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Urine output (UO) criterion may increase the sensitivity of the definition of acute kidney injury (AKI). We determined whether the empirically derived definition for oliguria (0.5 ml/kg/h) is independently associated with adverse outcome. Data analysis included hourly recorded UO from the prospective, multicenter FINNAKI study conducted in 16 Finnish intensive care units. Confounder-adjusted association of oliguria of different severity and duration primarily with the development of AKI defined by creatinine criterion (Cr-AKI) or renal replacement therapy (RRT) was assessed. Secondarily, we determined the association of oliguria with 90-day mortality. Of the 1966 patients analyzed for the development of AKI, 454 (23.1%) reached this endpoint. Within this AKI cohort, 312 (68.7%) developed Cr-AKI, 21 (4.6%) commenced RRT without Cr-AKI, and 121 (26.7%) commenced RRT with Cr-AKI. Episodes of severe oliguria (0.1 ml/kg/h) for more than 3 h were independently associated with the development of Cr-AKI or RRT. The shortest periods of consecutive oliguria independently associated with an increased risk for 90-day mortality were 6-12 h of oliguria from 0.3 to0.5 ml/kg/h, over 6 h of oliguria from 0.1 to0.3 ml/kg/h, and severe oliguria lasting over 3 h. Thus, our findings underlie the importance of hourly UO measurements.Kidney International advance online publication, 9 September 2015; doi:10.1038/ki.2015.269.

Background Interleukin-18 (IL-18) is a pro-inflammatory protein, which mediates ischaemic tubular injury, and has been suggested to be a sensitive and specific biomarker for acute kidney injury (AKI). The predictive value of IL-18 in the diagnosis, evolution, and outcome of AKI in critically ill patients is still unclear. Methods We measured urine IL-18 from critically ill patients at intensive care unit (ICU) admission and 24 h. We evaluated the association of IL-18 with developing new AKI, renal replacement therapy (RRT), and 90-day mortality. We calculated areas under receiver operating characteristics curves (AUCs), best cut-off values, and positive likelihood ratios (LR+) for IL-18 concerning these endpoints. Additionally, we compared the predictive value of IL-18 at ICU admission to that of urine neutrophil gelatinase-associated lipocalin (NGAL). Results In this study population of 1439 patients the highest urine IL-18 during the first 24 h in the ICU associated with the development of AKI with an AUC [95% confidence interval (CI)] of 0.586 (0.546–0.627) and with the development of Stage 3 AKI with an AUC (95% CI) of 0.667 (0.591–0.774). IL-18 predicted the initiation of RRT with an AUC (95% CI) of 0.655 (0.572–0.739), and 90-day mortality with an AUC (95% CI) of 0.536 (0.497–0.574). Conclusions IL-18 had poor-to-moderate ability to predict AKI, RRT, or 90-day mortality in this large cohort of critically ill patients. Thus, it should be used with caution for diagnostic or predictive purposes in the critically ill.

Induction of a polycyclic aromatic hydrocarbon-metabolizing cytochrome P450 isoform CYP1A1 is regulated by aromatic hydrocarbon receptor (AHR). High inducibility of CYP1A1, possibly due to genetic polymorphisms, has been considered to be a risk factor for lung cancer in tobacco smokers. The relationship between low or high pulmonary expression of CYP1A1 and polymorphic genotypes of CYP1A1 and AHR was investigated in 73 active smokers. CYP1A1 expression was determined in surgical lung samples by measuring ethoxyresorufin O-deethylase (EROD) activity and by immunostaining for CYP1A1 protein. The most common allelic variants of CYP1A1 and AHR in Finns, i.e. the MspI variant (CYP1A1*2A), I462V variant (CYP1A1*2B), and -459C to T variant of CYP1A1 and the R554K variant (AHR*2) of AHR were studied using polymerase chain reaction based methods. EROD activity correlated positively with the daily cigarette consumption (r = 0.45). There was additional variation in EROD activity independent of the amount of smoking e.g. among those who smoked one pack per day until the day of operation, EROD activity ranged from 4-142 (median 48) pmol/min/mg. The frequencies of the MspI, 462V, and -459T variant alleles of CYP1A1 and 554K variant allele of AHR were 0.158, 0.055, 0.055 and 0.075, respectively. No differences were observed in the frequencies of polymorphic genotypes between the smokers with low and those with high expression, when the relationship was studied using a regression analysis adjusted for cigarette consumption. Our results thus indicate that the interindividual variation of CYP1A1 levels in smokers' lung tissue is not attributable to genetic polymorphisms of CYP1A1 or AHR tested in this study.

SUMMARY Health promotion research is distinct in some respects from research within its contributing disciplines. A study was conducted in Finland to identify the special characteristics and distinctiveness of health promotion research, to develop a set of specific quality evaluation criteria for health promotion research, and to test the usefulness of such criteria in selecting research applications for funding. A wide range of discussions supplemented a systematic literature review with experts within and outside Finland. The review was conducted with regard to the content of health promotion, its basic principles, as well as theories and models used to steer practical health promotion activities. This resulted in a proposal for quality criteria for health promotion research. Key informants from Finnish universities and institutes evaluated the criteria in three Delphi rounds, and they were suitably revised. The utility of the revised criteria was tested using 31 research proposals. After further revision, the criteria were tested with a further 16 research proposals. Seven health promotion research quality criteria were developed by these methods, as were seven general criteria of research quality, applicable to all social research, whether in the health promotion arena or not. The 14 criteria will undergo continuous revision for improvement, but they are already at this stage thought to be suitable for use by (a) funding agencies in the design of calls for health promotion research proposals, and calls for tenders; (b) researchers who respond to calls for health promotion research proposals and/or calls for tenders; (c) evaluators and proposal review groups; and (d) reviewers and auditors of research progress.

Cytochrome P4501A1 (CYP1A1), which is involved in the metabolic activation of polycyclic aromatic hydrocarbon procarcinogens derived from tobacco smoke, is induced in the lung up to 100-fold because of tobacco smoking. Our aim was to study whether promoter methylation has any role in the smoking-associated expression of CYP1A1 in human lung. Methylation of CpG sites up to 1.4 kb upstream of CYP1A1 gene was studied first by sequencing. Because methylation was observed between nucleotides -1400 and -1000, a methylation-specific single-strand conformational polymorphism method was designed for the region between nucleotides -1411 and -1295 that contains five potential methylation sites, one of them at the xenobiotic responsive element core sequence. Single-strand conformational polymorphism was used on DNA from normal lung samples and peripheral WBCs of smokers and nonsmokers, and on human lung adenocarcinoma (A549) and bronchial epithelial (Beas-2B) cell lines. In lung tissue complete or partial methylation occurred in 33% of heavy smokers (15 cigarettes/day, n = 30), 71% of light smokers (or =15 cigarettes/day or quitted 1-7 days earlier, n = 42), and in 98% of nonsmokers (never and ex-smokers, n = 49). Methylation was found to increase in 1-7 days after quitting smoking. In active smokers the lack of methylation in the studied region of CYP1A1 promoter was associated with a slightly higher pulmonary 7-ethoxyresorufin O-deethylase activity in the regression models allowing for the daily tobacco consumption and age. No association was observed in WBC between methylation and tobacco smoking. In lung-derived cell lines the methylation remained stable regardless of induction with benzo(a)pyrene, but a higher induction was observed in Beas-2B cells, which also had less methylation than A549 cells. The association of tobacco smoking with CYP1A1 methylation in the lung suggests that promoter methylation is involved in the regulation of CYP1A1 induction in vivo.

The FHIT gene, at 3p14.2, has been suggested to form a molecular target to damage induced by human lung carcinogens. We examined aberrant expression of the Fhit protein and allele loss at the FHIT gene in a series of lung cancer cases, mainly of non-small cell carcinoma (NSCLC) histology. We had detailed data on tobacco smoke exposure and occupational asbestos exposure available for the cases. The principal aim of the present study was to investigate whether absent or reduced Fhit expression or FHIT allele loss was associated with exposure to these pulmonary carcinogens. We detected reduced Fhit expression in 62% (33/53) of the cases analysed. Prevalence of allele loss at the FHIT locus was 22% (20/89). Reduced protein expression was common both in the asbestos-exposed (67%) and non-exposed cases (59%); [odds ratio (OR) 1.4, 95% confidence interval (CI) 0.4-4.9]. LOH frequencies differed somewhat between the two groups and were 25% vs. 16%, respectively (OR 1.8; 95% CI 0.5-5.9). Absent or reduced expression was common in smokers, with no significant difference found between current smokers and non-smokers (mainly former smokers) (OR 1.4, 95% CI 0.5-4.5). NSCLCs with squamous cell histology exhibited both aberrant expression (OR 3.1, 95% CI 0.9-10.3) and allele loss (OR 3.3, 95% CI 0.9-12.7) more frequently than adenocarcinoma. Finally, we found that FHIT allele loss was increased in stage II or more advanced disease (OR 2.5, 95% CI 0.9-7.4), and in poorly differentiated tumours (grade 3, OR 2.6, 95% CI 0.8-8.1). In conclusion, our present data support significance of FHIT inactivation in development of lung cancer.

Background Hyperresponsiveness to inhaled non-infectious microbial particles (NIMPs) has been associated with illnesses in the airways. Hypersensitivity pneumonitis (HP) is considered to be the prototype for these NIMPs-related diseases; however, there is no consensus on the definitions or diagnostic criteria for HP and the spectrum of related illnesses. Methods and Findings In order to identify the possible diagnostic markers for illnesses associated with NIMPs in alveolar lining fluid, we performed a proteomic analysis using a two-dimensional difference gel electrophoresis on bronchoalveolar lavage (BAL) fluid from patients with exposure to NIMPs in the context of damp building-related illness (DBRI) or conditions on the borderline to acute HP, designated here as agricultural type of microbial exposure (AME). Samples from patients with HP and sarcoidosis (SARC) were included for reference. Results were compared to results of healthy subjects (CTR). Western blot was used for validation of potential marker proteins from BAL fluid and plasma. Protein expression patterns suggest a close similarity between AME and HP, while DBRI was similar to CTR. However, in DBRI the levels of the inflammation associated molecules galectin-3 and alpha-1-antitrypsin were increased. A novel finding emerging from this study was the increases of semenogelin levels in BAL fluid from patients with AME, HP and SARC. Histone 4 levels were increased in AME, HP and SARC. Elevated plasma levels of histone 2B were detected in HP and SARC, suggesting it to be a potential blood indicator for inflammatory diseases of the lungs. Conclusions In this study, the proteomic changes in bronchoalveolar lavage of DBRI patients were distinct from other NIMP exposure associated lung diseases, while changes in AME overlapped those observed for HP patient samples. Some of the proteins identified in this study, semenogelin and histone 4, could function as diagnostic markers for differential diagnosis between DBRI and HP-like conditions.

Asbestos, a group of naturally occurring mineral fibers, is a significant lung carcinogen. Exposure to asbestos fibers induces the formation of reactive oxygen species in cells and, subsequently, DNA double-strand breaks (DSBs), the most serious form of DNA damage related to transformation of cells. As a part of the DNA damage response, H2AX histone variant molecules are phosphorylated at ser139, producing γH2AX foci at the site of DSBs, and these serve as a docking site for DNA repair molecule complexes. Thereby, γH2AX foci are considered a sensitive marker for DSBs. DNA damage response has not thoroughly been investigated in particle carcinogenesis. Here, we studied fiber-induced DSB formation in two human lung epithelial cell lines, the cancer cell line A549 and the transformed cell line BEAS-2B to provide further knowledge on DNA damage associated with fiber exposure as a risk factor for lung cancer.A sub-lethal asbestos fiber concentration of 2 μg /cm2 was determined, by cell viability tests, as suitable for working with the A549 and BEAS-2B cells. Then, we studied the kinetics of fiber induced DSB formation in terms of H2AX phosphorylation. Foci of γH2AX can be detected using specific antibody in immunocytochemistry assays. A549 and BEAS-2B cells were exposed to asbestos fibers for 4, 24 and 48 h, and γH2AX foci were counted. Concurrent non-exposed control cultures were settled at each time point. At 4 h, the control group displayed remarkable endogenous DSB formation, possibly due to replication stress. In exposed cultures, the formation of γH2AX foci peaked at 24 h. We also explored whether it is possible, by using γH2AX antibody in a chromatin immunoprecipitation followed by next generation sequencing, to find out the distribution of DSBs at 24 h in the fiber-exposed A549 cells. The sequences involved in γH2AX foci were genome-widely distributed. To conclude, the kinetics of fiber-induced γH2AX foci formation in the A549 and BEAS-2B cells was partly interfered by endogenously formed DSBs. This study revealed sequences that may be implicated within γH2AX foci for further elucidation on their contribution to lung tumor progression in particle carcinogenesis. Citation Format: Eeva Kettunen, Päivi Tuominen, Satu Suhonen, Julia Catalán, Sisko L. Anttila, Penny Nymark, Hannu Norppa. Fiber-induced DNA damage response in human lung epithelial cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 627. doi:10.1158/1538-7445.AM2013-627