Bacterial pseudaminic acid binding to Siglec-10 induces a macrophage interleukin-10 response and suppresses phagocytosis.

Pseudaminic acid (Pse) on pathogenic bacteria exopolysaccharide engages with the sialic acid-binding immunoglobulin-type lectin (Siglec)-10 receptor on macrophages via the critical 7-N-acetyl group. This binding stimulates macrophages to secrete interleukin 10 that suppresses phagocytosis against bacteria, but can be reverted by blocking Pse-Siglec-10 interaction with Pse-binding protein as a promising therapy.

Klebsiella pneumoniae K2 capsular polysaccharide degradation by a bacteriophage depolymerase does not require trimer formation.

K2-capsular Klebsiella pneumoniae is a hypervirulent pathogen that causes fatal infections. Here, we describe a phage tailspike protein, named K2-2, that specifically depolymerizes the K2 capsular polysaccharide (CPS) of K. pneumoniae into tetrasaccharide repeating units. Nearly half of the products contained O-acetylation, which was thought crucial to the immunogenicity of CPS. The product-bound structures of this trimeric enzyme revealed intersubunit carbohydrate-binding grooves, each accommodating three tetrasaccharide units of K2 CPS. The catalytic residues and the key interactions responsible for K2 CPS recognition were identified and verified by site-directed mutagenesis. Further biophysical and functional characterization, along with the structure of a tetrameric form of K2-2, demonstrated that the formation of intersubunit catalytic center does not require trimerization, which could be nearly completely disrupted by a single-residue mutation in the C-terminal domain. Our findings regarding the assembly and catalysis of K2-2 provide cues for the development of glycoconjugate vaccines against K. pneumoniae infection. IMPORTANCE: Generating fragments of capsular polysaccharides from pathogenic bacteria with crucial antigenic determinants for vaccine development continues to pose challenges. The significance of the C-terminal region of phage tailspike protein (TSP) in relation to its folding and trimer formation remains largely unexplored. The polysaccharide depolymerase described here demonstrates the ability to depolymerize the K2 CPS of K. pneumoniae into tetrasaccharide fragments while retaining the vital O-acetylation modification crucial for immunogenicity. By carefully characterizing the enzyme, elucidating its three-dimensional structures, conducting site-directed mutagenesis, and assessing the antimicrobial efficacy of the mutant enzymes against K2 K. pneumoniae, we offer valuable insights into the mechanism by which this enzyme recognizes and depolymerizes the K2 CPS. Our findings, particularly the discovery that trimer formation is not required for depolymerizing activity, challenge the current understanding of trimer-dependent TSP activity and highlight the catalytic mechanism of the TSP with an intersubunit catalytic center.

A lectin from Crenomytilus grayanus as a probe for the detection of widespread cancerous and metastatic cells.

A novel Gal-binding lectin from mussels (Crenomytilus grayanus, CGL) with 6 binding sites in the dimeric structure has been previously shown to have antifungal, anticancer, and antibacterial activities. In this study, a glycan array was used to confirm that CGL recognizes a range of non-reducing end α- or ß-linked Gal glycans on normal cells but not sialic acid-capped glycans. This finding suggests that CGL has potential in the tumor detection due to the hyper-sialylation present in cell surface glycans from cancer cells. To evaluate the feasibility of this possibility, we labeled CGL with biotin and then mixed it with streptavidin-horseradish peroxidase (HRP) to create a CGL-biotin-SP complex as a probe for use in enzyme-linked lectin assays. CGL-biotin-SP successfully distinguished not only HeLa cells and de-sialylated HeLa cells that mimic normal cell surface glycans but also lung and breast cancer cells with different metastatic abilities. This work provides the insights into a new Gal-binding lectin by establishing its specificity and also demonstrates practical applications in cancer diagnosis greater than other reported lectins.

Structural and biological insights into Klebsiella pneumoniae surface polysaccharide degradation by a bacteriophage K1 lyase: implications for clinical use.

BACKGROUND: K1 capsular polysaccharide (CPS)-associated Klebsiella pneumoniae is the primary cause of pyogenic liver abscesses (PLA) in Asia. Patients with PLA often have serious complications, ultimately leading to a mortality of ~ 5%. This K1 CPS has been reported as a promising target for development of glycoconjugate vaccines against K. pneumoniae infection. The pyruvylation and O-acetylation modifications on the K1 CPS are essential to the immune response induced by the CPS. To date, however, obtaining the fragments of K1 CPS that contain the pyruvylation and O-acetylation for generating glycoconjugate vaccines still remains a challenge. METHODS: We analyzed the digested CPS products with NMR spectroscopy and mass spectrometry to reveal a bacteriophage-derived polysaccharide depolymerase specific to K1 CPS. The biochemical and biophysical properties of the enzyme were characterized and its crystal structures containing bound CPS products were determined. We also performed site-directed mutagenesis, enzyme kinetic analysis, phage absorption and infectivity studies, and treatment of the K. pneumoniae-infected mice with the wild-type and mutant enzymes. RESULTS: We found a bacteriophage-derived polysaccharide lyase that depolymerizes the K1 CPS into fragments of 1-3 repeating trisaccharide units with the retention of the pyruvylation and O-acetylation, and thus the important antigenic determinants of intact K1 CPS. We also determined the 1.46-Å-resolution, product-bound crystal structure of the enzyme, revealing two distinct carbohydrate-binding sites in a trimeric ß-helix architecture, which provide the first direct evidence for a second, non-catalytic, carbohydrate-binding site in bacteriophage-derived polysaccharide depolymerases. We demonstrate the tight interaction between the pyruvate moiety of K1 CPS and the enzyme in this second carbohydrate-binding site to be crucial to CPS depolymerization of the enzyme as well as phage absorption and infectivity. We also demonstrate that the enzyme is capable of protecting mice from K1 K. pneumoniae infection, even against a high challenge dose. CONCLUSIONS: Our results provide insights into how the enzyme recognizes and depolymerizes the K1 CPS, and demonstrate the potential use of the protein not only as a therapeutic agent against K. pneumoniae, but also as a tool to prepare structurally-defined oligosaccharides for the generation of glycoconjugate vaccines against infections caused by this organism.

A hexasaccharide from capsular polysaccharide of carbapenem-resistant Klebsiella pneumoniae KN2 is a ligand of Toll-like receptor 4.

Klebsiella pneumoniae serotype KN2 is a carbapenem-resistant strain and leads to the health care-associated infections, such as bloodstream infections. Its capsular polysaccharide (CPS) was isolated and cleaved by a specific enzyme from a bacteriophage into a hexasaccharide-repeating unit. With GC-MS, NMR, and Mass analyses, the structure of KN2 CPS was determined to be {→3)-ß-D-Glcp-(1→3)-[α-D-GlcpA-(1→4)-ß-D-Glcp-(1→6)]-α-D-Galp-(1→6)-ß-D-Galp-(1→3)-ß-D-Galp-(1→}n. We demonstrated that 1 µg/mL CPS could stimulate J774A.1 murine macrophages to release tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in vitro. Also, we proved that KN2 CPS induced the immune response through Toll-like receptor 4 (TLR4) in the human embryonic kidney (HEK)-293 cells. Strikingly, the hexasaccharide alone shows the same immune response as the CPS, suggesting that the hexasaccharide can shape the adaptive immunity to be a potential vaccine adjuvant. The glucuronic acid (GlcA) on other polysaccharides can affect the immune response, but the GlcA-reduced KN2 CPS and hexasaccharide still maintain their immunomodulatory activities.

A GalNAc/Gal-specific lectin modulates immune responses via toll-like receptor 4 independently of carbohydrate-binding ability.

Toll-like receptor 4 (TLR4) recognizes various protein ligands; however, the protein-TLR4 binding model is unclear. Here we demonstrate a Crenomytilus grayanus lectin (CGL)-TLR4/MD2 model to show that CGL interacts with a TLR4/myeloid differentiation factor 2 (MD2) complex independently of sugar-binding properties. CGL could suppress lipopolysaccharide-induced immune responses significantly, suggesting that TLR4 itself has potential as a therapeutic target.

In vitro and in vivo activities of imipenem combined with BLI-489 against class D ß-lactamase-producing Acinetobacter baumannii.

BACKGROUND: According to our preliminary study, BLI-489 has the potential to inhibit the hydrolysing activity of OXA-51-like ß-lactamase produced by carbapenem-resistant Acinetobacter baumannii (CRAb). OBJECTIVES: In the present study, the in vitro and in vivo activities of imipenem combined with BLI-489 against CRAb producing carbapenem-hydrolysing class D ß-lactamases (CHDLs), namely OXA-23, OXA-24, OXA-51 and OXA-58, were determined. METHODS: A chequerboard analysis of imipenem and BLI-489 was performed using 57 and 7 clinical CRAb isolates producing different CHDLs and MBLs, respectively. Four representative strains harbouring different CHDL genes were subjected to a time-kill assay to evaluate the synergistic effects. An in silico docking analysis was conducted to simulate the interactions between BLI-489 and the different families of CHDLs. The in vivo activities of this combination were assessed using a Caenorhabditis elegans survival assay and a mouse pneumonia model. RESULTS: Chequerboard analysis showed that imipenem and BLI-489 had a synergistic effect on 14.3, 92.9, 100, 16.7 and 100% of MBL-, OXA-23-, OXA-24-like-, OXA-51-like- and OXA-58-producing CRAb isolates, respectively. In the time-kill assay, imipenem and BLI-489 showed synergy against OXA-24-like-, OXA-51-like- and OXA-58-, but not OXA-23-producing CRAb isolates after 24 h. The in silico docking analysis showed that BLI-489 could bind to the active sites of OXA-24 and OXA-58 to confer strong inhibition activity. The combination of imipenem and BLI-489 exhibited synergistic effects for the rescue of CRAb-infected C. elegans and mice. CONCLUSIONS: Imipenem combined with BLI-489 has synergistic effects against CHDL-producing CRAb isolates.

Bacteriophage Tail-Spike Proteins Enable Detection of Pseudaminic-Acid-Coated Pathogenic Bacteria and Guide the Development of Antiglycan Antibodies with Cross-Species Antibacterial Activity.

Pseudaminic acid (Pse), a unique carbohydrate in surface-associated glycans of pathogenic bacteria, has pivotal roles in virulence. Owing to its significant antigenicity and absence in mammals, Pse is considered an attractive target for vaccination or antibody-based therapies against bacterial infections. However, a specific and universal probe for Pse, which could also be used in immunotherapy, has not been reported. In a prior study, we used a tail spike protein from a bacteriophage (ΦAB6TSP) that digests Pse-containing exopolysaccharide (EPS) from Acinetobacter baumannii strain 54149 (Ab-54149) to form a glycoconjugate for preparing anti-Ab-54149 EPS serum. We report here that a catalytically inactive ΦAB6TSP (I-ΦAB6TSP) retains binding ability toward Pse. In addition, an I-ΦAB6TSP-DyLight-650 conjugate (Dy-I-ΦAB6TSP) was more sensitive in detecting Ab-54149 than an antibody purified from anti- Ab-54149 EPS serum. Dy-I-ΦAB6TSP also cross-reacted with other pathogenic bacteria containing Pse on their surface polysaccharides (e.g., Helicobacter pylori and Enterobacter cloacae), revealing it to be a promising probe for detecting Pse across bacterial species. We also developed a detection method that employs I-ΦAB6TSP immobilized on microtiter plate. These results suggested that the anti-Ab-54149 EPS serum would exhibit cross-reactivity to Pse on other organisms. When this was tested, this serum facilitated complement-mediated killing of H. pylori and E. cloacae, indicating its potential as a cross-species antibacterial agent. This work opens new avenues for diagnosis and treatment of multidrug resistant (MDR) bacterial infections.

Pseudaminic Acid on Exopolysaccharide of Acinetobacter baumannii Plays a Critical Role in Phage-Assisted Preparation of Glycoconjugate Vaccine with High Antigenicity.

Pseudaminic acid (Pse) has been known for participating in crucial bacterial virulence and thus is an attractive target in the development of glycoconjugate vaccine. Particularly, this therapeutic alternative was suggested to be a potential solution against antibiotic resistant Acinetobacter baumannii that poses a serious global health threat. Also, Pse was found to be involved in the exopolysaccharide (EPS) of mild antibiotic resistant A. baumannii strain 54149 ( Ab-54149) of which specific glycosyl linkage can be depolymerized by phage ΦAB6 tailspike protein (ΦAB6TSP). In this study, we found that the antibodies induced by Ab-54149 EPS was capable of recognizing a range of EPS of other clinical A. baumannii strains, and deemed as a great potential material for vaccination. To efficiently acquire homogeneous EPS-derived oligosaccharide with significant immunogenic activity for the production of glycoconjugate, we used the ΦAB6TSP for the fragmentation of Ab-54149 EPS instead of chemical methods. Moreover, insight into the ligand binding characterization of ΦAB6TSP suggested the branched Pse on the Ab-54149 EPS served as a recognition site of ΦAB6TSP. The serum boosted by ΦAB6TSP-digested product and carrier protein CRM197 conjugate complex displayed specific sensitivity toward Ab-54149 EPS with bacterial killing activity. Strikingly, Pse is an ideal epitope with strong antigenicity, profiting the application of the probe for pathogen detection and glyco-based vaccine.

Structural basis for fragmenting the exopolysaccharide of Acinetobacter baumannii by bacteriophage ΦAB6 tailspike protein.

With an increase in antibiotic-resistant strains, the nosocomial pathogen Acinetobacter baumannii has become a serious threat to global health. Glycoconjugate vaccines containing fragments of bacterial exopolysaccharide (EPS) are an emerging therapeutic to combat bacterial infection. Herein, we characterize the bacteriophage ΦAB6 tailspike protein (TSP), which specifically hydrolyzed the EPS of A. baumannii strain 54149 (Ab-54149). Ab-54149 EPS exhibited the same chemical structure as two antibiotic-resistant A. baumannii strains. The ΦAB6 TSP-digested products comprised oligosaccharides of two repeat units, typically with stoichiometric pseudaminic acid (Pse). The 1.48-1.89-Å resolution crystal structures of an N-terminally-truncated ΦAB6 TSP and its complexes with the semi-hydrolyzed products revealed a trimeric ß-helix architecture that bears intersubunit carbohydrate-binding grooves, with some features unusual to the TSP family. The structures suggest that Pse in the substrate is an important recognition site for ΦAB6 TSP. A region in the carbohydrate-binding groove is identified as the determinant of product specificity. The structures also elucidated a retaining mechanism, for which the catalytic residues were verified by site-directed mutagenesis. Our findings provide a structural basis for engineering the enzyme to produce desired oligosaccharides, which is useful for the development of glycoconjugate vaccines against A. baumannii infection.

A Multivalent Marine Lectin from Crenomytilus grayanus Possesses Anti-cancer Activity through Recognizing Globotriose Gb3.

In this study, we report the structure and function of a lectin from the sea mollusk Crenomytilus grayanus collected from the sublittoral zone of Peter the Great Bay of the Sea of Japan. The crystal structure of C. grayanus lectin (CGL) was solved to a resolution of 1.08 Å, revealing a ß-trefoil fold that dimerizes into a dumbbell-shaped quaternary structure. Analysis of the crystal CGL structures bound to galactose, galactosamine, and globotriose Gb3 indicated that each CGL can bind three ligands through a carbohydrate-binding motif involving an extensive histidine- and water-mediated hydrogen bond network. CGL binding to Gb3 is further enhanced by additional side-chain-mediated hydrogen bonds in each of the three ligand-binding sites. NMR titrations revealed that the three binding sites have distinct microscopic affinities toward galactose and galactosamine. Cell viability assays showed that CGL recognizes Gb3 on the surface of breast cancer cells, leading to cell death. Our findings suggest the use of this lectin in cancer diagnosis and treatment.

Parity, age at first birth and risk of death from kidney cancer: a population-based cohort study in Taiwan.

BACKGROUND: This study was undertaken to examine whether there is an association between parity and age at first birth and risk of kidney cancer. METHODS: The study cohort consisted of 1 292 462 women who had a first and singleton childbirth between 1 January 1978 and 31 December 1987. We tracked each woman from the time of her first childbirth to 31 December 2009, and their vital status was ascertained by linking records with the computerized mortality database. Cox proportional hazard regression models were used to estimate the hazard ratios (HRs) of death from kidney cancer associated with parity and age at first birth. RESULTS: There were 95 kidney cancer deaths during 34,980,246 person-years of follow-up. The mortality rate of kidney cancer was 0.27 cases per 100,000 person-years. The adjusted HR was 1.88 [95% confidence interval (CI) 1.10-3.19] for women who gave birth between 24 and 26 years of age and 2.52 (95% CI 1.44-4.40) for women who gave birth after 26 years of age, when compared with women who gave birth when <23 years of age. A trend of increasing risk of kidney cancer was seen with increasing age at first birth. The adjusted HR was 0.88 (95% CI 0.49-1.59) for women who had two children and 0.89 (95% CI 0.47-1.67) for women with three or more births, when compared with women who had given birth to only one child. CONCLUSION: This study is the first to suggest that early age at first birth may confer a protective effect on the risk of kidney cancer.

The risk of upper gastrointestinal bleeding in patients treated with hemodialysis: a population-based cohort study.

BACKGROUND: There are no prior studies that have estimated the risk of upper gastrointestinal bleeding (UGIB) among the dialysis population relative to the general population. The aim of this study was to examine the risk of UGIB among end-stage renal disease (ESRD) patients during a 6-year period following their initiation of hemodialysis (HD) therapy in Taiwan- a country with the highest incidence of ESRD in the world, using general population as an external comparison group. METHODS: Data were obtained from the Taiwan National health Insurance Research Database. In total, 796 patients who were beginning HD between 1999 and 2003 were recruited as the study cohort and 3,184 patients matched for age and sex were included as comparison cohort. Multivariate Cox proportional hazard regression models were used to adjust for confounding and to compare the 6-year UGIB-free survival rate between these two cohorts. RESULTS: The incidence rate of UGIB (42.01 per 1000 person-year) was significantly higher in the HD cohort than in the control cohort (27.39 per 1000 person-years). After adjusting for potential confounders, the adjusted hazard ratios for UGIB during the 6-year follow-up periods for HD patients was 1.27 (95% CI=1.03-1.57) compared to patients in the comparison cohort. CONCLUSIONS: We conclude that HD patients were at an increased risk for UGIB compared with the general population.

Statin use and the risk of bladder cancer: a population-based case-control study.

OBJECTIVE: The aim of this study was to investigate whether the use of statins is associated with bladder cancer risk. METHODS: The authors conducted a population-based case-control study in Taiwan. Cases consisted of all patients who were aged 50 years and older and had a first-time diagnosis of bladder cancer, for the period between 2004 and 2010. The controls were matched to cases by age, sex and index date. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by using multiple logistic regression. RESULTS: The authors examined 325 bladder cancer cases and 1300 controls. The unadjusted ORs for any statin prescription was 0.94 (95% CI 0.70 - 1.28) and the adjusted OR was 0.88 (95% CI 0.61 - 1.25). Compared with no use of statins, the adjusted ORs were 0.72 (95% CI 0.40 - 1.28) for the group having been prescribed statins with cumulative defined daily dose (DDDs) below 56 DDDs, 0.81 (95% CI 0.46 - 1.43) for the group with cumulative dose between 56 DDDs and 196 DDDs, and 1.11 (95% CI 0.67 - 1.85) for the group with cumulative statin use of 196 DDDs or more. CONCLUSIONS: The present data do not provide evidence to support either beneficial or harmful associations between statin use and bladder cancer risk.

Statin use and the risk of kidney cancer: a population-based case-control study.

OBJECTIVE: To investigate whether the use of statins was associated with kidney cancer risk. METHODS: We conducted a population-based case-control study in Taiwan. Cases consisted of all patients who were aged 50 years and older, and had a first-time diagnosis of kidney cancer for the period between 2005 and 2009. The controls were matched to cases by age, sex, and index date. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by using multiple logistic regression. RESULTS: We examined 177 kidney cancer cases and 708 controls. The adjusted OR for any statin prescription was 1.08 (95% CI = 0.70 - 1.67). Compared with no use of statins, the adjusted ORs were 0.91 (95% CI = 0.50 - 1.63) for the group having been prescribed statins with cumulative defined daily dose (DDDs) below 105 and 1.28 (95% CI = 0.73 - 2.23) for the group with cumulative statin use of 105 DDDs or more. CONCLUSIONS: The present data do not provide evidence to support either beneficial or harmful associations between statin use and kidney cancer risk. However, there is a trend of increased kidney cancer risk with higher cumulative DDDs, and consequently that it is prudent to continue monitoring cancer incidence among long-standing statin users.

Statin use and the risk of gallstone disease: a population-based case-control study.

OBJECTIVE: The aim of this study was to investigate whether the use of statins was associated with a decreased risk of gallstone disease. METHODS: We conducted a population-based case-control study in Taiwan. Cases consisted of all patients who were aged 50 years and older and had a first-time diagnosis of gallstone disease or cholecystectomy for the period between 2005 and 2009. The controls were matched to cases by age, sex and index date. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by using multiple logistic regression. RESULTS: We examined 1014 gallstone disease cases and 1014 controls. The unadjusted ORs for any statin prescription was 1.06 (95% CI 0.86 to 1.29), and the adjusted OR was 1.14 (95% CI 0.90 to 1.43). Compared with no use of statins, the adjusted ORs were 1.05 (95% CI 0.72 to 1.54) for the group having been prescribed statins with cumulative defined daily doses (DDDs) below 41.53, 1.12 (95% CI 0.84 to 1.50) for the group with cumulative dose between 41.54 and 334.81 DDD, and 1.30 (95% CI 0.86 to 1.95) for the group with cumulative statin use of 334.81 DDDs or more. CONCLUSIONS: This study does not provide support for a beneficial association between usage of statin and gallstone disease.

Risk of herpes zoster in patients treated with long-term hemodialysis: a matched cohort study.

BACKGROUND: The risk of herpes zoster in the dialysis population relative to the general population is not known. The aim of this study was to perform a population-based cohort study to investigate the risk of herpes zoster after the initiation of hemodialysis therapy in patients with end-stage renal disease (ESRD) in Taiwan, a country with the highest incidence of ESRD in the world. STUDY DESIGN: Matched cohort study. SETTING & PARTICIPANTS: Data were obtained from the Taiwan National Health Insurance Research Database. 843 patients who were beginning hemodialysis therapy in 1999-2003 were included as the study cohort and 3,372 patients without ESRD matched for age and sex were included as a comparison cohort. A multivariate frailty Cox proportional hazard regression model was used to adjust for confounding and compare the 6-year herpes zoster-free survival rate between these 2 cohorts. PREDICTORS: Hemodialysis. OUTCOMES: Herpes zoster. RESULTS: Mean years of follow-up were 4.73 and 5.49 for the hemodialysis and comparison cohorts, respectively. 868 patients developed herpes zoster throughout the study period, 294 from the hemodialysis cohort and 574 from the comparison cohort. The incidence rate of herpes zoster (73.34 events/1,000 person-year) was significantly higher in the hemodialysis cohort than in the control cohort (31.03 events/1,000 person-years). After adjusting for potential confounders, the adjusted HR of herpes zoster was 1.98 (95% CI, 1.72-2.27). LIMITATIONS: We expect that some patients with mild zoster chose not to seek medical help. CONCLUSIONS: We conclude that patients treated with long-term hemodialysis are at an increased risk of herpes zoster compared with the general population.

Analgesic use and the risk for progression of chronic kidney disease.

PURPOSE: The chronic effect of various analgesics on the progression of chronic kidney disease (CKD) is inconclusive. There is also lack of information on the renal safety of selective cyclooxygenase-2 (COX-2) inhibitors. This study aimed to clarify the renal risk of analgesic use in CKD patients. METHODS: A cohort study using a nationally representative database randomly sampled from National Health Insurance (NHI) enrollees was performed. The study population included a total of 19,163 newly diagnosed CKD patients. Clinical conditions were defined by diagnostic codes and exposure information on analgesics was derived from service claims. Cox proportional hazard model was used to assess the association between analgesic use and the risk of progression to end stage renal disease (ESRD). RESULTS: CKD patients using acetaminophen, aspirin, and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) had an increased risk for ESRD with multivariable-adjusted HRs (95%CIs) of 2.92 (2.47-3.45), 1.96 (1.62-2.36), and 1.56 (1.32-1.85), respectively. The trends toward higher risk with increasing exposure dose were significant for all classes of analgesics (all P for trend < 0.001). Among COX-2 inhibitors, only rofecoxib, but not celecoxib, shows a significant risk association with ESRD (HR = 1.98; 95%CI, 1.15-3.40). CONCLUSIONS: Our data indicated exacerbating effects of acetaminophen, aspirin, and non-selective NSAIDs on CKD in a dose-dependent manner. For COX-2 inhibitors, only rofecoxib showed an increased risk for ESRD. Although the possibility of residual confounding cannot be completely ruled out, given the common use of analgesics, the possible relation suggested by this study warrants further investigation.

Air pollution and hospital admissions for congestive heart failure: are there potentially sensitive groups?

Recent studies have shown that air pollution is a risk factor for hospitalization for congestive heart failure (CHF). However, there is limited evidence to suggest what subpopulations are at greater risk from air pollution. This study was undertaken to examine the modifying effect of specific secondary diagnosis (including hypertension, diabetes, dysrhythmia, and chronic obstructive pulmonary disease) on the relationship between hospital admissions for CHF and ambient air pollutants. Hospital admissions for CHF and ambient air pollution data for Taipei were obtained for the period from 1996 to 2005. The relative risk of hospital admission was estimated using a case-crossover approach. None of the secondary diagnosis we examined (hypertension, diabetes, dysrhythmia, and chronic obstructive pulmonary disease (COPD)) showed much evidence of effect modification.

Air pollution and hospital admissions for congestive heart failure in a tropical city: Kaohsiung, Taiwan.

This study was undertaken to determine whether there was an association between air pollutant levels and hospital admissions for congestive heart failure (CHF) in Kaohsiung, Taiwan. Hospital admissions for CHF and ambient air pollution data for Kaohsiung were obtained for the period 1996-2004. The relative risk of hospital admission was estimated using a case-crossover approach, controlling for weather variables, day of the week, seasonality, and long-term time trends. In the single-pollutant models, on warm days (> 25 degrees C) statistically significant positive associations were found in all pollutants except sulfur dioxide (SO(2)). On cool days (< 25 degrees C), all pollutants were significantly associated with CHF admissions. For the two-pollutant model, CO and O(3) were significant in combination with each of the other four pollutants on warm days. On cool days, NO(2) remained statistically significant in all the two-pollutant models. This study provides evidence that higher levels of ambient air pollutants increase the risk of hospital admissions for CHF and that the effects of air pollutants on hospital admissions for CHF were temperature dependent.