Untangling the Debate: The Ethics of Human Enhancement

Human enhancement, in which nanotechnology is expected to play a major role, continues to be a highly contentious ethical debate, with experts on both sides calling it the single most important issue facing science and society in this brave, new century. This paper is a broad introduction to the symposium herein that explores a range of perspectives related to that debate. We will discuss what human enhancement is and its apparent contrast to therapy; and we will begin to tease apart the myriad intertwined issues that arise in the debate: (1) freedom & autonomy, (2) health & safety, (3) fairness & equity, (4) societal disruption, and (5) human dignity

Independent effect of prior exacerbation frequency and disease severity on the risk of future exacerbations of COPD: a retrospective cohort study

Few studies have researched the independent effect of COPD severity on the risk of future exacerbations adjusted by previous exacerbation frequency. We aimed to analyse the independent effect of COPD severity on the risk of exacerbations in the following year, and whether this effect was stronger or not than the effect of a previous history of exacerbations. We conducted a retrospective population-based cohort study including 900 patients with confirmed COPD. Exacerbation frequency was observed for the previous year and for the following year. Patients were defined as ‘Frequent Exacerbator’ (FE) phenotype if they suffered ?2 exacerbations in a year, and were categorised according to the severity of COPD (GOLD Grades 1–4). Odds ratios (ORs) were estimated by logistic regression adjusting for age, gender, smoking status, severity of COPD and being FE in the previous year. The main predictor of being FE among all grades of COPD severity was a history of frequent exacerbations in the previous year: adjusted OR 4.97; 95% confidence interval (CI) (3.54–6.97). COPD severity was associated with a higher risk of being FE: Crude OR GOLD Grade 4 3.86; 95% CI (1.50–9.93). However, this association diminished after adjusting for being FE in the previous year: adjusted OR 2.08; 95% CI (0.75–5.82). Our results support that a history of frequent exacerbations in the previous year is the most important independent predictor of exacerbations in the following year, also among the most severe COPD patients. Severity of COPD would be associated with a higher risk of exacerbations, but this effect would be partly determined by the exacerbations suffered in the previous year

Antiproliferative activity of PEP005, a novel ingenol angelate that modulates PKC functions, alone and in combination with cytotoxic agents in human colon cancer cells

PEP005 is a novel ingenol angelate that modulates protein kinases C (PKC) functions by activating PKCδ and inhibiting PKCα. This study assessed the antiproliferative effects of PEP005 alone and in combination with several other anticancer agents in a panel of 10 human cancer cell lines characterised for expression of several PKC isoforms. PEP005 displayed antiproliferative effects at clinically relevant concentrations with a unique cytotoxicity profile that differs from that of most other investigated cytotoxic agents, including staurosporine. In a subset of colon cancer cells, the IC50 of PEP005 ranged from 0.01–140 μM. The antiproliferative effects of PEP005 were shown to be concentration- and time-dependent. In Colo205 cells, apoptosis induction was observed at concentrations ranging from 0.03 to 3 μM. Exposure to PEP005 also induced accumulation of cells in the G1 phase of the cell cycle. In addition, PEP005 increased the phosphorylation of PKCδ and p38. In Colo205 cells, combinations of PEP005 with several cytotoxic agents including oxaliplatin, SN38, 5FU, gemcitabine, doxorubicin, vinorelbine, and docetaxel yielded sequence-dependent antiproliferative effects. Cell cycle blockage induced by PEP005 in late G1 lasted for up to 24 h and therefore a 24 h lag-time between PEP005 and subsequent exposure to cytotoxics was required to optimise PEP005 combinations with several anticancer agents. These data support further evaluation of PEP005 as an anticancer agent and may help to optimise clinical trials with PEP005-based combinations in patients with solid tumours

Predictors of Hospitalized Exacerbations and Mortality in Chronic Obstructive Pulmonary Disease

Background and Aim Exacerbations of chronic obstructive pulmonary disease (COPD) carry significant consequences for patients and are responsible for considerable health-care costs?particularly if hospitalization is required. Despite the importance of hospitalized exacerbations, relatively little is known about their determinants. This study aimed to analyze predictors of hospitalized exacerbations and mortality in COPD patients. Methods This was a retrospective population-based cohort study.We selected 900 patients with confirmed COPD aged 35 years by simple random sampling among all COPD patients in Cantabria (northern Spain) on December 31, 2011. We defined moderate exacerbations as events that led a care provider to prescribe antibiotics or corticosteroids and severe exacerbations as exacerbations requiring hospital admission.We observed exacerbation frequency over the previous year (2011) and following year (2012). We categorized patients according to COPD severity based on forced expiratory volume in 1 second (Global Initiative for Chronic Obstructive Lung Disease [GOLD] grades 1?4). We estimated the odds ratios (ORs) by logistic regression, adjusting for age, sex, smoking status, COPD severity, and frequent exacerbator phenotype the previous year. Results Of the patients, 16.4%had 1 severe exacerbations, varying from 9.3%in mild GOLD grade 1 to 44%in very severe COPD patients. A history of at least two prior severe exacerbations was positively associated with new severe exacerbations (adjusted OR, 6.73; 95%confidence interval [CI], 3.53?12.83) and mortality (adjusted OR, 7.63; 95%CI, 3.41?17.05). Older age and several comorbidities, such as heart failure and diabetes, were similarly associated. Conclusions Hospitalized exacerbations occurred with all grades of airflow limitation. A history of severe exacerbations was associated with new hospitalized exacerbations and mortality

Caspase-mediated protein kinase C-δ cleavage is necessary for apoptosis of vascular smooth muscle cells

Apoptotic death of vascular smooth muscle cells (SMCs) is a prominent feature of blood vessel remodeling and various vascular diseases. We have previously shown that protein kinase C-δ (PKC-δ) plays a critical role in SMC apoptosis. In this study, we tested the importance of PKC-δ proteolytic cleavage and tyrosine phosphorylation within the apoptosis pathway. Using hydrogen peroxide as a paradigm for oxidative stress, we showed that proteolytic cleavage of PKC-δ occurred in SMCs that underwent apoptosis, while tyrosine phosphorylation was detected only in necrotic cells. Furthermore, using a peptide (z-DIPD-fmk) that mimics the caspase-3 binding motif within the linker region of PKC-δ, we were able to prevent the cleavage of PKC-δ, as well as apoptosis. Inhibition of PKC-δ with rottlerin or small-interfering RNA diminished caspase-3 cleavage, caspase-3 activity, cleavage of poly (ADP-ribose) polymerase, cleavage of PKC-δ, and DNA fragmentation, confirming the previously reported role of PKC-δ in initiation of apoptosis. In contrast, z-DIPD-fmk markedly diminished caspase-3 activity, cleavage of PKC-δ, and DNA fragmentation without affecting cleavage of caspase-3 and poly (ADP-ribose) polymerase. Taken together, our data suggest that caspase-3-mediated PKC-δ cleavage underlies SMC apoptosis induced by oxidative stress, and that PKC-δ acts both upstream and downstream of caspase-3