Anti-PAD4 autoantibodies in rheumatoid arthritis: levels in serum over time and impact on PAD4 activity as measured with a small synthetic substrate

Isoform 4 of the human peptidylarginine deiminase (hPAD4) enzyme may be responsible for the citrullination of antigens in rheumatoid arthritis (RA) and has been shown to be itself the target of disease-specific autoantibodies. Here, we have tested whether the level of serum anti-hPAD4 antibodies in RA patients is stable over a period of 10 years and whether the antibodies influence hPAD4-mediated deimination of the small substrate N-α-Benzoyl-l-arginine ethyl ester. RA sera (n = 128) obtained at baseline and after 10 years were assessed for anti-hPAD4 antibodies by a specific immunoassay. For 118 RA patients, serum anti-hPAD4 IgG levels were stable over 10 years. Seven patients who were negative for anti-PAD4 IgG at baseline had become positive after 10 years. Further, total IgG from selected RA patients and controls were purified, and a fraction was depleted for anti-hPAD4 antibodies. Kinetic deimination assays were performed with total IgG and depleted fractions. The kcat and Km values of hPAD4-mediated deimination of N-α-Benzoyl-l-arginine ethyl ester were not affected by the depletion of the anti-hPAD4 antibodies from the total IgG pool. In conclusion, RA patients remain positive for anti-hPAD4 antibodies over time and some patients who are initially anti-hPAD4 negative become positive later in the disease course. The anti-hPAD4 antibodies did not affect the enzymatic activity of hPAD4 when the small substrate N-α-Benzoyl-l-arginine ethyl ester was used. However, this finding may not exclude an effect of these autoantibodies on citrullination of protein substrates in RA

Family members’ experiences of “wait and see” as a communication strategy in end-of-life decisions

The aim of this study is to examine family members’ experiences of end-of-life decision-making processes in Norwegian intensive care units (ICUs) to ascertain the degree to which they felt included in the decision-making process and whether they received necessary information. Were they asked about the patient’s preferences, and how did they view their role as family members in the decision-making process? A constructivist interpretive approach to the grounded theory method of qualitative research was employed with interviews of 27 bereaved family members of former ICU patients 3–12 months after the patient’s death. The core finding is that relatives want a more active role in end-of-life decision-making in order to communicate the patient’s wishes. However, many consider their role to be unclear, and few study participants experienced shared decision-making. The clinician’s expression “wait and see” hides and delays the communication of honest and clear information. When physicians finally address their decision, there is no time for family participation. Our results also indicate that nurses should be more involved in family–physician communication. Families are uncertain whether or how they can participate in the decision-making process. They need unambiguous communication and honest information to be able to take part in the decision-making process. We suggest that clinicians in Norwegian ICUs need more training in the knowledge and skills of effective communication with families of dying patients

Life histories of the copepods Pseudocalanus minutus, P. acuspes (Calanoida) and Oithona similis (Cyclopoida) in the Arctic Kongsfjorden (Svalbard)

The year-round variation in abundance and stage-specific (vertical) distribution of Pseudocalanus minutus and Oithona similis was studied in the Arctic Kongsfjorden, Svalbard. Maxima of vertically integrated abundance were found in November with 111,297 ind m−2 for P. minutus and 704,633 ind m−2 for O. similis. Minimum abundances comprised 1,088 ind m−2 and 4,483 ind m−2 in June for P. minutus and O. similis, respectively. The congener P. acuspes only occurred in low numbers (15–213 ind m−2), and successful reproduction was debatable. Reproduction of P. minutus took place in May/June, and stage distribution revealed a 1-year life cycle with copepodids CIII, CIV, and CV as the overwintering stages. Oithona similis exhibited two main reproductive peaks in June and August/September, respectively. Moreover, it reproduced more or less continuously throughout the whole year with all stages occurring during the entire sampling period, suggesting two generations per year. Both species migrated towards greater depth in November, but O. similis preferred to stay longer in the upper 100 m as compared to Pseudocalanus. The reproduction of the two species in Kongsfjorden seemed to be linked to phytoplankton dynamics

Coronary artery surgery: cardiotomy suction or cell salvage?

Coronary artery bypass grafting (CABG) today results in what may be regarded as acceptable levels of blood loss with many institutions avoiding allogeneic red cell transfusion in over 60% of their patients. The majority of cardiac surgeons employ cardiotomy suction to preserve autologous blood during on-pump coronary artery bypass surgery; however the use of cardiotomy suction is associated with a more pronounced systemic inflammatory response and a resulting coagulopathy as well as exacerbating the microembolic load. This leads to a tendency to increased blood loss, transfusion requirement and organ dysfunction. Conversely, the avoidance of cardiotomy suction in coronary artery bypass surgery is not associated with an increased transfusion requirement. There is therefore no indication for the routine use of cardiotomy suction in on-pump coronary artery surgery

The Discovery of LOX-1, its Ligands and Clinical Significance

LOX-1 is an endothelial receptor for oxidized low-density lipoprotein (oxLDL), a key molecule in the pathogenesis of atherosclerosis.The basal expression of LOX-1 is low but highly induced under the influence of proinflammatory and prooxidative stimuli in vascular endothelial cells, smooth muscle cells, macrophages, platelets and cardiomyocytes. Multiple lines of in vitro and in vivo studies have provided compelling evidence that LOX-1 promotes endothelial dysfunction and atherogenesis induced by oxLDL. The roles of LOX-1 in the development of atherosclerosis, however, are not simple as it had been considered. Evidence has been accumulating that LOX-1 recognizes not only oxLDL but other atherogenic lipoproteins, platelets, leukocytes and CRP. As results, LOX-1 not only mediates endothelial dysfunction but contributes to atherosclerotic plaque formation, thrombogenesis, leukocyte infiltration and myocardial infarction, which determine mortality and morbidity from atherosclerosis. Moreover, our recent epidemiological study has highlighted the involvement of LOX-1 in human cardiovascular diseases. Further understandings of LOX-1 and its ligands as well as its versatile functions will direct us to ways to find novel diagnostic and therapeutic approaches to cardiovascular disease

ICAR: endoscopic skull‐base surgery

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Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference