Eureka: objective assessment of the empty pelvis syndrome to measure volumetric changes in pelvic dead space following pelvic exenteration.

BACKGROUND: Large tissue defects following pelvic exenteration (PE) fill with fluid and small bowel, leading to the empty pelvis syndrome (EPS). EPS causes a constellation of complications including pelvic sepsis and reduced quality of life. EPS remains poorly defined and cannot be objectively measured. Pathophysiology of EPS is multifactorial, with increased pelvic dead space potentially important. This study aims to describe methodology to objectively measure volumetric changes relating to EPS. METHODS: The true pelvis is defined by the pelvic inlet and outlet. Within the true pelvis there is physiological pelvic dead space (PDS) between the peritoneal reflection and the inlet. This dead space is increased following PE and is defined as the exenteration pelvic dead space (EPD). EPD may be reduced with pelvic filling and the volume of filling is defined as the pelvic filling volume (PFV). PDS, EPD, and PFV were measured intraoperatively using a bladder syringe, and Archimedes' water displacement principle. RESULTS: A patient undergoing total infralevator PE had a PDS of 50 ml. A rectus flap rendered the pelvic outlet watertight. EPD was then measured as 540 ml. Therefore there was a 10.8-fold increase in true pelvis dead space. An omentoplasty was placed into the EPD, displacing 130 ml; therefore, PFV as a percentage of EPD was 24.1%. CONCLUSIONS: This is the first reported quantitative assessment of pathophysiological volumetric changes of pelvic dead space; these measurements may correlate to severity of EPS. PDS, EPD, and PFV should be amendable to assessment based on perioperative cross-sectional imaging, allowing for potential prediction of EPS-related outcomes.

Patients' experiences of a suppoRted self-manAGeMent pAThway In breast Cancer (PRAGMATIC): quality of life and service use results.

PURPOSE: To describe trends and explore factors associated with quality of life (QoL) and psychological morbidity and assess breast cancer (BC) health service use over a 12-month period for patients joining the supported self-management (SSM)/patient-initiated follow-up (PIFU) pathway. METHODS: Participants completed questionnaires at baseline, 3, 6, 9 and 12 months that measured QoL (FACT-B, EQ 5D-5L), self-efficacy (GSE), psychological morbidity (GHQ-12), roles and responsibilities (PRRS) and service use (cost diary). RESULTS: 99/110 patients completed all timepoints; 32% (35/110) had received chemotherapy. The chemotherapy group had poorer QoL; FACT-B total score mean differences were 8.53 (95% CI: 3.42 to 13.64), 5.38 (95% CI: 0.17 to 10.58) and 8.00 (95% CI: 2.76 to 13.24) at 6, 9 and 12 months, respectively. The odds of psychological morbidity (GHQ12 >4) were 5.5-fold greater for those treated with chemotherapy. Financial and caring burdens (PRRS) were worse for this group (mean difference in change at 9 months 3.25 (95% CI: 0.42 to 6.07)). GSE and GHQ-12 scores impacted FACT-B total scores, indicating QoL decline for those with high baseline psychological morbidity. Chemotherapy patients or those with high psychological morbidity or were unable to carry out normal activities had the highest service costs. Over the 12 months, 68.2% participants phoned/emailed breast care nurses, and 53.3% visited a hospital breast clinician. CONCLUSION: The data suggest that chemotherapy patients and/or those with heightened psychological morbidity might benefit from closer monitoring and/or supportive interventions whilst on the SSM/PIFU pathway. Reduced access due to COVID-19 could have affected service use.

The association of stressful life events on weight loss efforts among African American breast cancer survivors.

OBJECTIVE: This study examined whether stressful life events were associated with weight loss, central adiposity, and health behavior changes of African American breast cancer survivors (AABCS) participating in a weight loss intervention. METHODS: We conducted a secondary-data analyses of Moving Forward, a weight loss efficacy trial for AABCS conducted in 2011-2014. Two-hundred forty-six eligible women were randomized to a 6-month interventionist-guided (IG) or self-guided (SG) weight loss intervention. Data was collected on height, weight, self-reported diet, and self-reported physical activity. Stress (e.g., financial, legal, employment, relationships, safety, prejudice) was measured using an abbreviated version of the Crisis in Family Systems (CRISYS) urban life stress measure. Generalized linear models stratified by group examined the degree to which stress was associated with weight loss or changes in central adiposity, physical activity, and diet during the intervention (Months 1-6) or maintenance (Months 7 to 12) phases. RESULTS: Participants reported a median of 3.0 life stressors (range 0 to 22) mostly relating to relationships, safety concerns, and financial problems. In the IG group during the intervention phase, exposure to life stressors was not associated with weight loss (p = 0.15) or change in central adiposity (p = 0.69), physical activity (p = 0.15), or diet (p = 0.26). We found similar associations for the maintenance phase and in the SG group. CONCLUSION/IMPLICATIONS: Despite facing stress across a myriad of domains (e.g., relationships, safety, finances), AABCS were successful at initiating and maintaining behaviors to achieve weight loss, reductions in central adiposity, and behavioral changes. Future randomized controlled trials are warranted that include more strategies to address the challenges that AABCS face, to determine whether AABCS in particular might benefit from interventions that address barriers (e.g., stress management) to weight loss. Such strategies are critical for improving quality of life and lowering the risk of cancer recurrence.

Screening, assessment and management of perioperative malnutrition: a survey of UK practice.

BACKGROUND: Perioperative malnutrition is common and is associated with increased mortality, complications and healthcare costs. Patients having surgery for cancer and gastro-intestinal disease are at particular risk. It is a modifiable pre-operative risk factor and perioperative clinicians are well placed to identify those at risk and instigate interventions shown to improve outcome. Thus, we conducted a survey of Perioperative Medicine Leads with the aim of assessing the current provision of nutritional screening and intervention pathways in the UK. METHODS: Perioperative Medicine Leads registered with the Royal College of Anaesthetists were asked to complete an online survey exploring current practice in screening, assessment and management of malnutrition in the perioperative period. The survey included a mixture of open and closed questions, graded response questions and options for free text. Where a response was not received, departments were phoned directly and e-mails sent to non-responders. RESULTS: We received 121 completed questionnaires from 167 Perioperative Medicine Leads (response rate of 72.5%). Seventy respondents (57.9%) reported using the Malnutrition Universal Screening Tool to screen patients; however, only 61 (50.4%) referred patients at nutritional risk onto a dietitian. Sixty (49.6%) lacked confidence in local ability to identify and manage malnutrition perioperatively, with 28 (23.1%) reporting having a structured pathway for managing malnourished patients. One hundred eleven respondents (91.7%) agreed that malnutrition impacts on quality of life after surgery and 105 (86.8%) felt adopting a standard protocol would improve outcomes for patients. Those reporting a lack of confidence in dealing with malnutrition perioperatively cited a lack of organisational support, patients being seen too close to surgery and lack of clarity around responsibility as key reasons for difficulties in managing this group of patients. CONCLUSIONS: Malnutrition in the perioperative period is a modifiable risk factor which is common and results in increased morbidity for patients and increased cost to healthcare systems. This survey highlights areas of practice where perioperative clinicians can improve the assessment and management of patients at nutritional risk prior to elective surgery.

The use of bioelectrical impedance analysis to predict post-operative complications in adult patients having surgery for cancer: A systematic review.

BACKGROUND: Patients undergoing surgery for cancer are at particular risk of post-operative complications. The pre-operative period is an opportunity to identify and mitigate risk factors and improve outcome. Bioelectrical impedance analysis (BIA) may offer an additional means of identifying patients at risk of post-operative morbidity. AIMS: The aim of this systematic review was to assess the use of measures and estimates of body composition determined by BIA as markers of peri-operative risk in adult patients undergoing elective surgery for cancer. METHODS: This review was performed in accordance with the PRISMA guidelines. The electronic databases of MEDLINE, EMBASE, CINAHL, CENTRAL and the Web of Science were searched from inception. Studies of adult participants having elective surgery for cancer were included if participants underwent BIA in the peri-operative period and were assessed for post-operative complications. RESULTS: 2578 studies were identified, of which 12 were eligible for inclusion. In total the studies report data from 1508 subjects. Five studies examined phase angle or standardized phase angle, six examined derived measures and one examined both. Eight of the 12 demonstrated an association between phase angle and/or body composition and an increased risk of post-operative complications. CONCLUSIONS: Bioelectrical impedance analysis in the peri-operative period may be useful in predicting the risk of complications following elective cancer surgery. Phase angle more consistently demonstrates an association than derived estimates. Further high quality studies are needed and should report the raw impedance values, standardized phase angle and the equations used to derive body composition.

Treatment Experiences, Information Needs, Pain and Quality of Life in Men with Metastatic Castrate-resistant Prostate Cancer: Results from the EXTREQOL Study.

AIMS: Delaying progression, ameliorating symptoms and maintaining quality of life (QoL) are primary aims of treatment for metastatic castrate-resistant prostate cancer (mCRPC). Real-world rather than clinical trial data about symptoms and side-effects are sparse. In EXTREQOL, patients' QoL, pain and information needs were recorded during treatment. MATERIAL AND METHODS: Men with mCRPC from 20 UK cancer centres starting various systemic mCRPC treatments completed QoL, pain and information needs questionnaires at baseline, 3 and 6 months. RESULTS: In total, 132 patients were recruited. Overall QoL declined significantly by 6 months (Functional Assessment of Cancer Therapy-Prostate [FACT-P] mean = -3.89, 95% confidence interval -6.7 to -1.05, P = 0.007; Trial Outcome Index [TOI] analysis mean = -3.10, 95% confidence interval -5.34 to -0.83, P = 0.007). Those who came off novel therapy and remained on luteinising hormone-releasing hormone agonist therapy alone had worse scores than patients receiving concomitant chemotherapy (Prostate Concerns Subscale mean difference = -4.45, 95% confidence interval -7.06 to -1.83, P = 0.001; TOI mean difference = -5.62, 95% confidence interval -10.97 to -0.26, P = 0.040). At 3 and 6 months, men who reported pain at baseline improved (43%, 40%), but for others pain levels remained the same (45%, 42%) or worsened (13%, 18%). Information regarding supportive care was lacking throughout the period of time on the study. CONCLUSION: Most mCRPC treated patients experience reduced QoL and inadequate pain control. More help with pain management and better information provision regarding supportive care is warranted.

Do drugs offering only PFS maintain quality of life sufficiently from a patient's perspective? Results from AVALPROFS (Assessing the 'VALue' to patients of PROgression Free Survival) study.

PURPOSE: Trials of novel drugs used in advanced disease often show only progression-free survival or modest overall survival benefits. Hypothetical studies suggest that stabilisation of metastatic disease and/or symptom burden are worth treatment-related side effects. We examined this premise contemporaneously using qualitative and quantitative methods. METHODS: Patients with metastatic cancers expected to live > 6 months and prescribed drugs aimed at cancer control were interviewed: at baseline, at 6 weeks, at progression, and if treatment was stopped for toxicity. They also completed Functional Assessment of Cancer Therapy (FACT-G) plus Anti-Angiogenesis (AA) subscale questionnaires at baseline then monthly for 6 months. RESULTS: Ninety out of 120 (75%) eligible patients participated: 41 (45%) remained on study for 6 months, 36 progressed or died, 4 had treatment breaks, and 9 withdrew due to toxicity. By 6 weeks, 66/69 (96%) patients were experiencing side effects which impacted their activities. Low QoL scores at baseline did not predict a higher risk of death or dropout. At 6-week interviews, as the side effect severity increased, patients were significantly less inclined to view the benefit of cancer control as worthwhile (X2 = 50.7, P < 0.001). Emotional well-being initially improved from baseline by 10 weeks, then gradually returned to baseline levels. CONCLUSION: Maintaining QoL is vital to most patients with advanced cancer so minimising treatment-related side effects is essential. As side effect severity increased, drugs that controlled cancer for short periods were not viewed as worthwhile. Patients need to have the therapeutic aims of further anti-cancer treatment explained honestly and sensitively.

Pseudomonas floridensis sp. nov., a bacterial pathogen isolated from tomato.

An unusual fluorescent pseudomonad was isolated from tomato exhibiting leaf spot symptoms similar to bacterial speck. Strains were fluorescent, oxidase- and arginine-dihydrolase-negative, elicited a hypersensitive reaction on tobacco and produced a soft rot on potato slices. However, the strains produced an unusual yellow, mucoid growth on media containing 5 % sucrose that is not typical of levan. Based on multilocus sequence analysis using 16S rRNA, gap1, gltA, gyrB and rpoD, these strains formed a distinct phylogenetic group in the genus Pseudomonas and were most closely related to Pseudomonas viridiflava within the Pseudomonassyringae complex. Whole-genome comparisons, using average nucleotide identity based on blast, of representative strain GEV388T and publicly available genomes representing the genus Pseudomonas revealed phylogroup 7 P. viridiflava strain UASW0038 and P. viridiflava type strain ICMP 2848T as the closest relatives with 86.59 and 86.56 % nucleotide identity, respectively. In silico DNA-DNA hybridization using the genome-to-genome distance calculation method estimated 31.1 % DNA relatedness between GEV388T and P. viridiflava ATCC 13223T, strongly suggesting the strains are representatives of different species. These results together with Biolog GEN III tests, fatty acid methyl ester profiles and phylogenetic analysis using 16S rRNA and multiple housekeeping gene sequences demonstrated that this group represents a novel species member of the genus Pseudomonas. The name Pseudomonas floridensis sp. nov. is proposed with GEV388T (=LMG 30013T=ATCC TSD-90T) as the type strain.

Therapeutic aims of drugs offering only progression-free survival are misunderstood by patients, and oncologists may be overly optimistic about likely benefits.

PURPOSE: The use of novel and often expensive drugs offering limited survival benefit in advanced disease is controversial. Treatment recommendations are influenced by patient characteristics and trial data showing overall response rates (ORR), progression-free survival (PFS) and overall survival (OS). PFS is frequently the primary outcome in licencing studies. PATIENTS AND METHODS: As part of a longitudinal study Assessing the 'VALue' to patients of PROgression Free Survival (AVALPROFS), oncologists completed checklists at baseline following consultations with patients. Questions probed perceived clinical benefits of the drugs to populations in general. Patients completed study-specific interview schedules at baseline, 6 weeks into treatment, and at withdrawal due to toxicity or progression. Patients also completed tumour- and treatment-specific quality of life questionnaires monthly for their time in the study. Only baseline results are reported here. RESULTS: Thirty-two UK oncologists discussed management options with 90 patients with heterogeneous advanced cancers. Oncologists' estimates of medical benefit in general from treatment varied between 10 and 80 %. They expected 46/90 (51 %) of their patients to derive some clinical benefit from the prescribed treatment but were either unsure or expected none for 44/90 (49 %). Predictions of life expectancy were variable but 62 % (56/90) of patients were expected to survive longer with treatment. A majority of patients 51/90 (57 %) had 'no idea' or were 'unclear' what PFS meant and 45/90 (50 %) thought extension of life was the primary therapeutic aim of treatment. CONCLUSION: Discussions between doctors and patients with metastatic disease about future management plans and likely therapeutic gains are challenging. Factors influencing decisions about putative benefits of novel drugs are often applied inconsistently can be overly optimistic and may even contradict published data.

Klebsiella pneumoniae Liver Abscess and Metastatic Endophthalmitis.

Introduction. Klebsiella pneumoniae is a well-known cause of liver abscess. Higher rates of liver abscess associated with Klebsiella pneumoniae are seen in Taiwan. Metastatic endophthalmitis is a common complication associated with a poor prognosis despite aggressive therapy. Case Report. We report a case of a 67-year-old Korean female with Klebsiella pneumoniae liver abscess. The patient developed metastatic endophthalmitis and ultimately succumbed to her disease despite aggressive medical and surgical treatment. Conclusion. Dissemination of Klebsiella pneumoniae is associated with significant morbidity and mortality. Liver abscesses preferably should be treated with percutaneous drainage, but surgical treatment is needed in some cases. Metastatic spread to the eye is a common complication that must be treated aggressively with intravenous antibiotics and surgical intervention if necessary.

Systematic review and meta-analysis of immunohistochemical prognostic biomarkers in resected oesophageal adenocarcinoma.

BACKGROUND: Oesophageal adenocarcinoma (OAC) is one of the fastest rising malignancies with continued poor prognosis. Many studies have proposed novel biomarkers but, to date, no immunohistochemical markers of survival after oesophageal resection have entered clinical practice. Here, we systematically review and meta-analyse the published literature, to identify potential biomarkers. METHODS: Relevant articles were identified via Ovid medline 1946-2013. For inclusion, studies had to conform to REporting recommendations for tumor MARKer (REMARK) prognostic study criteria. The primary end-point was a pooled hazard ratio (HR) and variance, summarising the effect of marker expression on prognosis. RESULTS: A total of 3059 articles were identified. After exclusion of irrelevant titles and abstracts, 214 articles were reviewed in full. Nine molecules had been examined in more than one study (CD3, CD8, COX-2, EGFR, HER2, Ki67, LgR5, p53 and VEGF) and were meta-analysed. Markers with largest survival effects were COX-2 (HR=2.47, confidence interval (CI)=1.15-3.79), CD3 (HR=0.51, 95% CI=0.32-0.70), CD8 (HR=0.55, CI=0.31-0.80) and EGFR (HR=1.65, 95% CI=1.14-2.16). DISCUSSION: Current methods have not delivered clinically useful molecular prognostic biomarkers in OAC. We have highlighted the paucity of good-quality robust studies in this field. A genome-to-protein approach would be better suited for the development and subsequent validation of biomarkers. Large collaborative projects with standardised methodology will be required to generate clinically useful biomarkers.

High division of the spinal accessory nerve and communication with a C2 branch of the cervical plexus: a previously unreported anatomical variant.

Anatomical variations of the spinal accessory nerve are well known. We describe a previously unreported variant in which the nerve divided high in level II after crossing the internal jugular vein and before entering the sternomastoid muscle. Both branches were joined by a communication from the C2 cervical root. We discuss the clinical implications of this finding.

Incidence of venous thromboembolism in elective foot and ankle surgery with and without aspirin prophylaxis.

The incidence of deep-vein thrombosis (DVT) and pulmonary embolism (PE) is thought to be low following foot and ankle surgery, but the routine use of chemoprophylaxis remains controversial. This retrospective study assessed the incidence of symptomatic venous thromboembolic (VTE) complications following a consecutive series of 2654 patients undergoing elective foot and ankle surgery. A total of 1078 patients received 75 mg aspirin as routine thromboprophylaxis between 2003 and 2006 and 1576 patients received no form of chemical thromboprophylaxis between 2007 and 2010. The overall incidence of VTE was 0.42% (DVT, 0.27%; PE, 0.15%) with 27 patients lost to follow-up. If these were included to create a worst case scenario, the overall VTE rate was 1.43%. There was no apparent protective effect against VTE by using aspirin. We conclude that the incidence of VTE following foot and ankle surgery is very low and routine use of chemoprophylaxis does not appear necessary for patients who are not in the high risk group for VTE.

Worsening severity of vitamin D deficiency is associated with increased length of stay, surgical intensive care unit cost, and mortality rate in surgical intensive care unit patients.

BACKGROUND: Vitamin D deficiency is the most common nutritional deficiency in the United States. It is seldom measured or recognized, and rarely is treated, particularly in critically ill patients. The purpose of this study was to investigate the prevalence and impact of vitamin D deficiency in surgical intensive care unit patients. We hypothesized that severe vitamin D deficiency increases the length of stay, mortality rate, and cost in critically ill patients admitted to surgical intensive care units. METHODS: We performed a prospective observational study of vitamin D status on 258 consecutive patients admitted to the Surgical Intensive Care Unit at Grady Memorial Hospital between August 2009 and January 2010. Vitamin D levels (25 [OH]2 vitamin-D3) were measured by high-pressure liquid chromatography and tandem mass spectrometry. Vitamin D deficiency was defined as follows: severe deficiency was categorized as less than 13 ng/mL; moderate deficiency was categorized as 14 to 26 ng/mL; mild deficiency was categorized as 27 to 39 ng/mL; and normal levels were categorized as greater than 40 ng/mL. RESULTS: Of the 258 patients evaluated, 70.2% (181) were men, and 29.8% (77) were women; 57.6% (148) were African American and 32.4% (109) were Caucasian. A total of 138 (53.5%) patients had severe vitamin D deficiency, 96 (37.2%) had moderate deficiency, 18 (7.0%) had mild deficiency, and 3 (1.2%) of the patients had normal vitamin D levels. The mean length of stay in the Surgical Intensive Care Unit for the severe vitamin D-deficient group was 13.33 ± 19.5 days versus 7.29 ± 15.3 days and 5.17 ± 6.5 days for the moderate and mild vitamin D-deficient groups, respectively, which was clinically significant (P = .002). The mean treatment cost during the patient stay in the surgical intensive care unit was $51,413.33 ± $75,123.00 for the severe vitamin D-deficient group, $28,123.65 ± $59,752.00 for the moderate group, and $20,414.11 ± $25,714.30 for the mild vitamin D-deficient group, which also was clinically significant (P = .027). More importantly, the mortality rate for the severe vitamin D-deficient group was 17 (12.3%) versus 11 (11.5%) in the moderate group (P = .125). Because no deaths occurred in the mildly or normal vitamin D-deficient groups, we compared the mortality rate between severe/moderate and mild/normal vitamin D groups (P = .047). CONCLUSIONS: In univariate analysis, severe and moderate vitamin D deficiency was related inversely to the length of stay in the surgical intensive care unit (r = .194; P = .001), related inversely to surgical intensive care unit treatment cost (r = .194; P = .001) and mortality (r = .125; P = .023), compared with the mild vitamin D-deficient group, after adjusting for age, sex, race, and comorbidities (myocardial infarctions, acute renal failure, and pneumonia); the length of stay, surgical intensive care unit cost, and mortality remained significantly associated with vitamin D deficiency.

An audit of rubella IgG antibody status in antenatal women in a NHS Trust over 5 years (2005-2009).

Rubella, a vaccine-preventable infection. This study examined the antibody status of 11 987 pregnant women during 2005-2009. Results showed a non-significant decrease in those with antibody levels of <4·0 IU/ml from 29/2312 (1·3%) in 2005 to 21/2447 (0·9%) in 2009 (χ² for linear trend=0·279, P=0·56) but a significant increase in those with levels of <10 IU/ml from 88/2312 (3·8%) in 2005 to 124/2447 (5·1%) in 2009 (χ² for linear trend=10·27, P=0·001). In women born before 1983 (pre-pubertal vaccination) the proportion of first pregnancies with titres <4 IU was 1·1% (21/2002) compared to 3·4% (69/2022) in those born after 1983 (χ²=25·176, P<0·0001) and 2·2% (44/2002) for titres <10 IU compared to 14·0% (282/2022) for those born after 1983 (χ²=171·43, P<0·0001). The potential impact of the increase is difficult to determine, requiring further monitoring. This paper discusses the effect of changing immunization programmes on rubella susceptibility in pregnant women.

Familial glucocorticoid resistance caused by a novel frameshift glucocorticoid receptor mutation.

CONTEXT: Familial glucocorticoid resistance is a rare condition with a typical presentation of women with hirsutism and hypertension, with or without hypokalemia. OBJECTIVE: The aim was to determine the cause of apparent glucocorticoid resistance in a young woman. PATIENTS AND METHODS: We studied a family with a novel glucocorticoid receptor (GR) mutation and a surprisingly mild phenotype. Their discovery resulted from serendipitous measurement of serum cortisol with little biochemical or clinical evidence for either hyperandrogenism or mineralocorticoid excess. RESULTS: The causative mutation was identified as a frameshift mutation in exon 6. Transformed peripheral blood lymphocytes were generated to analyze GR expression in vitro. Carriers of the mutation had less full-length GR, but the predicted mutant GR protein was not detected. However, this does not exclude expression in vivo, and so the mutant GR (Δ612GR) was expressed in vitro. Simple reporter gene assays suggested that Δ612GR has dominant negative activity. Δ612GR was not subject to ligand-dependent Ser211 phosphorylation or to ligand-dependent degradation. A fluorophore-tagged construct showed that Δ612GR did not translocate to the nucleus in response to ligand and retarded translocation of the wild-type GR. These data suggest that Δ612GR is not capable of binding ligand and exerts dominant negative activity through heterodimerization with wild-type GR. CONCLUSION: Therefore, we describe a novel, naturally occurring GR mutation that results in familial glucocorticoid resistance. The mutant GR protein, if expressed in vivo, is predicted to exert dominant negative activity by impairing wild-type GR nuclear translocation.

Interferon-inducible factor 16 is a novel modulator of glucocorticoid action.

Previously, we used cDNA expression profiling to identify genes associated with glucocorticoid (Gc) sensitivity. We now identify which of these directly influence Gc action. Interferon-inducible protein 16 (IFI16), bone morphogenetic protein receptor type II (BMPRII), and regulator of G-protein signaling 14 (RGS14) increased Gc transactivation, whereas sialyltransferase 4B (SIAT4B) had a negative effect. Amyloid beta (A4) precursor-protein binding, family B, member 1 (APBB1/Fe65) and neural cell expressed developmentally down-regulated 9 (NEDD9) were without effect. Only IFI16 potentiated Gc repression of NF-kappaB. In addition, IFI16 affected basal expression, and Gc induction of endogenous target genes. IFI16 did not affect glucocorticoid receptor (GR) expression, ligand-dependent repression of GR expression, or the ligand-dependent induction of GR phosphorylation on Ser-211 or Ser-203. Coimmunoprecipitation revealed an interaction, suggesting that IFI16 modulation of GR function is mediated by protein crosstalk. Transfection analysis with GR mutants showed that the ligand-binding domain of GR binds IFI16 and is the target domain for IFI16 regulation. Analysis of human lung sections identified colocalization of GR and IFI16, suggesting a physiologically relevant interaction. We demonstrate that IFI16 is a novel modulator of GR function and show the importance of analyzing variation in Gc sensitivity in humans, using appropriate technology, to drive discovery.

Thiazolidinediones are partial agonists for the glucocorticoid receptor.

Although thiazolidinediones were designed as specific peroxisome proliferator-activated receptor (PPAR)-gamma-ligands, there is evidence for some off-target effects mediated by a non-PPARgamma mechanism. Previously we have shown that rosiglitazone has antiinflammatory actions not explicable by activation of PPARgamma,but possibly by the glucocorticoid receptor (GR). Rosiglitazone induces nuclear translocation both of GR-green fluorescent protein, and endogenous GR in HeLa and U20S cells but with slower kinetics than dexamethasone. Rosiglitazone also induces GR phosphorylation (Ser211), a GR ligand-binding-specific effect. Rosiglitazone drives luciferase expression from a simple glucocorticoid-response element containing reporter gene in a GR-dependent manner (EC50 4 microm), with a similar amplitude response to the partial GR agonist RU486. Rosiglitazone also inhibits dexamethasone-driven reporter gene activity (IC50 2.9 microm) in a similar fashion to RU486, suggesting partial agonist activity. Importantly we demonstrate a similar effect in PPARgamma-null cells, suggesting both GR dependence and PPARgamma independence. Rosiglitazone also activates a GAL4-GR chimera, driving a upstream activating sequence promoter, demonstrating DNA template sequence independence and furthermore enhanced steroid receptor coactivator-1-GR interaction, measured by a mammalian two-hybrid assay. Both ciglitazone and pioglitazone, structurally related to rosiglitazone, show similar effects on the GR. The antiproliferative effect of rosiglitazone is increased in U20S cells that overexpress GR, suggesting a biologically important GR-dependent component of rosiglitazone action. Rosiglitazone is a partial GR agonist, affecting GR activation and trafficking to influence engagement of target genes and affect cell function. This novel mode of action may explain some off-target effects observed in vivo. Additionally, antagonism of glucocorticoid action may contribute to the antidiabetic actions of rosiglitazone.