bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of prior statin use on 30-day mortality for patients hospitalized with community-acquired pneumonia
Authors: Mortensen Eric M , Restrepo Marcos I , Anzueto Antonio , Pugh Jacqueline
Published: July 2005

Background

Recent studies suggest that HMG-CoA reductase inhibitors ("statins") may have beneficial effects for patients at risk for some types of infections. We examined the effect of prior outpatient use of statins on mortality for patients hospitalized with community-acquired pneumonia.

Methods

A retrospective cohort study conducted at two tertiary teaching hospitals. Eligible subjects were admitted with a diagnosis of, had a chest x-ray consistent with, and had a discharge ICD-9 diagnosis of pneumonia. Subjects were excluded if they were "comfort measures only" or transferred from another acute care hospital. Subjects were considered to be on a medication if they were taking it at the time of presentation.

Results

Data was abstracted on 787 subjects at the two hospitals. Mortality was 9.2% at 30-days and 13.6% at 90-days. At presentation 52% of subjects were low risk, 34% were moderate risk, and 14% were high risk based on the pneumonia severity index. In the multivariable regression analysis, after adjusting for potential confounders including a propensity score, the use of statins at presentation (odds ratio 0.36, 95% confidence interval 0.14–0.92) was associated with decreased 30-day mortality.

Discussion

Prior outpatient statin use was associated with decreased mortality in patients hospitalized with community-acquired pneumonia despite their use being associated with comorbid illnesses likely to contribute to increased mortality. Confirmatory studies are needed, as well as research to determine the mechanism(s) of this protective effect.
Prediction of the general transcription factors associated with RNA polymerase II in Plasmodium falciparum: conserved features and differences relative to other eukaryotes
Authors: Callebaut Isabelle , Prat Karine , Meurice Edwige , Mornon Jean-Paul , Tomavo Stanislas
Published: July 2005

Background

To date, only a few transcription factors have been identified in the genome of the parasitePlasmodium falciparum, the causative agent of malaria. Moreover, no detailed molecular analysis of its basal transcription machinery, which is otherwise well-conserved in the crown group of eukaryotes, has yet been reported. In this study, we have used a combination of sensitive sequence analysis methods to predict the existence of several parasite encoded general transcription factors associated with RNA polymerase II.

Results

Several orthologs of general transcription factors associated with RNA polymerase II can be predicted among the hypothetical proteins of theP. falciparumgenome using the two-dimensional Hydrophobic Cluster Analysis (HCA) together with profile-based search methods (PSI-BLAST). These predicted orthologous genes encoding putative transcription factors include the large subunit of TFIIA and two candidates for its small subunit, the TFIIE β-subunit, which would associate with the previously known TFIIE α-subunit, the TFIIF β-subunit, as well as the p62/TFB1 subunit of the TFIIH core. Within TFIID, the putative orthologs of TAF1, TAF2, TAF7 and TAF10 were also predicted. However, no candidates for TAFs with classical histone fold domain (HFD) were found, suggesting an unusual architecture of TFIID complex of RNA polymerase II in the parasite.

Conclusion

Taken together, these results suggest that more general transcription factors may be present in theP. falciparumproteome than initially thought. The prediction of these orthologous general transcription factors opens the way for further studies dealing with transcriptional regulation inP. falciparum. These alternative and sensitive sequence analysis methods can help to identify candidates for other transcriptional regulatory factors inP. falciparum. They will also facilitate the prediction of biological functions for several orphan proteins from other apicomplexan parasites such asToxoplasma gondii,Cryptosporidium parvumandEimeria.
Application of four dyes in gene expression analyses by microarrays
Authors: Staal Yvonne CM , van Herwijnen Marcel HM , van Schooten Frederik J , van Delft Joost HM
Published: July 2005

Background

DNA microarrays are widely used in gene expression analyses. To increase throughput and minimize costs without reducing gene expression data obtained, we investigated whether four mRNA samples can be analyzed simultaneously by applying four different fluorescent dyes.

Results

Following tests for cross-talk of fluorescence signals, Alexa 488, Alexa 594, Cyanine 3 and Cyanine 5 were selected for hybridizations. For self-hybridizations, a single RNA sample was labelled with all dyes and hybridized on commercial cDNA arrays or on in-house spotted oligonucleotide arrays. Correlation coefficients for all combinations of dyes were above 0.9 on the cDNA array. On the oligonucleotide array they were above 0.8, except combinations with Alexa 488, which were approximately 0.5. Standard deviation of expression differences for replicate spots were similar on the cDNA array for all dye combinations, but on the oligonucleotide array combinations with Alexa 488 showed a higher variation.

Conclusion

In conclusion, the four dyes can be used simultaneously for gene expression experiments on the tested cDNA array, but only three dyes can be used on the tested oligonucleotide array. This was confirmed by hybridizations of control with test samples, as all combinations returned similar numbers of differentially expressed genes with comparable effects on gene expression.
A role for the Tec family kinase ITK in regulating SEB induced Interleukin-2 production in vivo via c-jun phosphorylation
Authors: Ragin Melanie J , Hu Jianfang , Henderson Andrew J , August Avery
Published: July 2005

Background

Exposure to Staphylococcal Enterotoxin B (SEB), a bacterial superantigen secreted by the Gram-positive bacteria Staphyloccocus aureus, results in the expansion and eventual clonal deletion and anergy of Vβ8+ T cells, as well as massive cytokine release, including Interleukin-2 (IL-2). This IL-2 is rapidly secreted following exposure to SEB and may contribute to the symptoms seen following exposure to this bacterial toxin. The Tec family kinase ITK has been shown to be important for the production of IL-2 by T cells stimulated in vitro and may represent a good target for blocking the production of this cytokine in vivo. In order to determine if ITK represents such a target, mice lacking ITK were analyzed for their response to SEB exposure.

Results

It was found that T cells from mice lacking ITK exhibited significantly reduced proliferative responses to SEB exposure in vitro, as well as in vivo. Examination of IL-2 production revealed that ITK null mice produced reduced levels of this cytokine in vitro, and more dramatically, in vivo. In vivo analysis of c-jun phosphorylation, previously shown to be critical for regulating IL-2 production, revealed that this pathway was specifically activated in SEB reactive Vβ8+ (but not non-reactive Vβ6+) T cells from WT mice, but not in Vβ8+ T cells from ITK null mice. However, toxicity analysis indicated that both WT and ITK null animals were similarly affected by SEB exposure.

Conclusion

These data show that ITK is required for IL-2 production induced by SEB in vivo, and may regulate signals leading IL-2 production, in part by regulating phosphorylation of c-jun. The data also suggest that perturbing T cell activation pathways leading to IL-2 does not necessarily lead to improved responses to SEB toxicity.
Psychophysiological effects of a web-based stress management system: A prospective, randomized controlled intervention study of IT and media workers [ISRCTN54254861]
Authors: Hasson Dan , Anderberg Ulla Maria , Theorell Töres , Arnetz Bengt B
Published: July 2005

Background

The aim of the present study was to assess possible effects on mental and physical well-being and stress-related biological markers of a web-based health promotion tool.

Methods

A randomized, prospectively controlled study was conducted with before and after measurements, involving 303 employees (187 men and 116 women, age 23–64) from four information technology and two media companies. Half of the participants were offered web-based health promotion and stress management training (intervention) lasting for six months. All other participants constituted the reference group. Different biological markers were measured to detect possible physiological changes.

Results

After six months the intervention group had improved statistically significantly compared to the reference group on ratings of ability to manage stress, sleep quality, mental energy, concentration ability and social support. The anabolic hormone dehydroepiandosterone sulphate (DHEA-S) decreased significantly in the reference group as compared to unchanged levels in the intervention group. Neuropeptide Y (NPY) increased significantly in the intervention group compared to the reference group. Chromogranin A (CgA) decreased significantly in the intervention group as compared to the reference group. Tumour necrosis factor α (TNFα) decreased significantly in the reference group compared to the intervention group. Logistic regression analysis revealed that group (intervention vs. reference) remained a significant factor in five out of nine predictive models.

Conclusion

The results indicate that an automatic web-based system might have short-term beneficial physiological and psychological effects and thus might be an opportunity in counteracting some clinically relevant and common stress and health issues of today.
Socioeconomic factors and adolescent pregnancy outcomes: distinctions between neonatal and post-neonatal deaths?
Authors: Markovitz Barry P , Cook Rebeka , Flick Louise H , Leet Terry L
Published: July 2005

Background

Young maternal age has long been associated with higher infant mortality rates, but the role of socioeconomic factors in this association has been controversial. We sought to investigate the relationships between infant mortality (distinguishing neonatal from post-neonatal deaths), socioeconomic status and maternal age in a large, retrospective cohort study.

Methods

We conducted a population-based cohort study using linked birth-death certificate data for Missouri residents during 1997–1999. Infant mortality rates for all singleton births to adolescent women (12–17 years, n = 10,131; 18–19 years, n = 18,954) were compared to those for older women (20–35 years, n = 28,899). Logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) for all potential associations.

Results

The risk of infant (OR 1.95, CI 1.54–2.48), neonatal (1.69, 1.24–2.31) and post-neonatal mortality (2.47, 1.70–3.59) were significantly higher for younger adolescent (12–17 years) than older (20–34 years) mothers. After adjusting for race, marital status, age-appropriate education level, parity, smoking status, prenatal care utilization, and poverty status (indicated by participation in WIC, food stamps or Medicaid), the risk of post-neonatal mortality (1.73, 1.14–2.64) but not neonatal mortality (1.43, 0.98–2.08) remained significant for younger adolescent mothers. There were no differences in neonatal or post-neonatal mortality risks for older adolescent (18–19 years) mothers.

Conclusion

Socioeconomic factors may largely explain the increased neonatal mortality risk among younger adolescent mothers but not the increase in post-neonatal mortality risk.
Children's acceptance of milk with xylitol or sorbitol for dental caries prevention
Authors: Castillo Jorge L , Milgrom Peter , Coldwell Susan E , Castillo Ramon , Lazo Rocio
Published: July 2005

Background

Xylitol, a polyol sugar, has been shown to reduce dental caries when mixed with food or chewing gum. This study examines the taste acceptability of xylitol in milk as a first step toward measuring the effectiveness of xylitol in milk for the reduction of dental caries in a public health program.

Methods

Three different types of milk (Ultra High Temperature (UHT), powder and evaporated) were tested for acceptability by 75 Peruvian children (25 per milk group, ages 4 to 7 years). Each group evaluated xylitol and sorbitol in one type of milk. In the first phase, each child was presented with a tray of four plastic cups containing 50 ml of milk with 0.021 g/ml xylitol, 0.042 g/ml xylitol, 0.042 g/ml sorbitol or no sugar. Each child was asked to taste the samples in a self-selected order. After tasting each sample, the child placed the milk cup in front of one of three cartoon faces (smile, frown or neutral) representing the child's response to the taste of each sample. In the second phase, the child was asked to rank order the milk samples within each category (smile, frown or neutral). Ranks within categories were then combined to obtain a rank ordering for all the test samples.

Results

The ranking from best to worst for the samples across categories (UHT, powder, evaporated) was xylitol (0.0.042 g/ml), sorbitol (0.042 g/ml), xylitol (0.021 g/ml) and milk alone (Friedman's ANOVA). Xylitol and sorbitol were preferred over milk alone, and xylitol (0.042 g/ml) was preferred to sorbitol (0.042 g/ml)(p < .05 sign test).

Conclusion

Milk sweetened with xylitol is well accepted by Peruvian children ages 4–7 years.
Multidrug Resistance-Associated Protein 1 (MRP1) mediated vincristine resistance: effects of N-acetylcysteine and Buthionine Sulfoximine
Authors: Akan Ilhan , Akan Selma , Akca Hakan , Savas Burhan , Ozben Tomris
Published: July 2005

Background

Multidrug resistance mediated by the multidrug resistance-associated protein 1 (MRP1) decreases cellular drug accumulation. The exact mechanism of MRP1 involved multidrug resistance has not been clarified yet, though glutathione (GSH) is likely to have a role for the resistance to occur. N-acetylcysteine (NAC) is a pro-glutathione drug. DL-Buthionine (S,R)-sulfoximine (BSO) is an inhibitor of GSH synthesis. The aim of our study was to investigate the effect of NAC and BSO on MRP1-mediated vincristine resistance in Human Embryonic Kidney (HEK293) and its MRP1 transfected 293MRP cells. Human Embryonic Kidney (HEK293) cells were transfected with a plasmid encoding whole MRP1 gene. Both cells were incubated with vincristine in the presence or absence of NAC and/or BSO. The viability of both cells was determined under different incubation conditions. GSH, Glutathione S-Transferase (GST) and glutathione peroxidase (GPx) levels were measured in the cell extracts obtained from both cells incubated with different drugs.

Results

N-acetylcysteine increased the resistance of both cells against vincristine and BSO decreased NAC-enhanced MRP1-mediated vincristine resistance, indicating that induction of MRP1-mediated vincristine resistance depends on GSH. Vincristine decreased cellular GSH concentration and increased GPx activity. Glutathione S-Transferase activity was decreased by NAC.

Conclusion

Our results demonstrate that NAC and BSO have opposite effects in MRP1 mediated vincristine resistance and BSO seems a promising chemotherapy improving agent in MRP1 overexpressing tumor cells.
Use of insecticide-treated nets (ITNs) following a malaria education intervention in Piron, Mali: a control trial with systematic allocation of households
Authors: Rhee Michelle , Sissoko Mahamadou , Perry Sharon , McFarland Willi , Parsonnet Julie , Doumbo Ogobara
Published: July 2005

Background

Insecticide-treated nets (ITNs) reduce malaria morbidity and mortality, but use is limited. A barrier to ITN use may be lack of knowledge regarding malaria transmission and prevention. This study is a controlled trial comparing ITN use and malaria knowledge levels between households in Piron, Mali, undertaken in 2003.

Methods

Households received net impregnation services either with or without antecedent education. The main outcome measure was ITN use, defined as impregnation of at least one of the household's existing bednets with insecticide during the study. Knowledge about malaria and prevention practices was assessed pre- and post- educational intervention. Results were analysed by household and by individual.

Results

Forty-nine percent (34/70) of households who received the educational component impregnated their nets in comparison to 35% (22/62) of households who did not (OR = 1.6 CI = 0.8–3.3, P = 0.19). In individual analysis, ITN use was significantly greater in participants who had received the educational intervention (48%) vs. individuals who did not (33%, OR = 1.9, P = 0.012). Knowledge levels about malaria significantly increased for each individual pre- versus post- educational intervention (average change score = 2.13, standard deviation = 1.97, t = -17.78, P < 0.001), although there was no difference found between educational (change score = 2.14) and control groups (change score = 2.12).

Conclusion

It is possible to educate individuals about malaria and to implement net impregnation services with limited resources. Greater accessibility to net-impregnation services is necessary but not sufficient to increase ITN use.
Risk of high blood pressure in salt workers working near salt milling plants: A cross-sectional and interventional study
Authors: Haldiya Kripa Ram , Mathur Murli Lal , Sachdev Raman , Saiyed Habibulla N
Published: July 2005

Background

Workers working close to salt milling plants may inhale salt particles floating in the air, leading to a rise in plasma sodium, which, in turn, may increase the blood pressure and the risk of hypertension.

Methods

To test the above hypothesis, occupational health check-up camps were organized near salt manufacturing units and all workers were invited for a free health examination. The workers who worked with dry salt in the vicinity of salt milling plants were defined as "non-brine workers," while those working in brine pans located far away from milling plants were defined as "brine workers." Blood pressure (BP) was measured during each clinical examination. In all, 474 non-brine workers and 284 brine workers were studied.

Results

Mean systolic blood pressure of non-brine workers (122.1 ± 13.3 mm Hg) was significantly higher than that of brine workers (118.8 ± 12.8 mm Hg, p < 0.01). Mean diastolic blood pressure of non-brine workers (71.5 ± 10.4 mm Hg) was significantly higher than that of brine workers (69.7 ± 9.4 mm Hg, p = 0.02). The prevalence of hypertension was significantly higher in non-brine workers (12.2%) than in brine workers (7.0%, p = 0.02). Nineteen salt workers were monitored while they used face masks and spectacles, for six days. Systolic, as well as diastolic, blood pressure of these workers began declining on the third day and continued to decline on the fourth day, but remained stationary up to the sixth day. The concentration of salt particles in the breathing zone of these workers was 376 mg/m3 air.

Conclusion

Inhalation of salt particles in non-brine workers may be an occupational cause of increased blood pressure.
A case report: Pavlovian conditioning as a risk factor of heroin 'overdose' death
Authors: Gerevich József , Bácskai Erika , Farkas Lajos , Danics Zoltán
Published: July 2005

Background

The authors present a case illustrating a mechanism leading directly to death which is not rare but has received little attention.

Case presentation

The case was evaluated by autopsy, investigation of morphine concentration in the blood, and clinical data. The heroin dose causing the 'overdose' death of a young man who had previously been treated a number of times for heroin addiction did not differ from his dose of the previous day taken in the accustomed circumstances. The accustomed dose taken in a strange environment caused fatal complications because the conditioned tolerance failed to operate. The concentration of morphine in the blood did not exceed the level measured during earlier treatment.

Conclusion

These results are in line with the data in the literature indicating that morphine concentrations measured in cases of drug-related death do not differ substantially from those measured in cases where the outcome is not fatal. A knowledge of the conditioning mechanism can contribute to prevention of fatal cases of a similar type. The harm reduction approach places great stress on preventive intervention based on data related to drug-related death.
Utility of a thematic network in primary health care: a controlled interventional study in a rural area
Authors: Coma del Corral Maria Jesús , Abaigar Luquín Pedro , Cordero Guevara José , Olea Movilla Angel , Torres Torres Gerardo , Lozano Garcia Javier
Published: July 2005

Background

UniNet is an Internet-based thematic network for a virtual community of users (VCU). It supports a virtual multidisciplinary community for physicians, focused on the improvement of clinical practice. This is a study of the effects of a thematic network such as UniNet on primary care medicine in a rural area, specifically as a platform of communication between specialists at the hospital and doctors in the rural area.

Methods

In order to study the effects of a thematic network such as UniNet on primary care medicine in a rural area, we designed an interventional study that included a control group. The measurements included the number of patient displacements due to disease, number of patient hospital stays and the number of prescriptions of drugs of low therapeutic utility and generic drug prescriptions by doctors. These data were analysed and compared with those of the control center.

Results

Our study showed positive changes in medical practice, reflected in the improvement of the evaluated parameters in the rural health area where the interventional study was carried out, compared with the control area. We discuss the strengths and weaknesses of UniNet as a potential medium to improve the quality of medical care in rural areas.

Conclusion

The rural doctors had an effective, useful, user-friendly and cheap source of medical information that may have contributed to the improvement observed in the medical quality indices.
PDZ domain-binding motif of human T-cell leukemia virus type 1 Tax oncoprotein is essential for the interleukin 2 independent growth induction of a T-cell line
Authors: Tsubata Chikako , Higuchi Masaya , Takahashi Masahiko , Oie Masayasu , Tanaka Yuetsu , Gejyo Fumitake , Fujii Masahiro
Published: July 2005

Background

Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia (ATL), whereas HTLV type 2 (HTLV-2), is not associated with ATL or any other leukemia. HTLV-1 encodes the transforming gene tax1, whose expression in an interleukin (IL)-2-dependent T-cell line (CTLL-2) induces IL-2-independent growth.

Results

In this study, we demonstrated that IL-2-independent growth induction by Tax1 was abrogated by mutations of the PDZ domain-binding motif (PBM) at the Tax1 C-terminus. HTLV-2 Tax2, which shares 75% amino acid identity with Tax1 but does not have a PBM, was not able to induce IL-2-independent growth of CTLL-2.

Conclusion

Our results suggest that Tax1, through interaction with PDZ domain protein(s) induces IL-2-independent growth, which may be a factor in multi-step leukemogenesis caused by HTLV-1.
High proportion of recurrent germline mutations in the BRCA1 gene in breast and ovarian cancer patients from the Prague area
Authors: Pohlreich Petr , Zikan Michal , Stribrna Jana , Kleibl Zdenek , Janatova Marketa , Kotlas Jaroslav , Zidovska Jana , Novotny Jan , Petruzelka Lubos , Szabo Csilla , Matous Bohuslav
Published: July 2005

Background

Germline mutations in the BRCA1 and BRCA2 genes have been shown to account for the majority of hereditary breast and ovarian cancers. The purpose of our study was to estimate the incidence and spectrum of pathogenic mutations in BRCA1/2 genes in high-risk Czech families.

Methods

A total of 96 Czech families with recurrent breast and/or ovarian cancer and 55 patients considered to be at high-risk but with no reported family history of cancer were screened for mutations in the BRCA1/2 genes. The entire coding sequence of each gene was analyzed using a combination of the protein truncation test and direct DNA sequencing.

Results

A total of 35 mutations in the BRCA1/2 genes were identified in high-risk families (36.5%). Pathogenic mutations were found in 23.3% of breast cancer families and in 59.4% of families with the occurrence of both breast and ovarian cancer. In addition, four mutations were detected in 31 (12.9%) women with early onset breast cancer. One mutation was detected in seven (14.3%) patients affected with both a primary breast and ovarian cancer and another in three (33.3%) patients with a bilateral breast cancer. A total of 3 mutations in BRCA1 were identified among 14 (21.4%) women with a medullary breast carcinoma. Of 151 analyzed individuals, 35 (23.2%) carried a BRCA1 mutation and 9 (6.0%) a BRCA2 mutation. One novel truncating mutation was found in BRCA1 (c.1747A>T) and two in BRCA2 (c.3939delC and c.5763dupT). The 35 identified BRCA1 mutations comprised 13 different alterations. Three recurrent mutations accounted for 71.4% of unrelated individuals with detected gene alterations. The BRCA1 c.5266dupC (5382insC) was detected in 51.4% of mutation positive women. The mutations c.3700_3704del5 and c.181T>G (300T>G) contributed to 11.4% and 8.6% of pathogenic mutations, respectively. A total of eight different mutations were identified in BRCA2. The novel c.5763dupT mutation, which appeared in two unrelated families, was the only recurrent alteration of the BRCA2 gene identified in this study.

Conclusion

Mutational analysis of BRCA1/2 genes in 151 high-risk patients characterized the spectrum of gene alterations and demonstrated the dominant role of the BRCA1 c.5266dupC allele in hereditary breast and ovarian cancer.
Recombinant human activated protein C resets thrombin generation in patients with severe sepsis – a case control study
Authors: de Pont Anne-Cornélie JM , Bakhtiari Kamran , Hutten Barbara A , de Jonge Evert , Vroom Margreeth B , Meijers Joost CM , Büller Harry R , Levi Marcel
Published: July 2005

Introduction

Recombinant human activated protein C (rhAPC) is the first drug for which a reduction of mortality in severe sepsis has been demonstrated. However, the mechanism by which this reduction in mortality is achieved is still not clearly defined. The aim of the present study was to evaluate the dynamics of the anticoagulant, anti-inflammatory and pro-fibrinolytic action of rhAPC in patients with severe sepsis, by comparing rhAPC-treated patients with case controls.

Methods

In this prospectively designed multicenter case control study, 12 patients who were participating in the ENHANCE study, an open-label study of rhAPC in severe sepsis, were treated intravenously with rhAPC at a constant rate of 24 μg/kg/h for a total of 96 h. Twelve controls with severe sepsis matching the inclusion criteria received standard therapy. The treatment was started within 48 h after the onset of organ failure. Blood samples were taken before the start of the infusion and at 4, 8, 24, 48, 96 and 168 h, for determination of parameters of coagulation and inflammation.

Results

Sepsis-induced thrombin generation as measured by thrombin-antithrombin complexes and prothrombin fragment F1+2, was reset by rhAPC within the first 8 h of infusion. The administration of rhAPC did not influence parameters of fibrinolysis and inflammation. There was no difference in outcome or occurrence of serious adverse events between the treatment group and the control group.

Conclusion

Sepsis-induced thrombin generation in severely septic patients is reset by rhAPC within the first 8 h of infusion without influencing parameters of fibrinolysis and inflammation.
TRIBUTE: A Phase III Trial of Erlotinib Hydrochloride (OSI-774) Combined With Carboplatin and Paclitaxel Chemotherapy in Advanced Non–Small-Cell Lung Cancer
Authors: Herbst Roy S. , Prager Diane , Hermann Robert , Fehrenbacher Lou , Johnson Bruce E. , Sandler Alan , Kris Mark G. , Tran Hai T. , Klein Pam , Li Xin , Ramies David , Johnson David H. , Miller Vincent A.
Published: July 2005

Purpose

Erlotinib is a potent reversible HER1/epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor with single-agent activity in patients with non–small-cell lung cancer (NSCLC). Erlotinib was combined with chemotherapy to determine if it could improve the outcome of patients with NSCLC.

Patients and Methods

TRIBUTE randomly assigned patients with good performance status and previously untreated advanced (stage IIIB/IV) NSCLC to erlotinib 150 mg/d or placebo combined with up to six cycles of carboplatin and paclitaxel, followed by maintenance monotherapy with erlotinib. Random assignment was stratified by stage, weight loss in the previous 6 months, measurable disease, and treatment center. The primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response (OR), and duration of response.

Results

There were 1,059 assessable patients (526 erlotinib; 533 placebo). Median survival for patients treated with erlotinib was 10.6 v 10.5 months for placebo (hazard ratio, 0.99; 95% CI, 0.86 to 1.16; P = .95). There was no difference in OR or median TTP. Patients who reported never smoking (72 erlotinib; 44 placebo) experienced improved OS in the erlotinib arm (22.5 v 10.1 months for placebo), though no other prespecified factors showed an advantage in OS with erlotinib. Erlotinib and placebo arms were equivalent in adverse events (except rash and diarrhea).

Conclusion

Erlotinib with concurrent carboplatin and paclitaxel did not confer a survival advantage over carboplatin and paclitaxel alone in patients with previously untreated advanced NSCLC. Never smokers treated with erlotinib and chemotherapy seemed to experience an improvement in survival and will undergo further investigation in future randomized trials.
An optimized isolation and labeling platform for accurate microRNA expression profiling
Authors: SHINGARA JACLYN , KEIGER KERRI , SHELTON JEFFREY , LAOSINCHAI-WOLF WALAIRAT , POWERS PATRICIA , CONRAD RICHARD , BROWN DAVID , LABOURIER EMMANUEL
Published: July 2005

MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression in both plants and animals. miRNA genes have been implicated in a variety of important biological processes, including development, differentiation, apoptosis, fat metabolism, viral infection, and cancer. Similar to protein-coding messenger RNAs, miRNA expression varies between tissues and developmental states. To acquire a better understanding of global miRNA expression in tissues and cells, we have developed isolation, labeling, and array procedures to measure the relative abundance of all of the known human mature miRNAs. The method relies on rapid isolation of RNA species smaller than ~40 nucleotides (nt), direct and homogenous enzymatic labeling of the mature miRNAs with amine modified ribonucleotides, and hybridization to antisense DNA oligonucleotide probes. A thorough performance study showed that this miRNA microarray system can detect subfemtomole amounts of individual miRNAs from <1 μg of total RNA, with 98% correlation between independent replicates. The system has been applied to compare the global miRNA expression profiles in 26 different normal human tissues. This comprehensive analysis identified miRNAs that are preferentially expressed in one or a few related tissues and revealed that human adult tissues have unique miRNA profiles. This implicates miRNAs as important components of tissue development and differentiation. Taken together, these results emphasize the immense potential of microarrays for sensitive and high-throughput analysis of miRNA expression in normal and disease states.
A mutational analysis of U12-dependent splice site dinucleotides
Authors: DIETRICH ROSEMARY C. , FULLER JOHN D. , PADGETT RICHARD A.
Published: July 2005

Introns spliced by the U12-dependent minor spliceosome are divided into two classes based on their splice site dinucleotides. The /AU-AC/ class accounts for about one-third of U12-dependent introns in humans, while the /GU-AG/ class accounts for the other two-thirds. We have investigated the in vivo and in vitro splicing phenotypes of mutations in these dinucleotide sequences. A 5′ A residue can splice to any 3′ residue, although C is preferred. A 5′ G residue can splice to 3′ G or U residues with a preference for G. Little or no splicing was observed to 3′ A or C residues. A 5′ U or C residue is highly deleterious for U12-dependent splicing, although some combinations, notably 5′ U to 3′ U produced detectable spliced products. The dependence of 3′ splice site activity on the identity of the 5′ residue provides evidence for communication between the first and last nucleotides of the intron. Most mutants in the second position of the 5′ splice site and the next to last position of the 3′ splice site were defective for splicing. Double mutants of these residues showed no evidence of communication between these nucleotides. Varying the distance between the branch site and the 3′ splice site dinucleotide in the /GU-AG/ class showed that a somewhat larger range of distances was functional than for the /AU-AC/ class. The optimum branch site to 3′ splice site distance of 11–12 nucleotides appears to be the same for both classes.
Patterns of genotoxicity and contaminant exposure: Evidence of genomic instability in the marsh frogs (rana ridibunda) of sumgayit, azerbaijan
Authors: Matson Cole W. , Palatnikov Grigoriy M. , McDonald Thomas J. , Autenrieth Robin L. , Donnelly K.C. , Anderson Todd A. , Canas Jaclyn E. , Islamzadeh Arif , Bickham John W.
Published: July 2005

The wetlands of Sumgayit in the Azerbaijan Republic contain complex mixtures of contaminants, including polycyclic aromatic hydrocarbons (PAHs), mercury, organochlorine pesticides, and polychlorinated biphenyls. Marsh frogs (Rana ridibunda) were collected from several contaminated wetlands within the city as well as from two reference sites outside the city. Sediment samples revealed heterogeneous patterns of PAH and mercury concentrations throughout Sumgayit, with the highest levels occurring east of the Sumgayit River, within the industrial zone. Flow cytometry and micronucleus assay revealed elevated estimates of genetic damage in frogs from the wetlands east of the Sumgayit River compared to frogs from the reference sites. Flow cytometric data showed a significant correlation with sediment mercury concentrations, whereas population micronucleus frequencies were significantly correlated with high-molecular-weight PAHs.
Biodegradation of bisphenol a and disappearance of its estrogenic activity by the green alga Chlorella fusca var. vacuolata
Authors: Hirooka Takashi , Nagase Hiroyasu , Uchida Kotaro , Hiroshige Yuji , Ehara Yoshie , Nishikawa Jun-ichi , Nishihara Tsutomu , Miyamoto Kazuhisa , Hirata Zazumasa
Published: July 2005

Bisphenol A (BPA) is known as an endocrine disruptor and often is found in landfill leachates. Removal of BPA by green alga, Chlorella fusca, was characterized, because we previously found that various phenols were well removed by this strain, including BPA. Chlorella fusca was able to remove almost all BPA in the concentration range from 10 to 80 μM for 168 h under continuous illumination at 18 W/m2. At the low light intensity of 2 W/m2, 82% of 40 μM BPA was removed, and only 27% was removed in the dark. Moreover, C. fusca could remove 90% of 40 μM BPA under the 8:16-h light:dark condition, which was almost as high as that under the continuous-light condition. The amount of BPA contained in the cells was less than the amount of BPA removed from the medium. Monohydroxybisphenol A was detected as an intermediate of BPA degradation. Moreover, estrogenic activity that originated from BPA in the culture medium also completely disappeared. Based on these results, BPA was finally degraded to compounds having nonestrogenic activity. Therefore, C. fusca can be considered a useful organism to remove BPA from landfill leachates.
Phytotoxicity and phytoaccumulation of trivalent and hexavalent chromium in brake fern
Authors: Su Yi , Han Fengxiang X. , Sridhar B.B. Maruthi , Monts David L.
Published: July 2005

A recently recognized hyperaccumulator plant, Chinese brake fern (Pteris vittata), has been found to extract very high concentration of arsenic from arsenic-contaminated soil. Chromium usually is a coexisting contaminant with arsenic in most contaminated soils. The potential application of ferns for phytoremediation of chromium(III)- and chromium(VI)-contaminated soils and their phytotoxicity to ferns has not been studied before. In this study, chromium distribution and phytotoxicity at the plant and cellular levels of brake ferns were studied using chemical analyses and scanning electron microscopy. The results show a higher phytotoxicity of Cr from Cr(VI)-contaminated soil to Chinese brake fern than from Cr(III)-contaminated soil. Phytotoxicity symptoms included significant decreases both in fresh biomass weight and relative water content (RWC), and also in leaf chlorosis during the late stage of growing. At higher concentrations (500 mg/kg Cr[VI] and 1,000 mg/kg Cr[III] addition), plants showed reduction in the number of palisade and spongy parenchyma cells in leaves. Compared with other plant species reported for phytoremediation of Cr(VI)-contaminated soil, brake fern took up and accumulated significant amounts of Cr (up to 1,145 mg/kg in shoots and 5,717 mg/kg in roots) and did not die immediately from phytotoxicity. Our study suggests that Chinese brake fern is a potential candidate for phytoremediation of Cr(VI)-contaminated soils, even though plants showed severe phytotoxic symptoms at higher soil Cr concentrations.
Evaluation of adult quail and egg production following exposure to perchlorate-treated water
Authors: Gentles Angella , Surles James , Smith Ernest E.
Published: July 2005

Twenty-three adult female northern bobwhite (Colinus virginianus) quail were exposed to 0, 0.01, 0.1, and 1 mM ammonium perchlorate (AP) in drinking water for 30 d. Eggs laid in all treatment groups, including control, were collected, dated, given an identification number, and weighed. On day 30 of exposure, 10 birds were euthanized by carbon dioxide asphyxiation. Gross toxicological endpoints and thyroid histology were evaluated in 10 birds. Egg production and accumulation of perchlorate in the eggs (n = 10) and liver (n = 5) were determined. Perchlorate did not affect body or organ weights significantly; however, at 1 mM, AP caused alteration of thyroid gland morphology. Perchlorate did not affect egg production, but significant accumulation was observed in the eggs and livers of exposed birds.
Induction of vitellogenin mRNA in juvenile chinese sturgeon (acipenser sinensis gray) treated with 17β-estradiol and 4-nonylphenol
Authors: Zhang Zhaobin , Hu Jianying , Jin Wei An, Fen , An Lihui , Tao Shu , Chen Jingsheng
Published: July 2005

It has been demonstrated that 4-nonylphenol (4-NP) exerts estrogenic effects in diverse fishes. The present study investigated the effects of 4-NP on Chinese sturgeon (Acipenser sinensis Gray) vitellogenin (VTG) gene expression. By reverse transcription-polymerase chain reaction (RT-PCR) using degenerate primers, a 462-base pair fragment of Chinese sturgeon VTG. corresponding to a 154-amino acid sequence, was amplified and sequenced. This sequence exhibited 152/154 identity to the amino acid sequence of white sturgeon (A. transmontano) VTG. Conventional RT-PCR and quantitative real-time RT-PCR were established and used to study the VTG and β-actin gene expression in the liver of juvenile Chinese sturgeon injected three times with 17β-estradiol (5 mg/kg body wt/week) or 4-NP (10 or 100 mg/kg/week) in the course of three weeks. Significant induction of VTG gene expression was detected in all treated groups, and no VTG mRNA was detected in the control group. The ratio of VTG to β-actin analyzed from the results of quantitative real-time RT-PCR reached 0.041 ± 0.024 (mean ± SD) in the group receiving 10 mg/kg/week of 4-NP and 4.51 ± 1.68 in the group receiving 100 mg/kg/week of 4-NP. Chemical analysis of 4-NP showed that the concentrations of 4-NP in the 10 mg/kg/week group and the 100 mg/kg/week group were 2.78 ± 2.41 and 31.38 ± 0.26 μg/g wet weight, respectively. Compared with the 4-NP concentrations (0.8–1.92 μg/g wet wt) in fish from the Yangtze River, China, a potential hazard exists regarding 4-NP in Chinese sturgeon. These results represent the first indication of the risk of endocrine-disrupting chemicals for Chinese sturgeon.
Effect of coexposure to DDT and manganese on freshwater invertebrates: Pore water from contaminated rivers and laboratory studies
Authors: Mejía-Saavedra Jesús , Sánchez-Armass Sergio , Santos-Medrano Gustavo E. , Gonzáaaalez-Amaro Roberto , Razo-Soto Israel , Rico-Martínez Roberto , Díaz-Barriga Fernando
Published: July 2005

An environmental survey of several rivers of the southern Huasteca area of Mexico revealed high concentrations of manganese (Mn) and the presence of DDT in the sediments and pore water. Therefore, acute (48-h) toxicities of Mn and DDT were assessed both independently and as a combination on 24-h-old neonates of Daphnia magna Strauss and Lecane quadridentata Ehrenberg. Daphnia magna showed high sensitivity to both toxicants, whereas L. quadridentata was highly resistant to DDT and less susceptible to Mn. For D. magna, the Mn and DDT coexposure was significantly more toxic than any of the singly tested compounds. When D. magna was exposed to sediment pore water, no association was found between the Mn content in the samples and the observed toxicity. Preliminary particle analysis of pore water showed different compounds of Mn, which apparently were not in bioavailable form.
Earthworm toxicity during chemical oxidation of diesel-contaminated sand
Authors: Shin Kyung-Hee , Jung Haeryong , Chang Peichun , Choi Heechul , Kim Kyoung-Woong
Published: July 2005

An ecotoxicity test with Eisenia fetida was performed to monitor the removal of diesel and toxicity variation during the ozonation process. The three-dimensional (3-D) cell test was introduced for the monitoring of the ozonation process, and the removal rate based on total petroleum hydrocarbons (TPHs) mass was about 95% near the ozone inlet ports. This high removal rate might be caused by the low soil organic matter (SOM) content and low water content of sand. The use of a fiber-optic transflection dip probe (FOTDP) demonstrated that more than half of the injected ozone was consumed by reactions with diesel or natural ozone-consuming materials. The earthworm toxicity test using Eisenia fetida demonstrated that diesel concentrations in soil exceeding 10,000 mg/kg caused a dose-dependent weight loss in earthworms and increased mortality. Toxic effects were reduced greatly or eliminated after ozonation, and the degradation products of the ozonation were not toxic to the earthworms at the concentrations tested. One specific result was that the sublethal test on the earthworm might be more sensitive for the evaluation of the quality of contaminated soil, for some samples, which did not result in mortality and produced an adverse effect on weight.
Effects of dredging in göteborg harbor, sweden, assessed by biomarkers in eelpout (zoarces viviparus)
Authors: Sturve Joachim , Berglund Åsa , Balk Lennart , Broeg Katja , Böhmert Björn , Massey Simon , Savva Demetris , Parkkonen Jari , Stephensen Eiríkur , Koehler Angela , Förlin Lars
Published: July 2005

We used a battery of biomarkers in fish to study the effects of the extensive dredging in Göteborg harbor situated at the river Göta älv estuary, Sweden. Eelpout (Zoarces viviparus) were sampled along a gradient into Göteborg harbor, both before and during the dredging. Biomarker responses in the eelpout before the dredging already indicated that fish in Göteborg harbor are chronically affected by pollutants under normal conditions compared to those in a reference area. However, the results during the dredging activities clearly show that fish were even more affected by remobilized pollutants. Elevated ethoxyresorufin-O-deethylase activities and cytochrome P4501A levels indicated exposure to polycyclic aromatic hydrocarbons. Elevated metallothionein gene expression indicated an increase in metal exposure. An increase in general cell toxicity, measured as a decrease in lysosomal membrane stability, as well as effects on the immune system also could be observed in eelpout sampled during the dredging. The results also suggest that dredging activities in the Göta älv estuary can affect larger parts of the Swedish western coast than originally anticipated. The present study demonstrates that the application of a set of biomarkers is a useful approach in monitoring the impact of anthropogenic activities on aquatic environments.
Isomer selectivity in aquatic toxicity and biodegradation of bifenthrin and permethrin
Authors: Liu Weiping , Gan Jianying , Lee Sangjin , Werner Inge
Published: July 2005

Synthetic pyrethroids are widely used insecticides, and contamination of surface aquatic ecosystems by pyrethroid residues from runoff is of particular concern because of potential aquatic toxicity. Pyrethroids also are chiral compounds consisting of multiple stereoisomers. In the present study, we evaluated the diastereomer and enantiomer selectivity of cis-bifenthrin (cis-BF) and permethrin (PM) in their aquatic toxicity and biodegradation. The 1R-cis enantiomer was the only enantiomer in cis-BF showing toxicity against Ceriodaphnia dubia. Incubation with pesticide-degrading bacteria showed that the trans diastereomer of PM was selectively degraded over the cis diastereomer, whereas the 1S-cis enantiomer in cis-BF or cis-PM was preferentially degraded over the corresponding 1R-cis enantiomer. The enantioselectivity was significantly greater for cis-PM than for cis-BF and also varied among different strains of bacteria. Isomer selectivity may be a common phenomenon in both aquatic toxicity and biodegradation of pyrethroids, and this should be considered when assessing ecotoxicological risks of these compounds in sensitive ecosystems.
Raoult's law-based method for determination of coal tar average molecular weight
Authors: Brown Derick G. , Gupta Lovleen , Moo-Young Horace Keith , Coleman Andrew J.
Published: July 2005

A Raoult's law-based method for determining the number average molecular weight of coal tars is presented. The method requires data from two-phase coal tar/water equilibrium experiments, which readily are performed in environmental laboratories. An advantage of this method for environmental samples is that it is not impacted by the small amount of inert debris often present in coal tar samples obtained from contaminated sites. Results are presented for 10 coal tars from nine former manufactured gas plants located in the eastern United States. Vapor pressure osmometry (VPO) analysis provided similar average molecular weights to those determined with the Raoult's law-based method, except for one highly viscous coal tar sample. Use of the VPO-based average molecular weight for this coal tar resulted in underprediction of the coal tar constituents' aqueous concentrations. Additionally, one other coal tar was not completely soluble in solvents used for VPO analysis. The results indicate that the Raoult's law-based method is able to provide an average molecular weight that is consistent with the intended application of the data (e.g., modeling the dissolution of coal tar constituents into surrounding waters), and this method can be applied to coal tars that may be incompatible with other commonly used methods for determining average molecular weight, such as vapor pressure osmometry.