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1.  The microstructure of collagen type I gel cross-linked with gold nanoparticles 
Scanning electron microscopy, transmission electron micrsocopy, rheomerty, and electrochemistry were used to provide insight into the microstructure of collagen type I gel (1% w/v) modified with the tiopronin-protected (N-(2-mercaptopropionyl)glycine) gold nanoparticles (TPAu), a multivalent crosslinker. The cross-linking reaction, performed via EDC (1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide) coupling, results in compliant, mechanically stable and continuous gels. The gels contain unusual interconnected collagen-TPAu particles. Electrochemical measurements of 4-hydroxy-(2,2,6,6-tetramethylpiperidine-1-oxyl) (4HT) diffusion within the gel reveal that the gel hindrance is nearly independent of the TPAu concentration. The properties of the collagen-TPAu gel make it suitable for potential biomedical applications, such as delivery of small molecule drugs.
PMCID: PMC3508363  PMID: 22796781
2.  Environmental Xenobiotics and the Antihormones Cyproterone Acetate and Spironolactone Use the Nuclear Hormone Pregnenolone X Receptor to Activate the CYP3A23 Hormone Response Element 
Molecular pharmacology  1998;54(6):1113-1117.
The pregnenolone X receptor (PXR), a new member of the nuclear hormone receptor superfamily, was recently demonstrated to mediate glucocorticoid agonist and antagonist activation of a hormone response element spaced by three nucleotides (DR-3) within the rat CYP3A23 promoter. Because many other steroids and xenobiotics can up-regulate CYP3A23 expression, we determined whether some of these other regulators used PXR to activate the CYP3A23 DR-3. Transient cotransfection of LLC-PK1 cells with (CYP3A23)2-tk-CAT and mouse PXR demonstrated that the organochlorine pesticides transnonachlor and chlordane and the nonplanar polychlorinated biphenyls (PCBs) each induced the CYP3A23 DR-3 element, and this activation required PXR. Additionally, this study found that PXR is activated to induce (CYP3A23)2-tk-CAT by antihormones of several steroid classes including the antimineralocorticoid spironolactone and the antiandrogen cyproterone acetate. These studies reveal that PXR is involved in the induction of CYP3A23 by pharmacologically and structurally distinct steroids and xenobiotics. Moreover, PXR-mediated PCB activation of the (CYP3A23)2-tk-CAT may serve as a rapid assay for effects of nonplanar PCBs.
PMCID: PMC3662300  PMID: 9855641
3.  Transporter-Mediated Protection Against Thiopurine-Induced Hematopoietic Toxicity 
Cancer Research  2008;68(13):4983-4989.
Thiopurines are effective immunosuppressants and anticancer agents, but intracellular accumulation of their active metabolites (6-thioguanine nucleotides, 6-TGNs) causes dose-limiting hematopoietic toxicity. Thiopurine S-methyltransferase (TPMT) deficiency is known to exacerbate thiopurine toxicity. However, many patients are highly sensitive to thiopurines for unknown reasons. We show that Mrp4 is abundant in myeloid progenitors and tested the role of the multidrug-resistance protein 4 (Mrp4), an ATP binding cassette (ATP) transporter of monophosphorylated nucleosides, in this unexplained thiopurine sensitivity. Mrp4-deficient mice experienced Mrp4 gene dosage–dependent toxicity caused by accumulation of 6-TGNs in their myelopoietic cells. Therefore, Mrp4 protects against thiopurine-induced hematopoietic toxicity by actively exporting thiopurine nucleotides. We then identified a single-nucleotide polymorphism (SNP) in human MRP4 (rs3765534) that dramatically reduces MRP4 function by impairing its cell membrane localization. This SNP is common (>18%) in the Japanese population and indicates that the increased sensitivity of some Japanese patients to thiopurines may reflect the greater frequency of this MRP4 SNP.
PMCID: PMC3323115  PMID: 18593894
4.  Defective glucagon secretion after intrahepatic but not non-hepatic islet autotransplantation 
Defective glucagon secretion during hypoglycemia after islet transplantation has been reported in animals and humans with type 1 diabetes. To ascertain whether this is true of islets from non-diabetic humans, subjects with autoislet transplantation in the intrahepatic site only (TP/IAT-H) or in intrahepatic plus non-hepatic (TP/IAT-H+NH) sites were studied. Glucagon responses were examined during stepped hypoglycemic clamps. Glucagon and symptom responses during hypoglycemia were virtually absent in subjects who received islets in the hepatic site only (glucagon increment over baseline = 1 +/− 6, pg/ml, mean +/− SE, n = 9, p = ns; symptom score = 1 +/− 1, p=ns). When islets were transplanted in both intrahepatic + non-hepatic sites, glucagon and symptom responses were not significantly different than Control Subjects (TP/IAT-H+NH: glucagon increment = 54 +/− 14, n = 5; symptom score = 7 +/− 3; Control glucagon increment = 67 +/− 15, n = 5; symptom score = 8 +/− 1). In contrast, glucagon responses to intravenous arginine were present in TP/IAT-H recipients (TP/IAT: glucagon response = 37 +/− 8, n=7).). Transplantation of a portion of the islets into a non-hepatic site should be seriously considered in TP/IAT to avoid post-transplant abnormalities in glucagon and symptom responses to hypoglycemia.
PMCID: PMC4440232  PMID: 25039984
Autoislets; defective glucagon secretion
5.  RC3H1 post-transcriptionally regulates A20 mRNA and modulates the activity of the IKK/NF-κB pathway 
Nature Communications  2015;6:7367.
The RNA-binding protein RC3H1 (also known as ROQUIN) promotes TNFα mRNA decay via a 3′UTR constitutive decay element (CDE). Here we applied PAR-CLIP to human RC3H1 to identify ∼3,800 mRNA targets with >16,000 binding sites. A large number of sites are distinct from the consensus CDE and revealed a structure-sequence motif with U-rich sequences embedded in hairpins. RC3H1 binds preferentially short-lived and DNA damage-induced mRNAs, indicating a role of this RNA-binding protein in the post-transcriptional regulation of the DNA damage response. Intriguingly, RC3H1 affects expression of the NF-κB pathway regulators such as IκBα and A20. RC3H1 uses ROQ and Zn-finger domains to contact a binding site in the A20 3′UTR, demonstrating a not yet recognized mode of RC3H1 binding. Knockdown of RC3H1 resulted in increased A20 protein expression, thereby interfering with IκB kinase and NF-κB activities, demonstrating that RC3H1 can modulate the activity of the IKK/NF-κB pathway.
The RNA-binding protein RC3H1/ROQUIN1 promotes the degradation of mRNA by binding to a consensus CDE present in the 3′UTR. Here the authors expand the set of consensus sequences through which RCH31 binds and regulates mRNA encoding members of the DNA damage response and IKK/NF-κB pathway.
PMCID: PMC4510711  PMID: 26170170
6.  The External Quality Assurance Oversight Laboratory (EQAPOL) Proficiency Program for IFN-gamma Enzyme-Linked ImmunoSpot (IFN-γ ELISpot) assay 
The Interferon-gamma Enzyme-Linked ImmunoSpot (IFN-γ ELISpot) assay has been developed and used as an end-point assay in clinical trials for infectious diseases and cancer to detect the magnitude of antigen-specific immune responses. The ability to compare data generated by different laboratories across organizations is pivotal to understand the relative potency of different therapeutic and vaccine strategies. We developed an external proficiency program for the IFN-γ ELISpot assay that evaluates the laboratory performance based on five parameters: timeliness for data reporting; ability to handle cellular samples; detection of background (non-specific) responses; accuracy to consensus of the results; and precision of the measurements. Points are awarded for each criterion, and the sum of the points is used to determine a numeric and adjectival performance rating. Importantly, the evaluation of the accuracy to the consensus mean for the detection of antigen-specific responses using laboratory-specific procedures informs each laboratory and its sponsor on the degree of concordance of its results with those obtained by other laboratories. This study will ultimately provide the scientific community with information on how to organize and implement an external proficiency program to evaluate longitudinally the performance of the participating laboratories and, therefore, fulfill the requirements of the GCLP guidelines for laboratories performing end-point IFN-γ ELISpot assay for clinical trials.
PMCID: PMC4138255  PMID: 24685833
7.  PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator–dependent autoimmunity 
PRKDC encodes for DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a kinase that forms part of a complex (DNA-dependent protein kinase [DNA-PK]) crucial for DNA double-strand break repair and V(D)J recombination. In mice DNA-PK also interacts with the transcription factor autoimmune regulator (AIRE) to promote central T-cell tolerance.
We sought to understand the causes of an inflammatory disease with granuloma and autoimmunity associated with decreasing T- and B-cell counts over time that had been diagnosed in 2 unrelated patients.
Genetic, molecular, and functional analyses were performed to characterize an inflammatory disease evocative of a combined immunodeficiency.
We identified PRKDC mutations in both patients. These patients exhibited a defect in DNA double-strand break repair and V(D)J recombination. Whole-blood mRNA analysis revealed a strong interferon signature. On activation, memory T cells displayed a skewed cytokine response typical of TH2 and TH1 but not TH17. Moreover, mutated DNA-PKcs did not promote AIRE-dependent transcription of peripheral tissue antigens in vitro. The latter defect correlated in vivo with production of anti–calcium-sensing receptor autoantibodies, which are typically found in AIRE-deficient patients. In addition, 9 months after bone marrow transplantation, patient 1 had Hashimoto thyroiditis, suggesting that organ-specific autoimmunity might be linked to nonhematopoietic cells, such as AIRE-expressing thymic epithelial cells.
Deficiency of DNA-PKcs, a key AIRE partner, can present as an inflammatory disease with organ-specific autoimmunity, suggesting a role for DNA-PKcs in regulating autoimmune responses and maintaining AIRE-dependent tolerance in human subjects.
PMCID: PMC4487867  PMID: 25842288
Autoimmune regulator; tolerance; DNA-dependent protein kinase catalytic subunit; PRKDC; autoimmunity; VDJ recombination; severe combined immunodeficiency; recombination-activating gene
8.  Self-Directed Weight Loss Strategies: Energy Expenditure Due to Physical Activity Is Not Increased to Achieve Intended Weight Loss 
Nutrients  2015;7(7):5868-5888.
Reduced physical activity and almost unlimited availability of food are major contributors to the development of obesity. With the decline of strenuous work, energy expenditure due to spontaneous physical activity has attracted increasing attention. Our aim was to assess changes in energy expenditure, physical activity patterns and nutritional habits in obese subjects aiming at self-directed weight loss. Methods: Energy expenditure and physical activity patterns were measured with a portable armband device. Nutritional habits were assessed with a food frequency questionnaire. Results: Data on weight development, energy expenditure, physical activity patterns and nutritional habits were obtained for 105 patients over a six-month period from an initial cohort of 160 outpatients aiming at weight loss. Mean weight loss was −1.5 ± 7.0 kg (p = 0.028). Patients with weight maintenance (n = 75), with substantial weight loss (>5% body weight, n = 20) and with substantial weight gain (>5% body weight, n = 10) did not differ in regard to changes of body weight adjusted energy expenditure components (total energy expenditure: −0.2 kcal/kg/day; non-exercise activity thermogenesis: −0.3 kcal/kg/day; exercise-related activity thermogenesis (EAT): −0.2 kcal/kg/day) or patterns of physical activity (duration of EAT: −2 min/day; steps/day: −156; metabolic equivalent unchanged) measured objectively with a portable armband device. Self-reported consumption frequency of unfavorable food decreased significantly (p = 0.019) over the six-month period. Conclusions: An increase in energy expenditure or changes of physical activity patterns (objectively assessed with a portable armband device) are not employed by obese subjects to achieve self-directed weight loss. However, modified nutritional habits could be detected with the use of a food frequency questionnaire.
PMCID: PMC4517033  PMID: 26193310
self-directed weight loss; energy expenditure; physical activity pattern; nutritional habits
9.  Associations of physical activity with depressiveness and coping in subjects with high-grade obesity aiming at bariatric surgery: a cross-sectional study 
Reduced physical activity is supposed to be associated with depressiveness and more passive coping patterns. For further evaluation of this assumed relation we studied energy expenditure due to physical activity - usually referred to as activity thermogenesis (AT) - together with depressiveness (clinical diagnosis, depression module of the Patient Health Questionnaire), and coping behaviours (Brief COPE Inventory) in 50 patients with high-grade obesity (42 ± 12 years; 9 with II° and 41 with III° obesity) aiming at bariatric surgery.
AT was assessed with a portable armband device (SenseWear™ armband). Depressiveness and coping were assessed using validated questionnaires.
Weight-adjusted non-exercise AT and intensity of physical activity (metabolic equivalent) correlated inversely with body mass index (non-exercise AT: r = −0.32, P < 0.05; mean metabolic equivalent: r = −0.37, P < 0.01) but not with depressiveness. The coping strategies “support coping” and “active coping” showed significant inverse correlations to a) weight-adjusted non-exercise AT (“support coping”: r = −0.34, P < 0.05; “active coping”: r = −0.36, P < 0.05), b) weight-adjusted exercise-related AT (“support coping”: r = −0.36, P < 0.05; “active coping”: r = −0.38, P < 0.01) and c) intensity of physical activity (for mean metabolic equivalent: “support coping”: r = −0.38, P < 0.01; “active coping”: r = −0.40, P < 0.01; for duration of exercise-related AT: “support coping”: r = −0.36, P < 0.05; “active coping”: r = −0.38, P < 0.01).
AT was not associated with depressiveness. Furthermore, supposed adaptive coping strategies of individuals aiming at bariatric surgery were negatively associated with AT.
PMCID: PMC4479107  PMID: 26110016
Bariatric surgery; Coping; Depression; Obesity; Physical activity
10.  Clinical trial simulation methods for estimating the impact of DPP-4 inhibitors on cardiovascular disease 
Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral antidiabetic agents for the treatment of type 2 diabetes mellitus, which lower blood glucose without causing severe hypoglycemia. However, the first cardiovascular (CV) safety trials have only recently reported their results, and our understanding of these therapies remains incomplete. Using clinical trial simulations, we estimated the effectiveness of DPP-4 inhibitors in preventing major adverse cardiovascular events (MACE) in a population like that enrolled in the SAVOR-TIMI (the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus – Thrombolysis in Myocardial Infarction) 53 trial.
We used the Archimedes Model to simulate a clinical trial of individuals (N=11,000) with diagnosed type 2 diabetes and elevated CV risk, based on established disease or multiple risk factors. The DPP-4 class was modeled with a meta-analysis of HbA1c and weight change, pooling results from published trials of alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin. The study treatments were added-on to standard care, and outcomes were tracked for 20 years.
The DPP-4 class was associated with an HbA1c drop of 0.66% (0.71%, 0.62%) and a weight drop of 0.14 (−0.07, 0.36) kg. These biomarker improvements produced a relative risk (RR) for MACE at 5 years of 0.977 (0.968, 0.986). The number needed to treat to prevent one occurrence of MACE at 5 years was 327 (233, 550) in the elevated CV risk population.
Consistent with recent trial publications, our analysis indicates that DPP-4 inhibitors do not increase the risk of MACE relative to the standard of care. This study provides insights about the long-term benefits of DPP-4 inhibitors and supports the interpretation of the published CV safety trial results.
PMCID: PMC4462855  PMID: 26089691
cardiovascular; DPP-4 inhibitors; simulation
11.  Risk factors and Outcomes of Infections Caused by Extremely Drug-Resistant Gram-Negative Bacilli in Patients Hospitalized in Intensive Care Units 
Extremely drug-resistant gram-negative bacilli (XDR-GNB) increasingly cause healthcare-associated infections (HAIs) in intensive care units (ICUs).
A matched case-control (1:2) study was conducted from February 2007 to January 2010 in 16 ICUs. Case and control subjects had HAIs caused by GNB susceptible to ≤1 antibiotic versus ≥2 antibiotics, respectively. Logistic and Cox proportional hazards regression assessed risk factors for HAIs and predictors of mortality, respectively.
Overall, 103 case and 195 control subjects were enrolled. An immunocompromised state (OR=1.55, p=0.047) and exposure to amikacin (OR=13.81, p<0.001), levofloxacin (OR=2.05, p=0.005), or trimethoprim-sulfamethoxazole (OR=3.42, p=0.009) were factors associated with XDR-GNB HAIs. Multiple factors in both case and control subjects significantly predicted increased mortality at different time intervals after HAI diagnosis. At 7 days, liver disease (Hazard Ratio [HZ]=5.52), immunocompromised state (HR=3.41), and bloodstream infection (HR=2.55) predicted mortality; at 15 days, age (HR=1.02 per year increase), liver disease (HR=3.34), and immunocompromised state (HR 2.03) predicted mortality; and at 30 days, age (HR=1.02 per one year increase), liver disease (HR=3.34), immunocompromised state (HR=2.03), and hospitalization in a medical ICU (HR=1.85) predicted mortality.
HAIs caused by XDR-GNB were associated with potentially modifiable factors. Age, liver disease, and immunocompromised state, but not XDR-GNB HAIs, were associated with mortality.
PMCID: PMC4083852  PMID: 24725516
12.  The metaphyseal bone defect in distal radius fractures and its implication on trabecular remodeling—a histomorphometric study (case series) 
The invention of the locking plate technology leads to alterations of treatment strategies at metaphyseal fracture sites with the concept of spontaneous remodeling of trabecular bone voids. Whereas trabecular regeneration has been proven in experimental animal studies, no histologic data exist on human fracture healing with special emphasis on bone voids.
In order to qualify the trabecular bone remodeling capacity in vivo, bone specimens from the metaphyseal bone void were analyzed 14 months after trauma using quantitative histomorphometry. Twenty-five patients with an unstable dorsally displaced distal radius fracture were fixed with a palmar locking plate without additional bone graft or substitute. At implant removal, specimens from the previous compression void were harvested with a trephine in a volar-dorsal direction. In 16 patients, histomorphometric analysis could be performed, comparing the dorsal trabecular network with the volar, non-compressed ultrastructure.
Significant differences for bone volume/total volume (BV/TV), trabecular number (TbN) and trabecular separation (TbSp), but not for trabecular thickness (TbTh) and osteoid volume/total volume (OV/TV), were detected. Neither patient age, defect size nor gender had a significant influence on bone remodeling.
The results of this study indicate that trabecular bone remodeling does not lead to pre-trauma bone quality in metaphyseal bone compression voids following reduction and application of a locking plate.
PMCID: PMC4429963  PMID: 25956925
Distal radius fracture; Bone void; Trabecular ultrastructure; Histomorphometry
13.  Procalcitonin and pyuria-based algorithm reduces antibiotic use in urinary tract infections: a randomized controlled trial 
BMC Medicine  2015;13:104.
Urinary tract infections (UTIs) are common drivers of antibiotic use. The minimal effective duration of antibiotic therapy for UTIs is unknown, but any reduction is important to diminish selection pressure for antibiotic resistance, costs, and drug-related side-effects. The aim of this study was to investigate whether an algorithm based on procalcitonin (PCT) and quantitative pyuria reduces antibiotic exposure.
From April 2012 to March 2014, we conducted a factorial design randomized controlled open-label trial. Immunocompetent adults with community-acquired non-catheter-related UTI were enrolled in the emergency department of a tertiary-care 600-bed hospital in northwestern Switzerland. Clinical presentation was used to guide initiation and duration of antibiotic therapy according to current guidelines (control group) or with a PCT-pyuria-based algorithm (PCT-pyuria group).
The primary endpoint was overall antibiotic exposure within 90 days. Secondary endpoints included duration of the initial antibiotic therapy, persistent infection 7 days after end of therapy and 30 days after enrollment, recurrence and rehospitalizations within 90 days.
Overall, 394 patients were screened, 228 met predefined exclusion criteria, 30 declined to participate, and 11 were not eligible. Of these, 125 (76% women) were enrolled in the intention-to-treat (ITT) analysis and 96 patients with microbiologically confirmed UTI constituted the per protocol group; 84 of 125 (67%) patients had a febrile UTI, 28 (22%) had bacteremia, 5 (4%) died, and 3 (2%) were lost to follow-up. Overall antibiotic exposure within 90 days was shorter in the PCT-pyuria group than in the control group (median 7.0 [IQR, 5.0–14.0] vs. 10.0 [IQR, 7.0–16.0] days, P = 0.011) in the ITT analysis. Mortality, rates of persistent infections, recurrences, and rehospitalizations were not different.
A PCT-pyuria-based algorithm reduced antibiotic exposure by 30% when compared to current guidelines without apparent negative effects on clinical outcomes.
Trial registration
Current controlled trials ISRCTN13663741, date applied: 22/05/2012, date assigned: 03/07/2012, last edited: 28/01/2014.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-015-0347-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4427918  PMID: 25934044
Antibiotic stewardship; Biomarker; Procalcitonin; Urinary tract infection
21.  Procalcitonin Improves the Glasgow Prognostic Score for Outcome Prediction in Emergency Patients with Cancer: A Cohort Study 
Disease Markers  2015;2015:795801.
The Glasgow Prognostic Score (GPS) is useful for predicting long-term mortality in cancer patients. Our aim was to validate the GPS in ED patients with different cancer-related urgency and investigate whether biomarkers would improve its accuracy. We followed consecutive medical patients presenting with a cancer-related medical urgency to a tertiary care hospital in Switzerland. Upon admission, we measured procalcitonin (PCT), white blood cell count, urea, 25-hydroxyvitamin D, corrected calcium, C-reactive protein, and albumin and calculated the GPS. Of 341 included patients (median age 68 years, 61% males), 81 (23.8%) died within 30 days after admission. The GPS showed moderate prognostic accuracy (AUC 0.67) for mortality. Among the different biomarkers, PCT provided the highest prognostic accuracy (odds ratio 1.6 (95% confidence interval 1.3 to 1.9), P < 0.001, AUC 0.69) and significantly improved the GPS to a combined AUC of 0.74 (P = 0.007). Considering all investigated biomarkers, the AUC increased to 0.76 (P < 0.001). The GPS performance was significantly improved by the addition of PCT and other biomarkers for risk stratification in ED cancer patients. The benefit of early risk stratification by the GPS in combination with biomarkers from different pathways should be investigated in further interventional trials.
PMCID: PMC4377367  PMID: 25861154
22.  Osmotic pressure induced tensile forces in tendon collagen 
Nature Communications  2015;6:5942.
Water is an important component of collagen in tendons, but its role for the function of this load-carrying protein structure is poorly understood. Here we use a combination of multi-scale experimentation and computation to show that water is an integral part of the collagen molecule, which changes conformation upon water removal. The consequence is a shortening of the molecule that translates into tensile stresses in the range of several to almost 100 MPa, largely surpassing those of about 0.3 MPa generated by contractile muscles. Although a complete drying of collagen would be relevant for technical applications, such as the fabrication of leather or parchment, stresses comparable to muscle contraction already occur at small osmotic pressures common in biological environments. We suggest, therefore, that water-generated tensile stresses may play a role in living collagen-based materials such as tendon or bone.
Water is an important component of collagen in tendons, bone and extracellular matrix, but its role in the mechanical function of protein is poorly understood. Here, the authors study the effects of osmotic pressure on contraction in collagen, suggesting that collagen could function as a mechanical actuator.
PMCID: PMC4354200  PMID: 25608644
23.  Prognostic value of procalcitonin in respiratory tract infections across clinical settings 
Critical Care  2015;19(1):74.
Whether the inflammatory biomarker procalcitonin provides prognostic information across clinical settings and different acute respiratory tract infections (ARIs) is poorly understood. In the present study, we investigated the prognostic value of admission procalcitonin levels to predict adverse clinical outcome in a large ARI population.
We analysed data from 14 trials and 4,211 ARI patients to study associations of admission procalcitonin levels and setting specific treatment failure and mortality alone at 30 days. We used multivariable hierarchical logistic regression and conducted sensitivity analyses stratified by clinical settings and ARI diagnoses to assess the results’ consistency.
Overall, 864 patients (20.5%) experienced treatment failure and 252 (6.0%) died. The ability of procalcitonin to differentiate patients with from those without treatment failure was highest in the emergency department setting (treatment failure area under the curve (AUC): 0.64 (95% confidence interval (CI): 0.61, 0.67), adjusted odds ratio (OR): 1.85 (95% CI: 1.61, 2.12), P <0.001; and mortality AUC: 0.67 (95% CI: 0.63, 0.71), adjusted OR: 1.82 (95% CI: 1.45, 2.29), P <0.001). In lower respiratory tract infections, procalcitonin was a good predictor of identifying patients at risk for mortality (AUC: 0.71 (95% CI: 0.68, 0.74), adjusted OR: 2.13 (95% CI: 1.82, 2.49), P <0.001). In primary care and intensive care unit patients, no significant association of initial procalcitonin levels and outcome was found.
Admission procalcitonin levels are associated with setting specific treatment failure and provide the most prognostic information regarding ARI in the emergency department setting.
PMCID: PMC4383063  PMID: 25887979
24.  Prostaglandin signaling regulates ciliogenesis by modulating intraflagellar transport 
Nature cell biology  2014;16(9):841-851.
Cilia are microtubule-based organelles that mediate signal transduction in a variety of tissues. Despite their importance, the signaling cascades that regulate cilia formation remain incompletely understood. Here we report that prostaglandin signaling affects ciliogenesis by regulating anterograde intraflagellar transport (IFT). Zebrafish leakytail (lkt) mutants display ciliogenesis defects, and lkt locus encodes an ATP-binding cassette transporter (ABCC4). We show that Lkt/ABCC4 localizes to the cell membrane and exports prostaglandin E2 (PGE2), a function that is abrogated by the Lkt/ABCC4T804M mutant. PGE2 synthesis enzyme Cyclooxygenase-1 and its receptor, EP4, which localizes to the cilium and activates cAMP-mediated signaling cascade, are required for cilia formation and elongation. Importantly, PGE2 signaling increases anterograde but not retrograde velocity of IFT and promotes ciliogenesis in mammalian cells. These findings lead us to propose that Lkt/ABCC4-mediated PGE2 signaling acts through a ciliary G-protein-coupled receptor, EP4, to upregulate cAMP synthesis and increase anterograde IFT, thereby promoting ciliogenesis.
PMCID: PMC4154319  PMID: 25173977
25.  Cyclic Nucleotide Compartmentalization: Contributions of Phosphodiesterases and ATP-Binding Cassette Transporters 
Cyclic nucleotides [e.g., cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP)] are ubiquitous second messengers that affect multiple cell functions from maturation of the egg to cell division, growth, differentiation, and death. The concentration of cAMP can be regulated by processes within membrane domains (local regulation) as well as throughout a cell (global regulation). The phosphodiesterases (PDEs) that degrade cAMP have well-known roles in both these processes. It has recently been discovered that ATP-binding cassette (ABC) transporters contribute to both local and global regulation of cAMP. This regulation may require the formation of macromolecular complexes. Some of these transporters are ubiquitously expressed, whereas others are more tissue restricted. Because some PDE inhibitors are also ABC transporter inhibitors, it is conceivable that the therapeutic benefits of their use result from the combined inhibition of both PDEs and ABC transporters. Deciphering the individual contributions of PDEs and ABC transporters to such drug effects may lead to improved therapeutic benefits.
PMCID: PMC4303346  PMID: 23072381
CFTR; cAMP; efflux; export; MRP4

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