respiratory illness from enterovirus/rhinovirus that was detectable in nasopharyngeal (NP) swabs. Within 24 h of onset of respiratory symptoms, the patient developed binocular diplopia which rapidly progressed to multiple cranial nerve dysfunctions (acute bulbar syndrome) over the next 24 h. Within the next 48 h, asymmetric flaccid paralysis of the left arm and urinary retention developed. While his neurological symptoms were evolving, the Centers for Disease Control reported that the enterovirus strain from the NP swabs was, in fact, Enterovirus-D68 (EV-D68). Magnetic resonance imaging of the brain demonstrated unique gray matter and anterior horn cell changes in the midbrain and spinal cord, respectively. Constellation of these neurological symptoms and signs was suggestive for postinfectious encephalomyelitis (acute disseminated encephalomyelitis [ADEM]) from EV-D68. Treatment based on the principles of ADEM included intensive physical therapy and other supportive measures, which resulted in a steady albeit slow improvement in his left arm and bulbar weakness, while maintaining stable allograft function.

A review of elementary school-based substance use prevention programs: identifying program attributes.

This article takes a systematic approach to reviewing substance use prevention programs introduced in elementary school (K-6th grade). Previous studies evaluating such programs among elementary school students showed mixed effects on subsequent substance use and related psychosocial factors. Thirty published evaluation studies of 24 elementary school-based substance use prevention programs were reviewed. The study selection criteria included searching for program evaluations from 1980 to 2008. Among 27 evaluation studies that examined program effects on substance use, 56% (n = 15) found significant decreases. In addition, programs most often demonstrated effects on increasing negative substance use attitudes, increasing knowledge, decreasing perceptions of prevalence rates (i.e., descriptive norms), and improving resistance skills. These results have implications for the appropriateness and value of introducing substance use prevention programs to youth in elementary school.

Phosphoinositide-dependent activation of the ADP-ribosylation factor GTPase-activating protein ASAP1. Evidence for the pleckstrin homology domain functioning as an allosteric site.

The ADP-ribosylation factor (Arf) family of GTP-binding proteins are regulators of membrane traffic and the actin cytoskeleton. Both negative and positive regulators of Arf, the centaurin beta family of Arf GTPase-activating proteins (GAPs) and Arf guanine nucleotide exchange factors, contain pleckstrin homology (PH) domains and are activated by phosphoinositides. To understand how the activities are coordinated, we have examined the role of phosphoinositide binding for Arf GAP function using ASAP1/centaurin beta4 as a model. In contrast to Arf exchange factors, phosphatidylinositol 4, 5-bisphosphate (PtdIns-4,5-P(2)) specifically activated Arf GAP. D3 phosphorylated phosphoinositides were less effective. Activation involved PtdIns-4,5-P(2) binding to the PH domain; however, in contrast to the Arf exchange factors and contrary to predictions based on the current paradigm for PH domains as independently functioning recruitment signals, we found the following: (i) the PH domain was dispensable for targeting to PDGF-induced ruffles; (ii) activation and recruitment could be uncoupled; (iii) the PH domain was necessary for activity even in the absence of phospholipids; and (iv) the Arf GAP domain influenced localization and lipid binding of the PH domain. Furthermore, PtdIns-4,5-P(2) binding to the PH domain caused a conformational change in the Arf GAP domain detected by limited proteolysis. Thus, these data demonstrate that PH domains can function as allosteric sites. In addition, differences from the published properties of the Arf exchange factors suggest a model in which feedforward and feedback loops involving lipid metabolites coordinate GTP binding and hydrolysis by Arf.

Identification of a new Pyk2 target protein with Arf-GAP activity.

Protein tyrosine kinase Pyk2 is activated by a variety of G-protein-coupled receptors and by extracellular signals that elevate intracellular Ca2+ concentration. We have identified a new Pyk2 binding protein designated Pap. Pap is a multidomain protein composed of an N-terminal alpha-helical region with a coiled-coil motif, followed by a pleckstrin homology domain, an Arf-GAP domain, an ankyrin homology region, a proline-rich region, and a C-terminal SH3 domain. We demonstrate that Pap forms a stable complex with Pyk2 and that activation of Pyk2 leads to tyrosine phosphorylation of Pap in living cells. Immunofluorescence experiments demonstrate that Pap is localized in the Golgi apparatus and at the plasma membrane, where it is colocalized with Pyk2. In addition, in vitro recombinant Pap exhibits strong GTPase-activating protein (GAP) activity towards the small GTPases Arf1 and Arf5 and weak activity towards Arf6. Addition of recombinant Pap protein to Golgi preparations prevented Arf-dependent generation of post-Golgi vesicles in vitro. Moreover, overexpression of Pap in cultured cells reduced the constitutive secretion of a marker protein. We propose that Pap functions as a GAP for Arf and that Pyk2 may be involved in regulation of vesicular transport through its interaction with Pap.

MUC1 synthetic peptide inhibition of intercellular adhesion molecule-1 and MUC1 binding requires six tandem repeats.

We reported recently that breast cancer-associated MUC1 is a ligand for intercellular adhesion molecule-1 (ICAM-1; L. H. Regimbald et al., Cancer Res., 56: 4244-4249, 1996). We report here the results of a competitive indirect binding assay to detect the molecular requirements for binding between ICAM-1 and MUC1. The assay involved inhibition of the binding of recombinant human ICAM-1 to a murine breast adenocarcinoma cell line transfected with human MUC1. The addition of a library of human MUC1 synthetic peptides ranging from 9 to 24 amino acids (aa) showed minimal or no inhibition. However, a 120-aa peptide that corresponds to six tandem repeats of the human mucin MUC1 was as effective an inhibitor as purified tumor MUC1 and MUC1 epitope (PDTRPAP)-specific antibody (B27.29). We conclude that the number of MUC1 tandem repeats necessary for an ordered tertiary structure (D. Fontenot et al., Cancer Res., 53: 5386-5394, 1993) is also important for ICAM-1 recognition. These findings are similar to those described recently for MUC1 induction of T-cell anergy (B. Agrawal et al., Nat. Med., 4: 43-49, 1998). This suggests that the anergy induction by MUC1 may be due to ICAM-1 binding by MUC1.

Excimer laser photorefractive keratectomy for myopia: six-month follow-up.

In this study, 108 eyes of 62 patients had photorefractive keratectomy (PRK) with a 193 nm excimer laser to correct myopia. The eyes were assigned to one of three groups: low, moderate, or high myopia. Six months after PRK, 88.9% of eyes in the low myopia group, 90.0% in the moderate myopia group, and 23.8% in the high myopia group achieved an uncorrected visual acuity of 20/40 or better. In the low myopia group, 88.9% were within +/- 1 diopter (D) of attempted correction, as were 70.0% in the moderate group and 18.8% in the high myopia group. There were no significant complications. We conclude that excimer laser PRK appears to be a safe and relatively accurate procedure to correct low to moderate myopia but not high myopia because of regression over time.

Steroid-resistant asthma. Cellular mechanisms contributing to inadequate response to glucocorticoid therapy.

The current study examined whether alterations in glucocorticoid receptor (GR) binding contribute to poor response to glucocorticoid therapy in asthma. 29 asthma patients with forced expiratory volume in 1 s (FEV1) < 70% predicted were studied. Patients were classified as steroid sensitive (SS) if their morning FEV1 increased > 30% after a 1-wk course of oral prednisone 20 mg twice daily and steroid resistant (SR) if they failed to increase > 15%. PBMC obtained from these two groups, 17 SR and 12 SS, as well as 12 normal controls were analyzed. SR patients had two distinguishable GR binding abnormalities: 15 of the 17 SR patients demonstrated a significantly reduced GR binding affinity, as compared with SS patients (P = 0.0001) and normal controls (P = 0.0001). This defect was localized to T cells and reverted to normal after 48 h in culture media. However, incubation with a combination of IL-2 and IL-4 sustained this abnormality. The other two SR patients had an abnormally low GR number with normal binding affinity that was not limited to T cells. Furthermore, GR number failed to normalize after incubation in media alone or IL-2 and IL-4. Therefore, SR asthma may be due to more than one abnormality, the majority related to a reversible cytokine-induced reduction in GR binding affinity and the second related to an irreversible reduction in GR number. These findings may have important implications for the design of alternative treatment approaches for recalcitrant asthma.