Polymorphisms in the CD14 gene associated with pulmonary function in farmers

RATIONALE AND OBJECTIVES: Farmers experience airway obstruction, which may be attributable in part to endotoxin inhalation. CD14 is a receptor for endotoxin. MATERIALS AND METHODS: Based on our findings of increased circulating CD14 associated with the CD14/-159 T allele, we hypothesized that carriers of this allele would have decreased lung function among endotoxin-exposed individuals. CD14/-159TT farmers (n = 19) had significantly lower lung function as measured by FEV1 (p = 0.028) and mean forced expiratory flow during the middle half of the FVC (FEF25-75) (p = 0.05) compared with farmers with the C allele (n = 78). Also, farmers with the CD14/-1619GG genotype (n =11) were associated with lower lung function (FEV1, p = 0.008; FEF25-75, p = 0.009) compared with farmers with the A allele (n = 86). RESULTS: No association between CD14/-550 and lung function was observed (FEV1, p = 0.32; FEF25-75, p = 0.11). Increased prevalence of wheezing was reported in farmers homozygous for CD14/-159T (p = 0.013) or CD14/-1619G (p = 0.019) compared with farmers with the CC or AA genotype, respectively. No association was found between TLR4/Asp299Gly and lung function or wheeze. CONCLUSION: We conclude that the CD14/-159 or CD14/-1619 loci may play a role in modulating lung function and wheeze among agricultural workers.     

Mutations in K-Ras linked to levels of osteoprotegerin and sensitivity to TRAIL-induced cell death in pancreatic ductal adenocarcinoma cells

Osteoprotegerin (OPG) is a soluble receptor expressed in the serum of patients with diabetes, arthritis and pancreatic cancer. While OPG has been considered a tumor survival factor for bone metastasizing breast and prostate cancers, the role of OPG in pancreatic cancer, which itself rarely metastasizes to bone, is not known. Pancreatic ductal adenocarcinoma (PDAC) cell lines were found to secrete OPG and the level of OPG production correlated with sensitivity to TRAIL-induced apoptosis. Silencing OPG sensitized cells to TRAIL-induced apoptosis. Interestingly, a positive correlation was noted between OPG production level and K-Ras mutation status. Earlier studies implicated K-Ras in conferring resistance to TRAIL-induced apoptosis in pancreatic cells and this study demonstrates that K-Ras mediated TRAIL resistance in pancreatic cancer cells occurs due to increased OPG production. Silencing K-Ras in pancreatic cancer cells decreased OPG levels and increased sensitivity to TRAIL-induced apoptosis. These observations indicate that OPG can play a role in both cell survival and in PDAC cell sensitivity to TRAIL-induced apoptosis, which may contribute to metastasis. Targeted inhibition of OPG binding to TRAIL may represent a therapeutic approach in the treatment of pancreatic cancer.     

Feasibility of using post-contrast dual-energy CT for pediatric radiation treatment planning and dose calculation

Objectives:When iodinated contrast is administered during CT simulation, standard practice requires a separate non-contrast CT for dose calculation. The objective of this study is to validate our hypothesis that since iodine affects Hounsfield units (HUs) more than electron density (ED), the information from post-contrast dual-layer CT (DLCT) would be sufficient for accurate dose calculation for both photon and proton therapy.Methods and materials:10 pediatric patients with abdominal tumors underwent DLCT scans before and after iodinated contrast administration for radiotherapy planning. Dose distributions with these DLCT-based methods were compared to those with conventional calibration-curve methods that map HU images to ED and stopping-power ratio (SPR) images.Results:For photon plans, conventional and DLCT approaches based on post-contrast scans underestimated the PTV D99 by 0.87 ± 0.70% (p = 0.18) and 0.36 ± 0.31% (p = 0.34), respectively, comparing to their non-contrast optimization plans. Renal iodine concentration was weakly associated with D99 deviation for both conventional (R² = 0.10) and DLCT (R² = 0.02) approaches. For proton plans, the clinical target volume D99 errors were 3.67 ± 2.43% (p = 0.0001) and 0.30 ± 0.25% (p = 0.40) for conventional and DLCT approaches, respectively. The proton beam range changed noticeably with the conventional approach. Renal iodine concentration was highly associated with D99 deviation for the conventional approach (R² = 0.83) but not for DLCT (R² = 0.007).Conclusion:Conventional CT with iodine contrast resulted in a large dosimetric error for proton therapy, compared to true non-contrast plans, but the error was less for photon therapy. These errors can be greatly reduced in the case of the proton plans if DLCT is used, raising the possibility of using only a single post-contrast CT for radiotherapy dose calculation, thus reducing the time and imaging dose required.Advances in knowledge:This study is the first to compare directly the differences in the calculated dose distributions between pre- and post-contrast CT images generated by single-energy CT and dual-energy CT methods for photon and proton therapy.     

Autoantibodies inhibit interleukin-7-mediated proliferation and are associated with the age-dependent loss of pre-B cells in autoimmune New Zealand Black Mice

Surface IgM+B220+ B cell precursors can be categorized as either leukosialin (CD43/S7) negative (late stage pre-B cells) or positive (pro-B/early pre-B cells). In autoimmune New Zealand Black (NZB) mice, bone marrow small pre-B cells (IgM-CD43-B220+) and pro-B/early pre-B cells (IgM-CD43+B220+) declined significantly with age. In particular, subpopulations of pro-B/early pre-B cells expressing the heat stable antigen (HSA) were found in lower proportions with age. Significant decreases in interleukin-7 (IL-7) colony forming units (CFU) were also seen in NZB mice by 6 to 8 months of age and accompanied alterations in the numbers of pro-B and pre-B cells in bone marrow. Concomitant with reduced numbers of B lineage precursor cells and IL-7 CFU in vivo, NZB mice produced serum IgM antibodies that strongly inhibited IL-7 CFU responses in vitro. Two monoclonal IgM antibodies (5G9, 2F5) derived from LPS stimulated 10-month-old NZB splenocytes recognized pre-B cell surface antigens on both pre-B cell lines and on IL-7 stimulated bone marrow pro-B/pre-B cells. However, these monoclonal antibodies (MoAb) failed to significantly stain ex vivo bone marrow cells. The 5G9 and 2F5 MoAbs also partially inhibited IL-7 CFU in vitro. These results suggest that NZB bone marrow becomes increasingly deficient in B cell precursors and especially in IL-7 responsive pre-B cells with age. IgM serum antibodies and monoclonal IgM antibodies derived from older NZB mice inhibit pre-B cell growth to IL-7. The production of such autoantibodies may interfere with B cell development in aging NZB mice by preventing IL-7-mediated proliferation.     

Immunoglobulin G from patients with heparin-induced thrombocytopenia binds to a complex of heparin and platelet factor 4

Heparin-induced thrombocytopenia (HIT) is an important complication of heparin therapy. Although there is general agreement that platelet activation in vitro by the HIT IgG is mediated by the platelet Fc receptor, the interaction among the antibody, heparin, and platelet membrane components is uncertain and debated. In this report, we describe studies designed to address these interactions. We found, as others have noted, that a variety of other sulfated polysaccharides could substitute for heparin in the reaction. Using polysaccharides selected for both size and charge, we found that reactivity depended on two independent factors: a certain minimum degree of sulfation per saccharide unit and a certain minimum size. Hence, highly sulfated but small (< 1,000 daltons) polysaccharides were not reactive nor were large but poorly sulfated polysaccharides. The ability of HIT IgG to recognize heparin by itself was tested by Ouchterlony gel diffusion, ammonium sulfate and polyethylene glycol precipitation, and equilibrium dialysis. No technique demonstrated reactivity. However, when platelet releasate was added to heparin and HIT IgG, a 50-fold increase in binding of radio-labeled heparin to HIT IgG was observed. The releasate was then depleted of proteins capable of binding to heparin by immunoaffinity chromatography. Only platelet factor 4-immunodepleted releasate lost its reactivity with HIT IgG and heparin. Finally, to determine whether the reaction occurred on the surface of platelets or in the fluid phase, washed platelets were incubated with HIT IgG or heparin and after a wash step, heparin or HIT IgG was added, respectively. Reactivity was only noted when platelets were preincubated with heparin. Consistent with these observations was the demonstration of the presence of PF4 on platelets using flow cytometry. These studies indicate that heparin and other large, highly sulfated polysaccharides bind to PF4 to form a reactive antigen on the platelet surface. HIT IgG then binds to this complex with activation of platelets through the platelet Fc receptors.     

Twitter Sentiment Predicts Affordable Care Act Marketplace Enrollment

Background

Traditional metrics of the impact of the Affordable Care Act (ACA) and health insurance marketplaces in the United States include public opinion polls and marketplace enrollment, which are published with a lag of weeks to months. In this rapidly changing environment, a real-time barometer of public opinion with a mechanism to identify emerging issues would be valuable.

Objective

We sought to evaluate Twitter’s role as a real-time barometer of public sentiment on the ACA and to determine if Twitter sentiment (the positivity or negativity of tweets) could be predictive of state-level marketplace enrollment.

Methods

We retrospectively collected 977,303 ACA-related tweets in March 2014 and then tested a correlation of Twitter sentiment with marketplace enrollment by state.

Results

A 0.10 increase in the sentiment score was associated with an 8.7% increase in enrollment at the state level (95% CI 1.32-16.13; P=.02), a correlation that remained significant when adjusting for state Medicaid expansion (P=.02) or use of a state-based marketplace (P=.03).

Conclusions

This correlation indicates Twitter’s potential as a real-time monitoring strategy for future marketplace enrollment periods; marketplaces could systematically track Twitter sentiment to more rapidly identify enrollment changes and potentially emerging issues. As a repository of free and accessible consumer-generated opinions, this study reveals a novel role for Twitter in the health policy landscape.     

Synergistic effect of age and body mass index on mortality and morbidity in general surgery

Background

The elderly population (aged 65 y and older) is expected to be the dominant age group in the United States by 2030. In addition, the prevalence of obesity in the United States is growing exponentially. Obese elderly patients are increasingly undergoing elective or emergent general surgery. There are few, if any, studies highlighting the combined effect of age and body mass index (BMI) on surgical outcomes. We hypothesize that increasing age and BMI synergistically impact morbidity and mortality in general surgery.

Materials and methods

We collected individual-level, de-identified patient data from the Michigan Surgical Quality Collaborative. Subjects underwent general surgery with general anesthetic, were >18 y, and had a BMI between 19 and 60. Primary and secondary outcomes were 30-d “Any morbidity” and mortality (from wound, respiratory, genitourinary, central nervous system, and cardiac systems), respectively. Preoperative risk variables included diabetes, dialysis, steroid use, cardiac risk, wound classification, American Society of Anesthesiology class, emergent cases, and 13 other variables. We conducted binary logistic regression models for 30-d morbidity and mortality to determine independent effects of age, BMI, interaction between both age and BMI, and a saturated model for all independent variables.

Results

We identified 149,853 patients. The average age was 54.6 y, and the average BMI was 30.9. Overall 30-d mortality was 2%, and morbidity was 6.7%. Age was a positive predictor for mortality and morbidity, and BMI was negatively associated with mortality and not significantly associated with morbidity. Age combined with higher BMI was positively associated with morbidity and mortality when the higher age groups were analyzed. Saturated models revealed age and American Society of Anesthesiology class as highest predictors of poor outcomes.

Conclusions

Although BMI itself was not a major independent factor predicting 30-d major morbidity or mortality, the morbidly obese, elderly (>50 and 70 y, respectively) subgroup may have an increased morbidity and mortality after general surgery. This information, along with patient-specific factors and their comorbidities, may allow us to better take care of our patients perioperatively and better inform our patients about their risk of surgical procedures.     

Canadian Cardiovascular Society/Canadian Anesthesiologists' Society/Canadian Heart Rhythm Society joint position statement on the perioperative management of patients with implanted pacemakers, defibrillators, and neurostimulating devices

There are more than 200,000 Canadians living with permanent pacemakers or implantable defibrillators, many of whom will require surgery or invasive procedures each year. They face potential hazards when undergoing surgery; however, with appropriate planning and education of operating room personnel, adverse device-related outcomes should be rare. This joint position statement from the Canadian Cardiovascular Society (CCS) and the Canadian Anesthesiologists' Society (CAS) has been developed as an accessible reference for physicians and surgeons, providing an overview of the key issues for the preoperative, intraoperative, and postoperative care of these patients. The document summarizes the limited published literature in this field, but for most issues, relies heavily on the experience of the cardiologists and anesthesiologists who contributed to this work. This position statement outlines how to obtain information about an individual's type of pacemaker or implantable defibrillator and its programming. It also stresses the importance of determining if a patient is highly pacemaker-dependent and proposes a simple approach for nonelective evaluation of dependency. Although the document provides a comprehensive list of the intraoperative issues facing these patients, there is a focus on electromagnetic interference resulting from electrocautery and practical guidance is given regarding the characteristics of surgery, electrocautery, pacemakers, and defibrillators which are most likely to lead to interference. The document stresses the importance of preoperative consultation and planning to minimize complications. It reviews the relative merits of intraoperative magnet use vs reprogramming of devices and gives examples of situations where one or the other approach is preferable.