Key issues surrounding the health impacts of electronic nicotine delivery systems (ENDS) and other sources of nicotine

Answer questions and earn CME/CNE Over the last decade, the use of electronic nicotine delivery systems (ENDS), including the electronic cigarette or e‐cigarette, has grown rapidly. More youth now use ENDS than any tobacco product. This extensive research review shows that there are scientifically sound, sometimes competing arguments about ENDS that are not immediately and/or completely resolvable. However, the preponderance of the scientific evidence to date suggests that current‐generation ENDS products are demonstrably less harmful than combustible tobacco products such as conventional cigarettes in several key ways, including by generating far lower levels of carcinogens and other toxic compounds than combustible products or those that contain tobacco. To place ENDS in context, the authors begin by reviewing the trends in use of major nicotine‐containing products. Because nicotine is the common core—and highly addictive—constituent across all tobacco products, its toxicology is examined. With its long history as the only nicotine product widely accepted as being relatively safe, nicotine‐replacement therapy (NRT) is also examined. A section is also included that examines snus, the most debated potential harm‐reduction product before ENDS. Between discussions of NRT and snus, ENDS are extensively examined: what they are, knowledge about their level of “harm,” their relationship to smoking cessation, the so‐called gateway effect, and dual use/poly‐use. CA Cancer J Clin 2017;67:449‐471. © 2017 American Cancer Society.     

Impact of eculizumab treatment on paroxysmal nocturnal hemoglobinuria: a treatment versus no‐treatment study

Intravascular hemolysis in Paroxysmal nocturnal hemoglobinuria (PNH) can effectively be controlled with eculizumab, a humanized monoclonal antibody that binds complement protein C5. We report here a retrospective comparison study between 123 patients treated with eculizumab in the recent period (>2005) and 191 historical controls (from the French registry). Overall survival (OS) at 6 years was 92% (95%CI, 87 to 98) in the eculizumab cohort versus 80% (95%CI 70 to 91) in historical controls diagnosed after 1985 (HR 0.38 [0.15 to 0.94], P = 0.037). There were significantly fewer thrombotic events (TEs) in the group of patients treated with eculizumab (4% [1–10]) as compared to the historical cohort (27% [20–34]). However, we found that TEs may still occur after the initiation of eculizumab treatment and that previous TEs still have a negative impact on survival. Evolutions to myelodysplastic syndrome or acute leukemia were similar in both cohorts. There was less evolution to aplastic anemia in the treatment group. In multivariate analysis, absence of a previous TE and treatment with eculizumab were associated with a better OS. Treatment with eculizumab improves overall survival in classic PNH patients without increasing the risk of clonal evolution. Am. J. Hematol. 91:366–370, 2016. © 2016 Wiley Periodicals, Inc.     

Diabetic foot disease is associated with reduced erythrocyte deformability

The pathogenesis of diabetic foot disease is multifactorial and encompasses microvascular and macrovascular pathologies. Abnormal blood rheology may also play a part in its development. Using a cell flow analyser (CFA), we examined the association between erythrocyte deformability and diabetic foot disease. Erythrocytes from diabetic patients with no known microvascular complications (n = 11) and patients suffering from a diabetic foot ulcer (n = 11) were isolated and their average elongation ratio (ER) as well as the ER distribution curve were measured. Average ER was decreased in the diabetic foot patients compared with the patients with diabetes and no complications (1·64 ± 0·07 versus 1·71 ± 0·1; P = 0·036). A significant rise in the percentage of minimally deformable red blood cells RBCs in diabetic foot patients compared with the patients with no complications was observed (37·89% ± 8·12% versus 30·61% ± 10·17%; P = 0·039) accompanied by a significant decrease in the percentage of highly deformable RBCs (12·47% ± 4·43% versus 17·49% ± 8·17% P = 0·046). Reduced erythrocyte deformability may slow capillary flow in the microvasculature and prolong wound healing in diabetic foot patients. Conversely, it may be the low‐grade inflammatory state imposed by diabetic foot disease that reduces erythrocyte deformability. Further study of the rheological changes associated with diabetic foot disease may enhance our understanding of its pathogenesis and aid in the study of novel therapeutic approaches.     

Recombinant thrombomodulin inhibits arterial smooth muscle cell proliferation induced by thrombin

PURPOSE: Restenosis after angioplasty or bypass grafting to restore circulation to ischemic organs is still an unsolved problem. Thrombin generated in high concentrations at the sites of vascular injury plays a central role in thrombosis and hemostasis. alpha-Thrombin has also been implicated as a mitogen for smooth muscle cell (SMC) proliferation that contributes to arterial restenosis. Thrombomodulin has a high affinity of binding with thrombin and converts thrombin from a procoagulant to an anticoagulant. This study was designed to examine whether thrombomodulin could also moderate the thrombin-mediated SMC proliferative response. METHODS: Porcine carotid artery SMCs (passages 4-7) were plated onto 96-well plates and incubated for 3 days. After growth arrest in a defined serum-free medium for 2 to 3 days, SMCs were subjected to the reagents as follows: (1) human alpha-thrombin, (2) recombinant human soluble thrombomodulin containing a chondroitin sulfate moiety, (3) thrombin receptor agonist peptide (SFLLRNPNDKYEPF), and (4) alpha-thrombin or thrombin receptor agonist peptide combined with recombinant thrombomodulin (rTM). The viability and proliferation status of SMCs were quantified with MTT (thiazolyl blue) mitochondrial function and bromodeoxyuridine (BrdU)-DNA incorporation assays. RESULTS: Human alpha-thrombin increased SMC proliferation in a dose dependent manner by more than 25% and 30% with thrombin 1 U/mL to 3 U/mL compared with control groups on day 7 (P <.006). rTM concentrations from 0.5 microg/mL to 3 microg/mL have no significant effect on SMC growth. The stimulation of SMC proliferation induced by alpha-thrombin at 0.5 U/mL, 1 U/mL, and 2 U/mL was significantly inhibited with rTM at 2 microg/mL and 3 microg/mL on days 3, 7, and 10 as evaluated with MTT assay (P <.01 to <.05) and BrdU-DNA incorporation assay on day 3 (P <.008). Thrombin receptor agonist peptide increased SMC BrdU-DNA incorporation at 48 hours (P <.007), and its effect was not altered by rTM. CONCLUSION: rTM containing all of the extracellular domains of thrombomodulin inhibits the effect of thrombin on SMC proliferation in vitro. Because thrombin is a mitogenic mediator of SMC in vascular injury, inhibition of its function in vivo could help to prevent SMC hyperplasia. The success of further studies in vivo may lead to use of rTM for decreasing or preventing arterial restenosis.     

Classification of schizophrenia patients and healthy controls from structural MRI scans in two large independent samples

The purpose of this study is to create a model that can classify schizophrenia patients and healthy controls based on whole brain gray matter densities (voxel-based morphometry, VBM) from structural magnetic resonance imaging (MRI) scans. In addition, we investigated the stability of the accuracy of the models, when built with different sample sizes. Using a support vector machine, we built a model from 239 subjects (128 patients and 111 healthy controls) and classified 71.4% correct (leave-one-out). We replicated and validated this result by testing the unaltered model on a completely independent sample of 277 subjects (155 patients and 122 healthy controls), scanned with a different scanner. The classification rate of the validation sample was 70.4%. The model's discriminative pattern showed, amongst other differences, gray matter density decreases in frontal and superior temporal lobes and hippocampus in schizophrenia patients with respect to healthy controls and increases in gray matter density in basal ganglia and left occipital lobe and. Larger training samples gave more reliable models: Models based on sample sizes smaller than N=130 should be considered unstable and can even score below chance.     

Bid regulation of neuronal apoptosis.

Bid is a BH3 domain only pro-apoptotic member of the Bcl-2 family which interacts with Bax to regulate apoptosis. Bax-deficient embryos show decreased neuronal programmed cell death in vivo and resistance to cytosine arabinoside (AraC)-induced neuronal apoptosis in vitro. In this report, we demonstrate that Bid-deficient embryos show no neurodevelopmental abnormalities, and Bid-deficiency has no effect on the in vitro apoptotic response of either telencephalic neural precursor cells or neurons to AraC-induced death. We conclude that bid does not play an essential role in either naturally occurring or genotoxin-induced neuronal cell death.     

Engraftment of human blood malignancies to the turkey embryo: A robust new in vivo model

Xenografting of human blood malignancies to immunodeficient SCID mice is a powerful research tool. We evaluate here whether the immunodeficient turkey embryo can also serve as a xenograft host for human blood malignancies. Human leukemia, lymphoma and myeloma lines engrafted robustly into medullary and extramedullary tissues of turkey embryos as detected by PCR, FACS and histology in 8–10 days. Four of eleven patient AML samples also engrafted the bone marrow. Grafts of two lines responded to chemotherapy with doxorubicin. The turkey embryo therefore has the potential to be a complementary xenograft model for the study of human blood malignancies.     

Peripheral Blood versus Bone Marrow from Unrelated Donors: Bone Marrow Allografts Have Improved Long-Term Overall and Graft-versus-Host Disease-Free,Relapse-Free Survival

Peripheral blood (PB) and bone marrow (BM) from unrelated donors can serve as a graft source for hematopoietic cell transplantation (HCT). Currently, PB is most commonly used in roughly 80% of adult recipients. Determining the long-term impact of graft source on outcomes would inform this decision. Data collected by the Center for International Blood and Marrow Transplant Research from 5200 adult recipients of a first HCT from an 8/8 or 7/8 HLA antigen-matched unrelated donor for treatment of acute leukemia, chronic myelogenous leukemia, or myelodysplastic syndrome between 2001 and 2011 were analyzed to determine the impact of graft source on graft-versus-host disease (GVHD) relapse-free survival (GRFS), defined as freedom from grade III/IV acute GVHD, chronic GVHD requiring immunosuppressive therapy, relapse, and death, and overall survival. GRFS at 2 years was superior in BM recipients compared with PB recipients (16%; 95% confidence interval [CI], 14% to 18% versus 10%; 95% CI, 8% to 11%; P <.0001) in the 8/8 HLA-matched cohort and 7/8 HLA-matched cohort (11%; 95% CI, 8% to 14% versus 5%; 95% CI, 4% to 7%; P?=?.001). With 8/8 HLA-matched unrelated donors, overall survival at 5 years was superior in recipients of BM (43%; 95% CI, 40% to 46% versus 38%; 95% CI, 36% to 40%; P?=?.014). The inferior 5-year survival in the PB cohort was attributable to a higher frequency of deaths while in remission compared with the BM cohort. For recipients of 7/8 HLA-matched grafts, survival at 5 years was similar in BM recipients and PB recipients (32% versus 29%; P?=?.329). BM grafts are associated with improved long-term GRFS and overall survival in recipients of matched unrelated donor HCT and should be considered the unrelated allograft of choice, when available, for adults with acute leukemia, chronic myelogenous leukemia, and myelodysplastic syndrome.