JCL roundtable: Lipids and inflammation in atherosclerosis

Clinical effort in lipidology focuses largely on mitigating effects of atherosclerosis, a pathologic process localized to the intimal layer of larger arteries. This JCL Roundtable brings together 3 leading researchers to discuss the current understanding of pathogenesis in atherosclerosis. We begin by recognizing that low density lipoprotein concentrations in arterial intima far exceed concentrations in other connective tissues, consistent with the response-to-retention hypothesis of atherogenesis. High density lipoproteins facilitate reverse cholesterol transport and also have antioxidant and anti-inflammatory roles. New evidence points to remnants of triglyceride-rich lipoproteins as promoters of atherogenesis, highlighted by deleterious effects of apolipoprotein C-III. The multifaceted role of inflammation is becoming clearer through discoveries related to leukocyte recruitment, efferocytosis, resolution of inflammation, and crystal formation. MicroRNAs represent a new, complex mode of gene regulation bearing on lipoprotein and inflammation biology. Progress in understanding atherosclerosis portends a future in which residual risk related to obesity, diabetes, and other factors will yield to new targeted therapies.     

Trichloroethylene: Mechanistic,epidemiologic and other supporting evidence of carcinogenic hazard

The chlorinated solvent trichloroethylene (TCE) is a ubiquitous environmental pollutant. The carcinogenic hazard of TCE was the subject of a 2012 evaluation by a Working Group of the International Agency for Research on Cancer (IARC). Information on exposures, relevant data from epidemiologic studies, bioassays in experimental animals, and toxicity and mechanism of action studies was used to conclude that TCE is carcinogenic to humans (Group 1). This article summarizes the key evidence forming the scientific bases for the IARC classification. Exposure to TCE from environmental sources (including hazardous waste sites and contaminated water) is common throughout the world. While workplace use of TCE has been declining, occupational exposures remain of concern, especially in developing countries. The strongest human evidence is from studies of occupational TCE exposure and kidney cancer. Positive, although less consistent, associations were reported for liver cancer and non-Hodgkin lymphoma. TCE is carcinogenic at multiple sites in multiple species and strains of experimental animals. The mechanistic evidence includes extensive data on the toxicokinetics and genotoxicity of TCE and its metabolites. Together, available evidence provided a cohesive database supporting the human cancer hazard of TCE, particularly in the kidney. For other target sites of carcinogenicity, mechanistic and other data were found to be more limited. Important sources of susceptibility to TCE toxicity and carcinogenicity were also reviewed by the Working Group. In all, consideration of the multiple evidence streams presented herein informed the IARC conclusions regarding the carcinogenicity of TCE.     

Molecular detection and quantification of pertussis and correlation with clinical outcomes in children

Pertussis is an under-recognized serious infection. Conventional cultures are insensitive and of limited utility after antibiotic exposure. We corroborated the utility of real-time polymerase chain reaction (PCR) as a diagnostic tool in pertussis and investigated its role as a prognostic tool by evaluating its benefit in the quantification of pertussis bacterial load. All pertussis-positive PCR tests (n = 104) submitted over 5 years were collected for retrospective study. PCR cycle threshold was compared to quantitative culture in 43. Compared to PCR, the sensitivity of culture was 41%. Our PCR assay reliably quantified bacterial load and was quantitatively reproducible. Higher bacterial load correlated with longer duration of hospitalization (P = 0.0003), and multivariate logistic regression models demonstrated this association to be independent. The study confirmed PCR as a superior diagnostic tool in pertussis. PCR quantification of bacterial load at initial diagnosis predicts later clinical disease severity, suggesting a potential benefit of PCR as a prognostic tool in pertussis.     

A systematic approach for identifying and presenting mechanistic evidence in human health assessments

Clear documentation of literature search and presentation methodologies can improve transparency in chemical hazard assessments. We sought to improve clarity for the scientific support for cancer mechanisms of action using a systematic approach to literature retrieval, selection, and presentation of studies. The general question was “What are the mechanisms by which a chemical may cause carcinogenicity in the target tissue?”. Di(2-ethylhexyl)phthalate was used as a case study chemical with a complex database of >3000 publications. Relevant mechanistic events were identified from published reviews. The PubMed search strategy included relevant synonyms and wildcards for DEHP and its metabolites, mechanistic events, and species of interest. Tiered exclusion/inclusion criteria for study pertinence were defined, and applied to the retrieved literature. Manual curation was conducted for mechanistic events with large literature databases. Literature trees documented identification and selection of the literature evidence. The selected studies were summarized in evidence tables accompanied by succinct narratives. Primary publications were deposited into the Health and Environmental Research Online (http://hero.epa.gov/) database and identified by pertinence criteria and key terms to permit organized retrieval. This approach contributes to human health assessment by effectively managing a large volume of literature, improving transparency, and facilitating subsequent synthesis of information across studies.     

Torsion in patients with superior oblique palsies: dynamic torsion during saccades and changes in Listing’s plane

Background The purpose was to assess intra- and post-saccadic torsion in superior oblique palsy (SOP) patients and the effect of surgery on torsion. Methods Eleven patients with a presumed congenital SOP and five with acquired SOP performed 10° vertical saccades over a range of ±20°. Eye movements were recorded with dual search coils. Dynamic torsion was calculated by subtracting the expected change in torsion during the saccade (based upon static torsion before and after the saccade) from the maximum intrasaccadic torsion. Eight healthy subjects were controls. We also examined the effects of surgery on dynamic torsion and the orientation of Listing’s plane in patients with congenital SOP who were operated on either by weakening of the inferior oblique muscle on the affected eye (n = 5), by recession of the inferior rectus muscle on the normal eye (n = 4) or by both procedures (n = 2). Postoperative recordings were obtained at least 1 month after surgery. Results Patients with congenital and acquired SOP showed an increased dynamic extorsion, primarily during downward saccades. Following a recession of the inferior oblique muscle in congenital SOP patients, half showed significant decreases in extorsion (up to 1.0°) during downward saccades by the affected eye. Following surgery all showed a temporal rotation of Listing’s plane (up to 15° for primary position). Conclusion Patients with a SOP show a characteristic pattern of dynamic torsion during vertical saccades differing from normals. Recession of the inferior oblique muscle leads to rotation of Listing’s plane in all congenital SOP patients and causes large changes in dynamic torsion in a subgroup of them, perhaps reflecting the heterogeneity of congenital SOP. This study was supported by the Deutsche Forschungsgemeinschaft DFG 860/2-1, Bonn Germany, Grant EYO1489, from the National Institute of Health, Bethesda, Maryland, the Abe Pollin scholarship fund, Swiss National Science Foundation Grant 3200B0-105434 and the Betty and David Koetser Foundation for Brain Research, Zurich, Switzerland.     

Eight-year mortality in the Emory Angioplasty versus Surgery Trial (EAST)

OBJECTIVES: To evaluate the long-term outcome of patients randomized to coronary bypass surgery or coronary angioplasty. BACKGROUND: The Emory Angioplasty versus Surgery Trial (EAST) is a single center randomized comparison of a strategy of initial coronary angioplasty (n = 198) or coronary bypass surgery (n = 194) for patients with multivessel coronary artery disease. The primary end point (death, myocardial infarction or a large ischemic defect at 3 years) was not different, and repeat revascularization was significantly greater in the angioplasty group. Subsequently, the National Heart, Lung and Blood Institute supported a five-year extension of the trial. METHODS: After the three year anniversary visit, annual questionnaires, telephone contact and examination of medical records were accomplished until death or the eight year anniversary in 100% of the patients surviving at 3 years. RESULTS: Survival at 8 years is 79.3% in the angioplasty group and 82.7% in the surgical group (p = 0.40). Patients with proximal left anterior descending stenosis and those with diabetes tended to have better late survival with surgical intervention although not reaching statistical significance. After the first 3 years, repeat interventions remained relatively equal for both treatment groups. CONCLUSIONS: Long-term survival is not significantly different between angioplasty and surgery, and late (three to eight year) revascularization procedures were infrequent. Patients without treated diabetes had similar survival in both groups.     

Elevated levels of 6-keto-prostaglandin-F1a from a lower extremity during external pneumatic compression

The synthesis of either fibrinolytic serine proteases or platelet inhibitory ecosonoids by the intact endothelial cell may limit thrombus development. In a preliminary study from this laboratory, an elevation in the level of 6-Keto-prostaglandin-F1?, the stable metabolite of prostacyclin (PGI2) was demonstrated in femoral vein plasma obtained during surgical treatment from an extremity undergoing external pneumatic compression. Simultaneously, no elevations in thromboxane B2, the stable metabolite of thromboxane A2, were observed. The present study is an inclusive prospective series of 26 patients. A single pneumatic compression stocking was applied to the left limb in patients who underwent an operation under general anesthesia. Base line venous samples (3 milliliters) were obtained from the femoral vein on the experimental side and the control contralateral side, as well as from the upper limb. Additional samples were drawn at 30 and 60 minutes after the onset of compression. Nine samples per patient (234 total) were analyzed for 6-Keto-prostaglandin-F1? by competitive binding radioimmunoassay in duplicate in a single blind manner. Base line values for the upper limb, right leg and left leg were 0.08 + 0.01 nanogram per milliliter; 0.14 + 0.03 nanogram per milliliter, and 0.13 + 0.02 nanogram per milliliter, respectively (no statistical difference). By 60 minutes of compression, control samples increased to 0.40 + 0.07 nanogram per milliliter (right leg) and 0.42 + 0.08 nanogram per milliliter (upper limb) while the experimental leg increased to 0.71 + 0.13 nanogram per milliliter (p less than 0.05 versus right leg, p less than 0.005 versus upper limb). There was no statistical difference at 60 minutes between the men and women.