Biomedical subjects

Andrea Baccarelli

Publications and source records attributed to Andrea Baccarelli.

At least 19 recordsLinked to original sources

PubMed2026

Blood mitochondrial heteroplasmic variants and cognitive performance in late midlife: REGARDS study.

BACKGROUND: Studies linking mitochondrial DNA (mtDNA) variants to cognition yielded inconsistent findings, and the underlying mechanisms remain unclear. We investigated whether mtDNA heteroplasmic variants were associated with cognitive outcomes, including the Montreal Cognitive Assessment (MoCA), in 197 late midlife adults from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort with complete data. METHODS: MtDNA was sequenced from blood using targeted deep sequencing. Adjusted linear and mixed-effects models examined the associations by functional regions, genes, total variant burden, nonsynonymous variants, and control regions. RESULTS: Heteroplasmic variants in the control region (β = -0.44, 95% CI: -0.83, -0.05, p = 0.027) and transfer RNA (tRNA) genes (β = -1.34, 95% CI: -2.58, -0.11, p = 0.034) were associated with MoCA baseline scores. Individual variants in cytochrome c oxidase subunit 1 (CO1) (β = -1.51, 95% CI: -2.54, -0.47, p = 0.005), NADH dehydrogenase subunit 1 (ND1) (β = -2.63, 95% CI: -4.56, -0.70, p = 0.008), and Displacement Loop (D-LOOP2) (β = -2.25, 95% CI: -4.20, -0.30, p = 0.025) was associated with reduced baseline MoCA scores. The ND6 (β = −1.23, 95% CI: −2.09, − 0.37, p = 0.006), ND4 (β = −1.11, 95% CI: −2.02, − 0.20, p = 0.018), ATP Synthase Membrane Subunit 8 (ATP8; β = −1.38, 95% CI: −2.63, − 0.13, p = 0.031), and D-LOOP1 (β = −0.61, 95% CI: −1.20, − 0.01, p = 0.045) genes suggested a potential association with executive function. Longitudinal Animal Fluency Test (AFT) scores were inversely associated with heteroplasmic variants in coding regions (β = -0.10, 95% CI: -0.19, -0.006, p = 0.049), the total number of variants (β = -0.06, 95% CI: -0.11, -0.003, p = 0.037) and total nonsynonymous variants (β = -0.11, 95% CI: -0.21, -0.01, p = 0.040). Variants in the control region were associated with the greatest decline in verbal fluency (β = −0.20, 95% CI: −0.39 to − 0.002, p = 0.049). No associations were observed between mitochondrial variants and verbal memory performance or the MoCA composite scores. CONCLUSIONS: Our study indicates that mitochondrial variants measured in blood may provide insight into cognitive function during midlife. However, additional studies are needed to validate these associations and to address potential power limitations in our study.

Humans↗

PubMed2006

Mannose-binding lectin-2 genetic variation and stomach cancer risk.

Deficiency of the mannose-binding lectin (MBL) protein, an antigen-recognition molecule involved in systemic and mucosal innate immunity, is determined by variant alleles in MBL2 gene promoter and exon-1 regions. We conducted a population-based study on 305 stomach cancer cases and 427 controls in Warsaw, Poland to determine whether MBL2 gene variants predispose to stomach cancer. Single nucleotide polymorphisms (SNPs) in MBL2 were determined by TaqMan. The 5 tested MBL2 variants are in complete linkage disequilibrium and comprise 6 different haplotypes. The risk of stomach cancer was increased in subjects carrying the H/H promoter genotype (OR = 1.8, 95%CI 1.1-2.9; p = 0.020) relative to L/L carriers, after adjustment for age, gender, education and smoking. Carrying at least one D exon-1 allele was associated with nonsignificant excess risk (OR = 1.5, 95% CI 0.9-2.4; p = 0.081). In haplotype analysis, the HYD haplotype was associated with increased risk of stomach cancer when compared with HYA, the most common haplotype (OR = 1.9, 95% CI 1.1-3.2; p = 0.021). In diplotype analysis, subjects carrying the YA/D haplotype combination showed the highest risk (OR = 3.0, 95% CI 1.2-7.1; p = 0.015), compared with YA/YA. Further analyses to examine the joint effect of MBL2 and IL-1B polymorphisms, previously shown to predispose to stomach cancer, indicated that the combination of at-risk IL-1B genotypes (CT or TT at location -511) and HYD MBL2 haplotype was associated with a 3.5-fold risk (OR = 3.5, 95% CI 1.6-7.6; p = 0.001). Our findings suggest that the codon 52 D MBL2 variant causing a cysteine > arginine replacement, but not B and C variants producing glycine substitutions, is specifically associated with gastric cancer risk.

Adult↗

PubMed2006

Antibacterial-coated tracheal tubes cleaned with the Mucus Shaver : a novel method to retain long-term bactericidal activity of coated tracheal tubes.

OBJECTIVE: To assess the long-term benefit from antibacterial coatings of the tracheal tube (ETT), and to keep clean the lumen of the ETT. DESIGN: Experimental animal study. SETTING: USA National Institutes of Health. SUBJECTS: Twelve sheep. INTERVENTIONS: Twelve ETTs were internally dip-coated with a silver-sulfadiazine in polyurethane. We developed a concentric inflatable silicone rubber "razor", the Mucus Shaver (MS), to shave the ETT lumen free of mucus. In a single pass, we cleaned all mucus from the internal surface of the ETT. CONTROL GROUP: Five intubated sheep were mechanically ventilated for 72 h. The ETT was suctioned every 6 h. STUDY GROUP: Six sheep were intubated and mechanically ventilated for 72 h. The ETT was suctioned and cleaned with the MS every 6 h. An additional sheep was intubated and mechanically ventilated for 168 h. Bacteriologic studies and scanning electron microscopy were performed to assess bacterial colonization and thickness of secretions on the internal surface of the ETT. MEASUREMENTS AND MAIN RESULTS: In the control group, the ETT was always heavily colonized: median debris thickness was 380 microm, range 270-550 microm. In the study group, there was no colonization and no secretions in the ETT, except for three ETT that were colonized solely at the very tip. CONCLUSIONS: Silver-based coating of ETT cleaned with the MS every 6 h significantly reduces accumulation of mucus/secretion and bacterial growth within the ETT following 72 h of mechanical ventilation.

Animals↗

PubMed2006

t(14;18) translocations in lymphocytes of healthy dioxin-exposed individuals from Seveso, Italy.

Dioxin exposure has been associated with non-Hodgkin's lymphoma (NHL) in epidemiological investigations. The NHL-related t(14;18) translocations can be detected at a low copy number in lymphocytes from healthy subjects. Exposure to NHL-associated carcinogens, such as dioxin or pesticides, may cause expansion of t(14;18)-positive clones. We investigated prevalence and frequency of circulating t(14;18)-positive lymphocytes in 144 healthy subjects from a population exposed to dioxin [plasma TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) range: <1.7-475.0 parts per trillion (p.p.t.)] after the Seveso, Italy, accident of 1976. t(14;18) translocations were measured in DNA from peripheral blood lymphocytes by high-sensitivity real-time quantitative polymerase chain reaction. We found that the frequency, but not the prevalence, of t(14;18) translocation-positive cells increased with increasing plasma TCDD. Among t(14;18)-positive subjects (n = 50;34.7%), the mean number of t(14;18) translocations/10(6) lymphocytes was 4.2 [95% confidence interval (CI), 2.9-6.2] in subjects with plasma TCDD < 10.0 p.p.t., 8.1 (95% CI, 4.9-13.3) in subjects with plasma TCDD between 10.0 and 50.0 and 12.5 (95% CI, 7.4-21.1) in subjects with plasma TCDD between 50.0 and 475.0 p.p.t. (P-trend = 0.003). As expected, t(14;18) frequency was associated with cigarette smoking and was highest in subjects who smoked for > or =16 years (mean = 12.6; 95% CI, 7.4-21.3; P = 0.01). Higher t(14;18) prevalence was found among individuals with fair hair color (P = 0.01) and light eye color (P = 0.04). No significant association between t(14;18)-and age was found. Our results show that dioxin exposure is associated with increased number of circulating t(14;18) positive cells. Whether this change in t(14;18) frequency is an indicator of elevated lymphoma risk remains speculative and needs further investigation for its potential impact on public health.

Adolescent↗

PubMed2006

Risk of lung cancer from exposure to dusts and fibers in Leningrad Province, Russia.

BACKGROUND: Exposures to several dusts and fibers (DFs) have been established or suggested as etiologic factors for lung cancer. METHODS: To investigate lung cancer risk in relation to exposure to DFs, we identified 540 pathologically-diagnosed lung cancer cases and 582 controls from the 1993-1998 autopsy records of the 88 hospitals of Leningrad Province, Russia. Lifetime job-specific exposure measurements were available for 15 organic, 15 man-made and 28 natural-inorganic agents. RESULTS: In male workers, increased risks were found for linen dust (OR = 3.68, 95% CI 1.00-13.6, adjusted for age, smoking and residence), and unspecified DFs (OR = 1.44, 95% CI 1.07-1.94). Small non-significant excess risks were observed for quartz dust (OR = 1.27; 95% CI 0.83-1.93) and man-made vitreous fibers (MMVFs) (OR = 1.82, 95% CI 0.88-3.75). In female subjects, risks were non-significantly associated with paper dust (OR = 1.77, 95% CI 0.74-4.20), and unspecified DFs (OR = 1.52, 95% CI 0.77-3.03). CONCLUSIONS: The study showed increased lung cancer risk for selected categories of DFs.

Adult↗

PubMed2006

Risk of lung cancer and exposure to industrial acids, solvents, and metals in leningrad province, Russia.

OBJECTIVE: We sought to investigate the association of occupational exposure to industrial acids, solvents, and metals with lung cancer in Leningrad Province, Russia, where an excess of occupationally related lung cancer was reported recently. METHODS: We identified 540 pathologically diagnosed lung cancer cases and 582 controls from the 1993-1998 autopsy records of the 88 Leningrad Province hospitals. Lifetime job-specific exposure measurements were available for 12 industrial acids, 15 solvents, and 17 metals. RESULTS: Exposures were frequent in the study group and mostly occurred after World War II. However, lung cancer risks for industrial acids (odds ratio [OR] = 1.2; 95% confidence interval [CI] = 0.8-1.7), solvents (OR = 0.8; 95% CI = 0.6-1.2), and metals (OR = 0.8; 95% CI = 0.5-1.0) were not increased. Also, no significant excess risk was found for any of the specific agents investigated. CONCLUSIONS: The excess of occupationally related lung cancer in the Province is not explained by exposure to the agents investigated.

Acids↗

PubMed2005

The role of CXCR4 receptor expression in breast cancer: a large tissue microarray study.

The chemokine receptor CXCR4 is an important factor in the migration, invasiveness, metastasis and proliferation of breast cancer cells. We have retrospectively analyzed the levels of expression of CXCR4 in a large cohort of breast cancers and pre-invasive breast samples linked to clinical data. A total of 1808 invasive breast carcinomas and 214 pre-invasive breast samples could be analyzed in correlation with basic clinico-pathological data such as hormone receptor status, HER2 status and tumor grade. The majority of breast cancers expressed either nuclear or cytoplasmic staining or both. CXCR4 cytoplasmic expression was associated with parameters of tumor aggressivity (tumor grade and lymph node status) and had prognostic value (age-adjusted hazard ratio=1.73; Confidence Interval: 1.07-2.77) with respect to disease-specific survival. CXCR4 positivity in the cytoplasm but not the nucleus was associated with HER2 expression and amplification as well as with hormone receptor negativity (both ER and PR). The percentage of nuclear staining increased from normal breast tissue (20%) to ductal carcinoma-in-situ DCIS (43%) to invasive cancer (67%) while CXCR4 was expressed in the cytoplasm of 67% of (DCIS) cases (double that in normal breast samples), suggesting an important role in breast tumor progression. The CXCR4 receptor is expressed in many breast cancers, justifying its development as a therapeutic target in breast cancer patients. Its cytoplasmic expression is associated with breast tumor progression, suggesting potential value as a diagnostic marker.

Adult↗

PubMed2005

Pesticide exposure and lung cancer mortality in Leningrad province in Russia.

This study was carried out to examine the association between pesticide exposure and lung cancer mortality. We conducted an autopsy based case-control study in Leningrad Province in Russia. A total of 540 lung cancer cases and 582 controls were identified among subjects who had died in the hospitals of the Leningrad province between 1993 and 1998. Using work history records, we assessed exposure to pesticide at the level of industry and job title. Unconditional logistic regression was used to calculate adjusted odds ratio for pesticide exposure and lung cancer mortality. There was no association between ever exposure to pesticide and lung cancer mortality overall (odds ratio=1.06, 95% confidence interval=0.82-1.36) and in both men (odds ratio=1.11, 95% confidence interval=0.84-1.46) and women (odds ratio=0.74, 95% confidence interval=0.37-1.46). We observed no statistically significant odds ratio by duration of pesticide exposure, intensity of pesticide exposure, and cumulative pesticide exposures with lung cancer mortality in both smokers and nonsmokers. Odds ratio also did not differ when the analysis was restricted to individuals who had exposure data with high confidence scores. Our findings suggest no associations between pesticide exposures and mortality of lung cancer in the population of the Leningrad province in Russia that deserves further evaluation.

Aged↗

PubMed2005

Comparison between six-year therapy with long-acting somatostatin analogs and successful surgery in acromegaly: effects on cardiovascular risk factors.

CONTEXT: The effects of chronic therapy with long-acting somatostatin analogs (SSTa) on metabolic and cardiovascular parameters have been partially elucidated in acromegalic patients. OBJECTIVE: The objective of this study was to compare the long-term effects of SSTa treatment and successful surgery on GH/IGF-I secretion and cardiovascular risk parameters in acromegaly. DESIGN, PATIENTS, AND INTERVENTION: This was a retrospective study of 36 acromegalic patients treated with SSTa and evaluated after a median of 66 months and of 33 sex-, age-, and body mass index-matched cured patients evaluated after a similar period of remission, all from the Institute of Endocrine Sciences (Milan, Italy). MAIN OUTCOME MEASURES: The main outcome measures were fasting and post-oral load glucose homeostasis, hemoglobin A(1c), insulin sensitivity and secretion by several indexes, lipid profile, and blood pressure. RESULTS: Fasting and areas under the glucose response curve rose in patients controlled (n = 29) and not controlled (n = 7) by SSTa, becoming higher than those in cured subjects. A 1% hemoglobin A(1c) increase was observed in all nondiabetic SSTa patients, but not in cured subjects. Basal insulin secretion and resistance, evaluated by homeostasis model assessment, decreased in all SSTa patients, whereas oral glucose tolerance test-derived insulin secretion and resistance, evaluated by insulinogenic index and oral glucose tolerance test-derived insulin secretion, improved only in SSTa-treated controlled patients. Triglycerides did not change during SSTa, whereas high-density lipoprotein cholesterol increased in SSTa-treated controlled patients. At the last visit, the contemporary presence of at least three cardiovascular risk factors was more frequent in patients treated with SSTa than in cured subjects. CONCLUSIONS: SSTa therapy induces long-lasting disease control and improvement of insulin sensitivity and high-density lipoprotein cholesterol levels in responsive patients. The progressive glucose homeostasis alterations, observed independently from the degree of cure, suggest the need for glucose homeostasis and peripheral vascular complications monitoring during chronic SSTa treatment.

Acromegaly↗

PubMed2005

Dioxin effects on neonatal and infant thyroid function: routes of perinatal exposure, mechanisms of action and evidence from epidemiology studies.

OBJECTIVES: Animal experiments suggest that thyroid function alterations in newborns and infants may represent one of the most sensitive markers of toxicity from 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Dioxin can be transferred from the mother to the offspring either in utero or through lactation. It has been suggested that thyroid-hormone alterations produced by dioxin in utero or shortly after birth may underlie long-term effects, such as cognitive-ability and neurodevelopment impairment. In the present review article, we appraise available evidence on the effects of perinatal exposure to dioxin on fetal and infant thyroid function. METHODS: We summarized the routes of perinatal dioxin exposure and research results on possible mechanisms of dioxin toxic effects on thyroid function. We performed a systematic review of epidemiology studies conducted on mother-child pairs exposed to background environmental levels to investigate dioxin effects on neonatal and infant thyroid function. RESULTS: Toxicological and mechanistic data indicate that dioxin may impair thyroid function in exposed newborns and infants. Investigations on background-exposed children have not consistently demonstrated an association between perinatal TCDD exposure and thyroid function, although some of the studies suggest that sub-clinical hypothyroidism may be induced by perinatal dioxin exposure within 3 months from birth. Between studies inconsistencies may be related to lab method differences, mixed exposures, and small sample size of the populations evaluated. CONCLUSION: Epidemiology studies have as yet failed to demonstrate an association between perinatal TCDD exposure and thyroid function alterations in human subjects, although suggestive evidence from animal and in-vitro experimental data is available.

Dioxins↗

PubMed2005

Handling of dioxin measurement data in the presence of non-detectable values: overview of available methods and their application in the Seveso chloracne study.

Exposure measurements of concentrations that are non-detectable or near the detection limit (DL) are common in environmental research. Proper statistical treatment of non-detects is critical to avoid bias and unnecessary loss of information. In the present work, we present an overview of possible statistical strategies for handling non-detectable values, including deletion, simple substitution, distributional methods, and distribution-based imputation. Simple substitution methods (e.g., substituting 0, DL/2, DL/ radical2, or DL for the non-detects) are the most commonly applied, even though the EPA Guidance for Data Quality Assessment discouraged their use when the percentage of non-detects is >15%. Distribution-based multiple imputation methods, also known as robust or "fill-in" procedures, may produce dependable results even when 50-70% of the observations are non-detects and can be performed using commonly available statistical software. Any statistical analysis can be conducted on the imputed datasets. Results properly reflect the presence of non-detectable values and produce valid statistical inference. We describe the use of distribution-based multiple imputation in a recent investigation conducted on subjects from the Seveso population exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in which 55.6% of plasma TCDD measurements were non-detects. We suggest that distribution-based multiple imputation be the preferred method to analyze environmental data when substantial proportions of observations are non-detects.

Acne Vulgaris↗

PubMed2005

CYP1A1 Val462 and NQO1 Ser187 polymorphisms, cigarette use, and risk for colorectal adenoma.

Cigarette use is a risk factor for colorectal adenoma, a known precursor of colorectal cancer. Polymorphic variants in NQO1 and CYP1A1 influence the activation of carcinogenic substances in tobacco smoke, possibly impacting on tobacco-associated risks for colorectal tumors. We investigated the association of cigarette smoking with risk for advanced colorectal adenoma in relation to the CYP1A1 Val(462) and NQO1 Ser(187) polymorphic variants. Subjects were 725 non-Hispanic Caucasian cases with advanced colorectal adenoma of the distal colon (descending colon, sigmoid and rectum) and 729 gender- and ethnicity-matched controls, randomly selected from participants in the prostate, lung, colorectal and ovarian cancer screening trial. Subjects carrying either CYP1A1 Val(462) or NQO1 Ser(187) alleles were weakly associated with risk of colorectal adenoma; however, subjects carrying both CYP1A1 Val(462) and NQO1 Ser(187) alleles showed increased risks (OR = 2.2, 95% CI = 1.1-4.5), particularly among recent (including current) (OR = 17.4, 95% CI = 3.8-79.8, P for interaction = 0.02) and heavy cigarette smokers (>20 cigarettes/day) (OR = 21.1, 95% CI = 3.9-114.4, P for interaction = 0.03) compared with non-smokers who did not carry either of these variants. These genotypes were unassociated with risk in non-smokers. In analysis of adenoma subtypes, the combined gene variants were most strongly associated with the presence of multiple adenoma (P = 0.002). In summary, joint carriage of CYP1A1 Val(462) and NQO1 Ser(187) alleles, particularly in smokers, was related to colorectal adenoma risk, with a propensity for formation of multiple lesions.

Adenoma↗

PubMed2005

CYP1A1 and CYP1B1 genotypes, haplotypes, and TCDD-induced gene expression in subjects from Seveso, Italy.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is highly toxic in experimental animals, and is known to induce cytochrome P450 (CYP) gene expression. We investigated the effect of CYP1A1 and CYP1B1 variant genotypes and haplotypes on CYP1A1 and CYP1B1 mRNA expression and ethoxyresorufin-O-deethylase (EROD) activity in lymphocytes from 121 subjects from the Seveso population, Italy, accidentally exposed to TCDD in 1976. The 3'UTR 3801T>C and I462V variants of CYP1A1 were present in 16% and 6% of the subjects, respectively. The frequency of CYP1B1 variants was 85.2% for L432V, 49.6% for R48G and A119S, and 28.7% for N453S. There was complete linkage disequilibrium (LD) among the CYP1B1 variant loci (D'=-1) and high LD among the CYP1A1 loci (D'=0.86). Gene expression measured by RT-PCR did not vary by CYP1B1 genotype in uncultured lymphocytes. However, when lymphocytes were treated in vitro with 10 nM TCDD, CYP1B1 and CYP1A1 mRNA expression was strongly induced and modified by CYP variant alleles. Specifically, the CYP1B1*3 haplotype (L432V) was associated with increased CYP1B1 mRNA expression (P=0.03), following an additive model; the CYP1A1 I462V polymorphism was positively, although not significantly, associated with CYP1A1 expression. The CYP1B1*3 variant may have affected CYP1B1 expression in subjects highly and acutely exposed to dioxin at the time of the accident. Although based on small number of subjects, a slight increase in eczema (P=0.05, n=8) and urticaria (P=0.02, n=2) was observed 20 years after the accident in subjects carrying the CYP1B1*3 allele. Genetic variation in cytochrome P450 induction may identify subjects with variable responsiveness to TCDD and potentially increased risk of disease.

Aryl Hydrocarbon Hydroxylases↗

PubMed2004

Aryl-hydrocarbon receptor-dependent pathway and toxic effects of TCDD in humans: a population-based study in Seveso, Italy.

Approximately 20 years after the Seveso, Italy accident, we conducted a population-based study to evaluate the impact of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure upon immune and mechanistically based biomarkers of dioxin response in humans. TCDD toxic effects are known to be mediated by the aryl-hydrocarbon receptor (AhR). We randomly selected 62 study subjects from the highest exposed zones and 59 from the surrounding non-contaminated area. Current lipid-adjusted plasma TCDD concentrations in these subjects ranged from 3.5 to 90 ng/kg (or ppt) and were negatively associated with plasma IgG concentrations (r=-0.35; P = 0.0002). The expression of genes in the AhR-dependent pathway, including AhR, aryl-hydrocarbon receptor nuclear translocator (ARNT), CYP1A1, and CYP1B1 transcripts, and the CYP1A1-associated 7-ethoxyresorufin-O-deethylase (EROD) activity was measured in lymphocytes. AhR mRNA levels in uncultured lymphocytes were negatively associated with plasma TCDD (P=0.03). When mitogen-induced lymphocytes were cultured with 10nM TCDD, all AhR-dependent genes were induced 1.2- to 13-fold. In these cells, plasma TCDD was associated with decreased EROD activity. Markers within the AhR pathway were correlated with one another. Our findings suggest the presence of long-term effects in the subjects exposed to TCDD after the Seveso accident.

Adult↗

PubMed2004

Endotracheal tubes coated with antiseptics decrease bacterial colonization of the ventilator circuits, lungs, and endotracheal tube.

BACKGROUND: Formation of a bacterial biofilm within the endotracheal tube (ETT) after tracheal intubation is rapid and represents a ready source of lung bacterial colonization. The authors investigated bacterial colonization of the ventilator circuit, the ETT, and the lungs when the ETT was coated with silver-sulfadiazine and chlorhexidine in polyurethane, using no bacterial/viral filter attached to the ETT. METHODS: Sixteen sheep were randomized into two groups. Eight sheep were intubated with a standard ETT (control group), and eight were intubated with a coated ETT (study group). Animals were mechanically ventilated for 24 h. At autopsy, the authors sampled the trachea, bronchi, lobar parenchyma, and ETT for quantitative bacterial cultures. Qualitative bacterial cultures were obtained from the filter, humidifier, inspiratory and expiratory lines, and water trap. ETTs were analyzed with light microscopy, scanning electron microscopy, and laser scanning confocal microscopy. RESULTS: In the control group, all eight ETTs were heavily colonized (10(5)-10(8) colony-forming units [cfu]/g), forming a thick biofilm. The ventilator circuit was always colonized. Pathogenic bacteria colonized the trachea and the lungs in five of eight sheep (up to 10(9) cfu/g). In the study group, seven of eight ETTs and their ventilator circuits showed no growth, with absence of a biofilm; one ETT and the respective ventilator circuit showed low bacterial growth (10(3)-10(4) cfu/g). The trachea was colonized in three sheep, although lungs and bronchi showed no bacterial growth, except for one bronchus in one sheep. CONCLUSIONS: Coated ETTs induced a nonsignificant reduction of the tracheal colonization, eliminated (seven of eight) or reduced (one of eight) bacterial colonization of the ETT and ventilator circuits, and prevented lung bacterial colonization.

Animals↗

PubMed2004

Evaluation of continuous aspiration of subglottic secretion in an in vivo study.

OBJECTIVE: Continuous aspiration of subglottic secretions (CASS) is believed to lower the incidence of ventilator-associated pneumonia. Animal studies to establish safety and efficacy of CASS have not been conducted. DESIGN: Prospective randomized animal study. SETTING: Animal-research facility at the U.S. National Institutes of Health. SUBJECTS: Twenty-two sheep. INTERVENTIONS: Sheep were randomized into three groups. In group C (control), eight sheep were kept prone, intubated with a standard endotracheal tube (ETT), and mechanically ventilated for 72 hrs with head and ETT elevated at an angle of 30 degrees. In group CASS-HU (CASS, head up), seven sheep were managed as group C and intubated with a Hi-Lo Evac, Mallinckrodt ETT (CASS suction kept at < or =20 mm Hg). In group CASS-HD (CASS, head down), seven sheep were kept prone with CASS, and the ETT and trachea were horizontal to promote spontaneous drainage of mucus from the ETT. MEASUREMENTS AND RESULTS: The lower respiratory tract in the CASS-HU group was heavily colonized in all seven sheep (median 4.6 x 10(9), range, 1.5 x 10(8) to 7.9 x 10(9) colony-forming units/g), with a reduction of lung bacterial colonization compared with the C group (p = .05). In group CASS-HD, the lower respiratory tract was not colonized in six of seven sheep. One sheep showed low levels of bacterial growth (median, 0; range, 0-2.2 x 10(5)). At autopsy, in all 14 sheep with CASS, we found tracheal mucosal injury of different degrees of severity at the level of the suction port of the ETT. CONCLUSIONS: In group CASS-HU, regardless of finding a marginal decrease of the bacterial colonization of the lower airways, there was pervasive trachea-bronchial-lung bacterial colonization. Second, there was minimal, or absent, bacterial colonization when the orientation of the CASS ETT was at, or just below, horizontal. Third, there was widespread injury to tracheal mucosa/submucosa from the use of CASS. Note that results of studies conducted in an animal model are always difficult to extrapolate to the clinical practice due to anatomical and functional differences.

Animals↗

PubMed2004

Dioxin revisited: developments since the 1997 IARC classification of dioxin as a human carcinogen.

In 1997 the International Agency for Research on Cancer (IARC) classified 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; the most potent dioxin congener) as a group 1 carcinogen based on limited evidence in humans, sufficient evidence in experimental animals, and extensive mechanistic information indicating that TCDD acts through a mechanism involving the aryl hydrocarbon receptor (AhR), which is present in both humans and animals. The judgment of limited evidence in humans was based primarily on an elevation of all cancers combined in four industrial cohorts. The group 1 classification has been somewhat controversial and has been challenged in the literature in recent years. In this article we review the epidemiologic and mechanistic evidence that has emerged since 1997. New epidemiologic evidence consists primarily of positive exposure-response analyses in several of the industrial cohorts, as well as evidence of excesses of several specific cancers in the Seveso accident cohort. There are also new data regarding how the AhR functions in mediating the carcinogenic response to TCDD. The new evidence generally supports the 1997 IARC classification.

Accidents, Occupational↗

PubMed2003

TCDD-mediated alterations in the AhR-dependent pathway in Seveso, Italy, 20 years after the accident.

Approximately 20 years after the Seveso, Italy, accident we conducted a population-based study to evaluate the impact of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure on cancer using mechanistically based biomarkers of dioxin response in humans. TCDD toxic effects are mediated by the aryl hydrocarbon receptor (AhR). We studied the AhR-dependent pathway in lymphocytes from 62 subjects randomly sampled from the highest exposed zones and 59 subjects from the surrounding non-contaminated area, frequency matched for age, gender and smoking. To our knowledge, this is the most comprehensive investigation to date designed to evaluate the key genes in the pathway, including AhR, aryl hydrocarbon receptor nuclear translocator, CYP1A1 and CYP1B1 transcripts and CYP1A1-associated 7-ethoxyresorufin O-deethylase (EROD) activity in a population heavily exposed to dioxin. Current lipid-adjusted plasma TCDD concentrations in these subjects ranged from 3.5 to 90 ng/kg (or p.p.t.) and were negatively associated with AhR mRNA in unstimulated peripheral blood mononuclear cells (P = 0.03). When mitogen-induced lymphocytes were cultured with 10 nM TCDD, all AhR-dependent genes were induced 1.2- to 13-fold. In these cells, plasma TCDD was associated with decreased EROD activity. In addition, there was a strong positive correlation between AhR and CYP1A1 expression (P = 0.001) and between AhR and CYP1B1 expression (P = 0.006). CYP1A1 expression was also strongly correlated with EROD activity (P = 0.001). The analysis of the expression of dioxin-inducible genes involved in carcinogenesis may help in determining dose-response relationships for human exposure to dioxin in vivo and in assessing the variability of human response, which may indicate the presence of subjects more susceptible to disease as a result of such exposures.

Aryl Hydrocarbon Hydroxylases↗