Implementation effect of institutional policy of EGD observation time on neoplasm detection.

BACKGROUND AND AIMS: The observation time in EGD is associated with detection rate of premalignant or neoplastic lesions in the upper GI (UGI) tract. The aim of this study was to evaluate an institutional policy of EGD observation time on the detection rate of UGI neoplasms. METHODS: From July 2017 to March 2019, all endoscopists were requested to comply with our institutional policy of spending more than 3 minutes of observation time in every screening EGD. Observation time was defined as the time from when the endoscope reached the duodenum to when it was withdrawn. We obtained a neoplasm detection rate (NDR) during this period and compared it with that of a baseline period from 2009 to 2015. RESULTS: During the study period, 30,506 EGDs were performed. Mean subject age was 49.9 ± 10.5 years, and 56.5% were men. All endoscopists achieved an average EGD observation time of more than 3 minutes during this period. Mean observation time was 3:35 ± 0:50, which was significantly longer than the baseline (2:38 ± 0:21, P < .001). NDR was .33%, which was higher than the baseline (.23%, P < .001). Even after adjusting for subjects' age and gender, smoking history, and endoscopists' biopsy sampling rate, prolonged EGD observation time of more than 3 minutes increased the NDR of UGI neoplasms (odds ratio, 1.51; 95% confidence interval, 1.21-1.75). CONCLUSIONS: This study provides evidence that implementing a protocol of a prolonged observation time could increase NDR. Observation time should be an important quality indicator of the EGD examination.

Picosecond Photobiology: Watching a Signaling Protein Function in Real Time via Time-Resolved Small- and Wide-Angle X-ray Scattering.

The capacity to respond to environmental changes is crucial to an organism's survival. Halorhodospira halophila is a photosynthetic bacterium that swims away from blue light, presumably in an effort to evade photons energetic enough to be genetically harmful. The protein responsible for this response is believed to be photoactive yellow protein (PYP), whose chromophore photoisomerizes from trans to cis in the presence of blue light. We investigated the complete PYP photocycle by acquiring time-resolved small and wide-angle X-ray scattering patterns (SAXS/WAXS) over 10 decades of time spanning from 100 ps to 1 s. Using a sequential model, global analysis of the time-dependent scattering differences recovered four intermediates (pR0/pR1, pR2, pB0, pB1), the first three of which can be assigned to prior time-resolved crystal structures. The 1.8 ms pB0 to pB1 transition produces the PYP signaling state, whose radius of gyration (Rg = 16.6 Å) is significantly larger than that for the ground state (Rg = 14.7 Å) and is therefore inaccessible to time-resolved protein crystallography. The shape of the signaling state, reconstructed using GASBOR, is highly anisotropic and entails significant elongation of the long axis of the protein. This structural change is consistent with unfolding of the 25 residue N-terminal domain, which exposes the ß-scaffold of this sensory protein to a potential binding partner. This mechanistically detailed description of the complete PYP photocycle, made possible by time-resolved crystal and solution studies, provides a framework for understanding signal transduction in proteins and for assessing and validating theoretical/computational approaches in protein biophysics.

Watching a signaling protein function in real time via 100-ps time-resolved Laue crystallography.

To understand how signaling proteins function, it is crucial to know the time-ordered sequence of events that lead to the signaling state. We recently developed on the BioCARS 14-IDB beamline at the Advanced Photon Source the infrastructure required to characterize structural changes in protein crystals with near-atomic spatial resolution and 150-ps time resolution, and have used this capability to track the reversible photocycle of photoactive yellow protein (PYP) following trans-to-cis photoisomerization of its p-coumaric acid (pCA) chromophore over 10 decades of time. The first of four major intermediates characterized in this study is highly contorted, with the pCA carbonyl rotated nearly 90° out of the plane of the phenolate. A hydrogen bond between the pCA carbonyl and the Cys69 backbone constrains the chromophore in this unusual twisted conformation. Density functional theory calculations confirm that this structure is chemically plausible and corresponds to a strained cis intermediate. This unique structure is short-lived (∼600 ps), has not been observed in prior cryocrystallography experiments, and is the progenitor of intermediates characterized in previous nanosecond time-resolved Laue crystallography studies. The structural transitions unveiled during the PYP photocycle include trans/cis isomerization, the breaking and making of hydrogen bonds, formation/relaxation of strain, and gated water penetration into the interior of the protein. This mechanistically detailed, near-atomic resolution description of the complete PYP photocycle provides a framework for understanding signal transduction in proteins, and for assessing and validating theoretical/computational approaches in protein biophysics.

Watching a signaling protein function: What has been learned over four decades of time-resolved studies of photoactive yellow protein.

Photoactive yellow protein (PYP) is a signaling protein whose internal p-coumaric acid chromophore undergoes reversible, light-induced trans-to-cis isomerization, which triggers a sequence of structural changes that ultimately lead to a signaling state. Since its discovery nearly 40 years ago, PYP has attracted much interest and has become one of the most extensively studied proteins found in nature. The method of time-resolved crystallography, pioneered by Keith Moffat, has successfully characterized intermediates in the PYP photocycle at near atomic resolution over 12 decades of time down to the sub-picosecond time scale, allowing one to stitch together a movie and literally watch a protein as it functions. But how close to reality is this movie? To address this question, results from numerous complementary time-resolved techniques including x-ray crystallography, x-ray scattering, and spectroscopy are discussed. Emerging from spectroscopic studies is a general consensus that three time constants are required to model the excited state relaxation, with a highly strained ground-state cis intermediate formed in less than 2.4 ps. Persistent strain drives the sequence of structural transitions that ultimately produce the signaling state. Crystal packing forces produce a restoring force that slows somewhat the rates of interconversion between the intermediates. Moreover, the solvent composition surrounding PYP can influence the number and structures of intermediates as well as the rates at which they interconvert. When chloride is present, the PYP photocycle in a crystal closely tracks that in solution, which suggests the epic movie of the PYP photocycle is indeed based in reality.

Real-time tracking of CO migration and binding in the α and ß subunits of human hemoglobin via 150-ps time-resolved Laue crystallography.

We have developed the method of picosecond Laue crystallography and used this capability to probe ligand dynamics in tetrameric R-state hemoglobin (Hb). Time-resolved, 2 Å-resolution electron density maps of photolyzed HbCO reveal the time-dependent population of CO in the binding (A) and primary docking (B) sites of both α and ß subunits from 100 ps to 10 µs. The proximity of the B site in the ß subunit is about 0.25 Å closer to its A binding site, and its kBA rebinding rate (~300 µs-1) is six times faster, suggesting distal control of the rebinding dynamics. Geminate rebinding in the ß subunit exhibits both prompt and delayed geminate phases. We developed a microscopic model to quantitatively explain the observed kinetics, with three states for the α subunit and four states for the ß subunit. This model provides a consistent framework for interpreting rebinding kinetics reported in prior studies of both HbCO and HbO2.

Protein structural dynamics in solution unveiled via 100-ps time-resolved x-ray scattering.

We have developed a time-resolved x-ray scattering diffractometer capable of probing structural dynamics of proteins in solution with 100-ps time resolution. This diffractometer, developed on the ID14B BioCARS (Consortium for Advanced Radiation Sources) beamline at the Advanced Photon Source, records x-ray scattering snapshots over a broad range of q spanning 0.02-2.5 A(-1), thereby providing simultaneous coverage of the small-angle x-ray scattering (SAXS) and wide-angle x-ray scattering (WAXS) regions. To demonstrate its capabilities, we have tracked structural changes in myoglobin as it undergoes a photolysis-induced transition from its carbon monoxy form (MbCO) to its deoxy form (Mb). Though the differences between the MbCO and Mb crystal structures are small (rmsd < 0.2 A), time-resolved x-ray scattering differences recorded over 8 decades of time from 100 ps to 10 ms are rich in structure, illustrating the sensitivity of this technique. A strong, negative-going feature in the SAXS region appears promptly and corresponds to a sudden > 22 A(3) volume expansion of the protein. The ensuing conformational relaxation causes the protein to contract to a volume approximately 2 A(3) larger than MbCO within approximately 10 ns. On the timescale for CO escape from the primary docking site, another change in the SAXS/WAXS fingerprint appears, demonstrating sensitivity to the location of the dissociated CO. Global analysis of the SAXS/WAXS patterns recovered time-independent scattering fingerprints for four intermediate states of Mb. These SAXS/WAXS fingerprints provide stringent constraints for putative models of conformational states and structural transitions between them.

Assessment of Cimetropium Bromide Use for the Detection of Gastric Neoplasms During Esophagogastroduodenoscopy.

Importance: Esophagogastroduodenoscopy (EGD) is a common procedure used to examine upper gastrointestinal diseases. Although cimetropium bromide and other antispasmodic agents are commonly administered as premedication to inhibit peristalsis during EGD examination, there are few data regarding the benefits of cimetropium bromide for the detection of gastric neoplasms. Objective: To investigate the association between the use of cimetropium bromide as premedication and gastric neoplasm detection rates during EGD examination. Design, Setting, and Participants: This propensity score-matched retrospective cohort study included 67 683 participants who received EGD screening at the Health Promotion Center of Seoul St. Mary's Hospital, The Catholic University of Korea, from January 2, 2010, to June 30, 2017. Data were analyzed from April 1 to December 30, 2021. Exposures: Participants were divided into 2 groups: those who received cimetropium bromide before EGD examination (intervention group) and those who did not (control group). Main Outcomes and Measures: Gastric neoplasm detection rates. Results: Among 67 683 participants, the mean (SD) age was 48.6 (10.8) years, and 36 517 participants (54.0%) were male; all participants were Asian (a racially homogenous population). Of those, 28 280 participants (41.8%; mean [SD] age, 50.3 [10.6] years; 57.8% male) received cimetropium bromide, and 39 403 participants (58.2%; mean [SD] age, 47.4 [10.8] years; 51.2% male) did not. Propensity score matching based on confounding variables yielded 41 670 matched participants (20 835 pairs). Detected lesions included 52 dysplasias (0.12%), 40 early cancers (0.10%), 7 advanced cancers (0.02%), and 3 lymphomas (0.01%). Gastric neoplasm detection rates were significantly higher in the intervention group (63 participants [0.30%]) vs the control group (39 participants [0.19%]; P = .02). A significant difference in the combined detection rate of dysplasia and early gastric cancer was found between those in the intervention group (57 participants [0.27%]) vs the control group (35 participants [0.17%]; P = .02). For small gastric lesions (<1 cm), those who received cimetropium bromide had higher detection rates (24 participants [0.12%]) than those who did not (11 participants [0.05%]; P = .03). Lesions in the gastric body were detected significantly more often in the intervention group (34 participants [0.16%]) vs the control group (15 participants [0.07%]; P = .007). In multivariate analyses involving all 67 683 participants, the use of cimetropium bromide was more likely to detect gastric neoplasms compared with nonuse (odds ratio, 1.42; 95% CI, 1.04-1.95; P = .03). Conclusions and Relevance: In this study, the use of cimetropium bromide as premedication was significantly associated with increased gastric neoplasm detection rates during EGD screening, and lesions in the gastric body were detected more frequently among those who received cimetropium bromide compared with those who did not. These findings suggest that cimetropium bromide may be considered as premedication before EGD examination among individuals with no contraindications.

Aspect ratio has no effect on genotoxicity of multi-wall carbon nanotubes.

Carbon nanotubes (CNTs) have specific physico-chemical and electrical properties that are useful for telecommunications, medicine, materials, manufacturing processes and the environmental and energy sectors. Yet, despite their many advantages, it is also important to determine whether CNTs may represent a hazard to the environment and human health. Like asbestos, the aspect ratio (length:diameter) and metal components of CNTs are known to have an effect on the toxicity of carbon nanotubes. Thus, to evaluate the toxic potential of CNTs in relation to their aspect ratio and metal contamination, in vivo and in vitro genotoxicity tests were conducted using high-aspect-ratio (diameter: 10-15 nm, length: ~10 µm) and low-aspect-ratio multi-wall carbon nanotubes (MWCNTs, diameter: 10-15 nm, length: ~150 nm) according to OECD test guidelines 471 (bacterial reverse mutation test), 473 (in vitro chromosome aberration test), and 474 (in vivo micronuclei test) with a good laboratory practice system. To determine the treatment concentration for all the tests, a solubility and dispersive test was performed, and a 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) solution found to be more suitable than distilled water. Neither the high- nor the low-aspect-ratio MWCNTs induced any genotoxicity in a bacterial reverse mutation test (~1,000 µg/plate), in vitro chromosome aberration test (without S9: ~6.25 µg/ml, with S9: ~50 µg/ml), or in vivo micronuclei test (~50 mg/kg). However, the high-aspect-ratio MWCNTs were found to be more toxic than the low-aspect-ratio MWCNTs. Thus, while high-aspect-ratio MWCNTs do not induce direct genotoxicity or metabolic activation-mediated genotoxicity, genotoxicity could still be induced indirectly through oxidative stress or inflammation.

Time-resolved X-ray scattering studies of proteins.

Time-resolved small- and wide-angle X-ray scattering studies of proteins in solution based on the pump-probe approach unveil structural information from intermediates over a broad range of length and time scales. In spite of the promise of this methodology, only a fraction of the wealth of information encoded in scattering data has been extracted in studies performed thus far. Here, we discuss the methodology, summarize results from recent time-resolved X-ray scattering studies, and examine the potential to extract additional information from these scattering curves.

[Change of Clostridium difficile colitis during recent 10 years in Korea].

BACKGROUND/AIMS: Our clinical experience and recent published literatures suggest that Clostridium difficile colitis (CDC) has become more common and potentially more pathogenic in recent years. The aim of study was to evaluate changes in the epidemiological features of CDC in hospitalized patients in Korea. METHODS: We retrospectively reviewed all patients of CDC diagnosed at Kangnam St. Mary Hospital from 1998 to 2007. CDC was defined as having a positive C. difficile cytotoxicity assay, or endoscopic or pathologic evidence of CDC. RESULTS: A total of 189 cases (male 73, female 116, mean age 63.3 years) of CDC were diagnosed during the study period. The prevalence of CDC increased from 1.9/10,000 patient admissions in 1998-1999 to 8.82/10,000 patient admissions in 2006-2007. One hundred sixty three indication for cases (86.2%) of patients identified a prior use of antibiotics in the 2 months preceding diagnosis. The most common antibiotic use was prophylactic use during perioperational period (33.3%) followed by pneumonia (23.3%). The overall response rate to initial antibiotics was 82.7%. One hundred seventy two (91%) patients were initially treated with metronidazole. The response rate was 84.3%. All patients with initial failure to metronidazole were successfully treated by vancomycin. The response rate of vancomycin as first treatment was 80%. Three deaths were associated with CDC despite the use of combination of metronidazole and vancomycin. CONCLUSIONS: The prevalence of CDC in hospitalized patients in Korea significantly increased from 1998 to 2007.

Survival after in-hospital cardiopulmonary resuscitation from 2003 to 2013: An observational study before legislation on the life-sustaining treatment decision-making act of Korean patients.

We analyzed cardiopulmonary resuscitation (CPR) rates, deaths preceded by CPR, and survival trends after in-hospital CPR, using a sample of nationwide Korean claims data for the period 2003 to 2013.The Korean National Health Insurance Service-National Sample Cohort is a stratified random sample of 1,025,340 subjects selected from among approximately 46 million Koreans. We evaluated the annual incidence of CPR per 1000 admissions in various age groups, hospital deaths preceded by CPR, and survival rate following in-hospital CPR. Analyses of the relationships between survival and patient and hospital characteristics were performed using logistic regression analysis.A total of 5918 in-hospital CPR cases from 2003 to 2013 were identified among eligible patients. The cumulative incidence of in-hospital CPR was 3.71 events per 1000 admissions (95% confidence interval 3.62-3.80). The CPR rate per 1000 admissions was highest among the oldest age group, and the rate decreased throughout the study period in all groups except the youngest age group. Hospital deaths were preceded by in-hospital CPR in 18.1% of cases, and the rate decreased in the oldest age group. The survival-to-discharge rate in all study subjects was 11.7% during study period, while the 6-month and 1-year survival rates were 8.0% and 7.2%, respectively. Survival tended to increase throughout the study period; however, this was not the case in the oldest age group. Age and malignancy were associated with lower survival rates, whereas myocardial infarction and diabetes mellitus were associated with higher survival rates.Our result shows that hospital deaths were preceded by in-hospital CPR in 18.1% of case, and the survival-to-discharge rate in all study subjects was 11.7% during the study period. Survival tended to increase throughout the study period except for the oldest age group. Our results provide reliable data that can be used to inform judicious decisions on the implementation of CPR, with the ultimate goal of optimizing survival rates and resource utilization.

Synergistic effect of ERK inhibition on tetrandrine-induced apoptosis in A549 human lung carcinoma cells.

Tetrandrine (TET), a bis-benzylisoquinoline alkaloid from the root of Stephania tetrandra, is known to have anti-tumor activity in various malignant neoplasms. However, the precise mechanism by which TET inhibits tumor cell growth remains to be elucidated. The present studies were performed to characterize the potential effects of TET on phosphoinositide 3-kinase/Akt and extracellular signal-regulated kinase (ERK) pathways since these signaling pathways are known to be responsible for cell growth and survival. TET suppressed cell proliferation and induced apoptosis in A549 human lung carcinoma cells. TET treatment resulted in a down-regulation of Akt and ERK phosphorylation in both time-/concentration-dependent manners. The inhibition of ERK using PD98059 synergistically enhanced the TET-induced apoptosis of A549 cells whereas the inhibition of Akt using LY294002 had a less significant effect. Taken together, our results suggest that TET: i) selectively inhibits the proliferation of lung cancer cells by blocking Akt activation and ii) increases apoptosis by inhibiting ERK. The treatment of lung cancers with TET may enhance the efficacy of chemotherapy and radiotherapy and increase the apoptotic potential of lung cancer cells.

Twenty-eight-day oral toxicity, genotoxicity, and gender-related tissue distribution of silver nanoparticles in Sprague-Dawley rats.

The antibacterial effect of silver nanoparticles has resulted in their extensive application in health, electronic, and home products. However, while the population exposed to silver nanoparticles continues to increase with ever new applications, silver nanoparticles remain a controversial research area as regards their toxicity to biological systems. In particular, the oral toxicity of silver nanoparticles is of particular concern to ensure public and consumer health. Accordingly, this study tested the oral toxicity of silver nanoparticles (60 nm) over a period of 28 days in Sprague-Dawley rats following Organization for Economic Cooperation and Development (OECD) test guideline 407 with Good Laboratory Practice (GLP) application. Eight-week-old rats, weighing about 283 g for the males and 192 g for the females, were divided into four 4 groups (10 rats in each group): vehicle control, low-dose group (30 mg/kg), middle-dose group (300 mg/kg), and high-dose group (1000 mg/kg). After 28 days of exposure, the blood biochemistry and hematology were investigated, along with a histopathological examination and silver distribution study. The male and female rats did not show any significant changes in body weight relative to the doses of silver nanoparticles during the 28-day experiment. However, some significant dose-dependent changes were found in the alkaline phsophatase and cholesterol values in either the male or female rats, seeming to indicate that exposure to over more than 300 mg of silver nanoparticles may result in slight liver damage. There were no statistically significant differences in the micronucleated polychromatic erythrocytes (MN PCEs) or ratio of polychromatic erythrocytes among the total erythrocytes after silver nanoparticle exposure when compared with the control. Therefore, the present results suggest that silver nanoparticles do not induce genetic toxicity in male and female rat bone marrow in vivo. Nonetheless, the tissue distribution of silver nanopaticles did show a dose-dependent accumulation of silver content in all the tissues examined. In particular, a gender-related difference in the accumulation of silver was noted in the kidneys, with a twofold increase in the female kidneys when compared with the male kidneys.

Serum immunoglobulin fused interferon-alpha inhibited tumor growth in athymic mice bearing colon 26 adenocarcinoma cells.

Interferon (IFN) has therapeutic potential for a wide range of infectious and proliferative disorders. However, the half-life of IFN is too short to have a stable therapeutic effect. To overcome this problem, serum immunoglobulin has been fused to IFN. In this study, the efficacy of serum immunoglobulin fused INFs (si-IFN1 and si-IFN2) was evaluated on athymic mice bearing colon 26 adenocarcinoma cells. Seven days after the implantation of tumor cells, each group of mice was injected once a week with si-IFN1 and si-IFN2 at two different concentrations (10 x : 30 microg/kg and 50 x : 150 microg/kg). A slight anti-tumoral effect was observed in all 10 x groups compared to the control. In the 50 x groups, however, si-IFN1 and si-IFN2 showed significant anti- tumoral effects compared to the control. To gain more information on the mechanisms associated with the decrease of tumor size, a Western blot assay of apoptosis-related molecules was performed. The protein expression of cytochrome c, caspase 9, 6, and 3 were increased by si-IFN1 and si-IFN2. These 2 IFNs also increased the expressions of p53, p21, Bax and Bad. Interestingly, si-IFN1 and si-IFN2 decreased the expression of VEGF-beta. Taken together, serum immunoglobulin fused IFNs increased therapeutic efficacy under current experimental condition.

Dynamics of Quaternary Structure Transitions in R-State Carbonmonoxyhemoglobin Unveiled in Time-Resolved X-ray Scattering Patterns Following a Temperature Jump.

It is well-known that tetrameric hemoglobin binds ligands cooperatively by undergoing a ligand-induced T → R quaternary structure transition, a structure-function relationship that has long served as a model system for understanding allostery in proteins. However, kinetic studies of the reverse, R → T quaternary structure transition following photolysis of carbonmonoxyhemoglobin (HbCO) reveal complex behavior that may be better explained by the presence of two different R quaternary structures coexisting in thermal equilibrium. Indeed, we report here time-resolved small- and wide-angle X-ray scattering (SAXS/WAXS) patterns of HbCO following a temperature jump that not only provide unambiguous evidence for more than one R state, but also unveil the time scale for interconversion between them. Since the time scale for the photolysis-induced R → T transition is likely different for different R-states, this structural heterogeneity must be accounted for to properly explain the kinetic heterogeneity observed in time-resolved spectroscopic studies following photolysis of HbCO.

Reasons for Surgery Cancellation in a General Hospital: A 10-year Study.

Background: This study researched related causes that make scheduled surgeries canceled not to be conducted and based on the research it is to derive issues in order to reduce surgery cancellation. Methods: We analyzed the association of surgery cancellation with patient characteristics, surgical characteristics and surgery schedule related characteristics, using electronic medical record (EMR) data on surgeries conducted at a university hospital in Korea over 10 years. Additionally, we examined the reasons for surgery cancellation based on patient and hospital characteristics. We used chi-square tests to analyze the distribution of various characteristics according to reasons for surgery cancellation. Multivariate logistic regression analyses were conducted to evaluate the factors associated with surgery cancellation. Results: Among 60,333 cases, surgery cancellation rate was 8.0%. The results of the logistic regression indicated a high probability of surgery cancellation when the patient was too old (odds ratio [OR]: 1.35, 95% confidence interval [CI]: 1.14⁻1.59), when it was a neurosurgery case (OR: 1.39, 95% CI: 1.21⁻1.59), when local anesthesia was used (OR: 1.15, 95% CI: 1.07⁻1.24) or when it was a planned surgery (OR: 2.45, 95% CI: 2.21⁻2.73). The surgery cancellation rate was lower when the patient was female (OR: 0.87, 95% CI: 0.82⁻0.93) or when the surgery was related to Obstetrics & Gynecology (OR: 0.53, 95% CI: 0.46⁻0.60) or Ophthalmology (OR: 0.66, 95% CI: 0.56⁻0.79). Among the canceled 4834 cases, the surgery cancellation rate for the reasons of patients was 93.2% and the surgery cancellation rate for the reasons of a hospital was 6.8%. Conclusions: This study found that there are related various causes to cancel operations, including patient characteristics, surgery related characteristics and surgery schedule related characteristics and it means that it would be possible for some reasons to be prevented. Every medical institution should consider the operation cancellation as an important issue and systematic monitoring should be needed.

Association of serum calcium concentrations with fibrinogen and homocysteine in nondiabetic Korean subjects.

Considerable evidence shows that increased serum calcium levels are associated with metabolic disorders, cardiovascular disease, and increased mortality. This study investigated whether serum calcium, within a normal range, is significantly associated with serum fibrinogen and homocysteine, markers of increased cardiovascular disease risk in nondiabetic Korean subjects.A cross-sectional analysis was performed on 1096 subjects (mean age, 55.1 ±â€Š11.1 years; 36.1% women) undergoing a general health checkup. Serum biochemistry was analyzed including serum albumin-corrected calcium (Cac), insulin resistance (IR, using homeostasis model assessment [HOMA]), fibrinogen, and homocysteine.Compared with patients within the lowest Cac quartile, those with higher Cac levels had increased fibrinogen and homocysteine levels as well as an increased proportion of smoking, dyslipidemia, and HOMA-IR. Correlation analyses revealed linear relationships for Cac with fibrinogen and homocysteine in both genders. After adjustment for confounding factors, serum Cac was significantly associated with high fibrinogen (odds ratio [OR] for the highest vs the lowest quartile = 1.76, 95% confidence interval [CI] = 1.09-2.83, P = 0.02) and homocysteine (OR = 1.83, 95% CI = 1.07-3.11, P = 0.027). Multivariate regression models showed that Cac was linearly associated with fibrinogen (standardized ß = 0.14, P < 0.001) and homocysteine (standardized ß = 0.07, P = 0.009).High normal calcium concentrations were independently associated with increased levels of fibrinogen and homocysteine. Further investigation is needed to validate whether slightly increased calcium levels within the normal range indicate a higher risk of cardiovascular disease.

Serum bilirubin levels are inversely associated with PAI-1 and fibrinogen in Korean subjects.

OBJECTIVES: Oxidative stress may contribute to atherosclerosis and increased activation of the coagulation pathway. Bilirubin may reduce activation of the hemostatic system to inhibit oxidative stress, which would explain its cardioprotective properties shown in many epidemiological studies. This study investigated the association of serum bilirubin with fibrinogen and plasminogen activator inhibitor-1 (PAI-1), respectively. METHODS: A cross-sectional analysis was performed on 968 subjects (mean age, 56.0 ± 11.2 years; 61.1% men) undergoing a general health checkup. Serum biochemistry was analyzed including bilirubin subtypes, insulin resistance (using homeostasis model of assessment [HOMA]), C-reactive protein (CRP), fibrinogen, and PAI-1. RESULTS: Compared with subjects with a total bilirubin (TB) concentration of <10.0 µmol/L, those with a TB concentration of >17.1 µmol/L had a smaller waist circumference, a lower triglyceride level, a lower prevalence of metabolic syndrome, and decreased HOMA-IR and CRP levels. Correlation analysis revealed linear relationships of fibrinogen with TB and direct bilirubin (DB), whereas PAI-1 was correlated with DB. After adjustment for confounding factors, bilirubin levels were inversely associated with fibrinogen and PAI-1 levels, respectively. Multivariate regression models showed a negative linear relationship between all types of bilirubin and fibrinogen, whereas there was a significant linear relationship between PAI-1 and DB. CONCLUSIONS: High bilirubin concentrations were independently associated with low levels of fibrinogen and PAI-1, respectively. The association between TB and PAI-1 was confined to the highest TB concentration category whereas DB showed a linear association with PAI-1. Bilirubin may protect against the development of atherothrombosis by reducing the hemostatic response.

Cap-independent protein translation is initially responsible for 4-(N-methylnitrosamino)-1-(3-pyridyl)-butanone (NNK)-induced apoptosis in normal human bronchial epithelial cells.

Evidences show that eukaryotic mRNAs can perform protein translation through internal ribosome entry sites (IRES). 5'-Untranslated region of the mRNA encoding apoptotic protease-activating factor 1 (Apaf-1) contains IRES, and, thus, can be translated in a cap-independent manner. Effects of changes in protein translation pattern through rapamycin pretreatment on 4-(methylnitrosamino)-1-(3-pyridyl)-butanone(NNK, tobacco-specific lung carcinogen)-induced apoptosis in human bronchial epithelial cells were examined by caspase assay, FACS analysis, Western blotting, and transient transfection. Results showed that NNK induced apoptosis in concentration- and time-dependent manners. NNK-induced apoptosis occurred initially through cap-independent protein translation, which during later stage was replaced by cap-dependent protein translation. Our data may be applicable as the mechanical basis of lung cancer treatment.

Molecular analysis of hprt mutation in B6C3F1 mice exposed to ozone alone and combined treatment of 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone and/or dibutyl phthalate for 32 and 52 weeks.

Potential toxicological interactions of 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and/or dibuthyl phthalate (DBP) on ozone were investigated after 32- and 52-wk exposures using hprt mutation assay. Male and female B6C3F1 mice exposed to ozone (0.5 ppm), NNK (1.0 mg/kg), DBP (5,000 ppm), and two or three combinations of these toxicants 6 h per day for 32- and 52-wk showed increases in the frequencies of TG rlymphocytes compared to the control groups. Additive interactions were noted from two combination groups compared to the ozone alone in both sexes of 32- and 52-wk studies. The most common specific mutation type in the hprt genes of test materials-treated male and female mice was transversion with very few transition. The results indicate that such dominant transversion may be responsible for toxicity and combined exposure to ozone, NNK, and DBP induces additive genotoxicities compared to ozone alone.