Sleep restriction attenuates amplitudes and attentional modulation of pain-related evoked potentials, but augments pain ratings in healthy volunteers

The experiment investigated the impact of sleep restriction on pain perception and related evoked potential correlates (laser-evoked potentials, LEPs). Ten healthy subjects with good sleep quality were investigated in the morning twice, once after habitual sleep and once after partial sleep restriction. Additionally, we studied the impact of attentional focussing on pain and LEPs by directing attention to (intensity discrimination) or away from the stimulus (mental arithmetic). Laser stimuli directed to the hand dorsum were rated as 30% more painful after sleep restriction (49+/-7 mm) than after a night of habitual sleep (38+/-7 mm). A significant interaction between attentional focus and sleep condition suggested that attentional focusing was less distinctive under sleep restriction. Intensity discrimination was preserved. In contrast, the amplitude of the early parasylvian N1 of LEPs was significantly smaller after a night of partial sleep restriction (-36%, p<0.05). Likewise, the amplitude of the vertex N2-P2 was significantly reduced (-34%, p<0.01); also attentional modulation of the N2-P2 was reduced. Thus, objective (LEPs) and subjective (pain ratings) parameters of nociceptive processing were differentially modulated by partial sleep restriction. We propose, that sleep reduction leads to an impairment of activation in the ascending pathway (leading to reduced LEPs). In contradistinction, pain perception was boosted, which we attribute to lack of pain control distinct from classical descending inhibition, and thus not affecting the projection pathway. Sleep-restricted subjects exhibit reduced attentional modulation of pain stimuli and may thus have difficulties to readily attend to or disengage from pain.

Retirement as a “language related major life event” and its consequences on the multilingualism of migrants

The present study investigates life stories of established Italian workforce migrants living in the city of Berne, Switzerland, in regard to “language related major life events” (De Bot, 2007). These events are important in terms of changes happening in the linguistic setting during the life span and influence language development. In this sense, during the process of retirement, a new phase of life begins, which, amongst other things, has to be reorganized in relation to social contact and language use. One of my main questions is how the subjects handle the changes happening within and after the process of retirement in respect to the use of different languages and how this “language related major life event” is constructed and described by the migrants. One of these changes happens due to the fact that, after retirement, the social network at the workplace (the primary source of language input) can get (partially) lost and with it, the use of the local language. The fact that migrants living in Berne are confronted with diglossia (Standard German and Swissgerman), that the Canton of Berne is bilingual (German and French) and that the migrants' mother tongue (Italian) is one of the Swiss national languages, makes this question even more interesting. A second question will consider the influence of the fact that most of the subjects in question lived with the idea of return migration, but as shown in a previous study (Alter/Vieillesse/Anziani, NFP 32, 1999), only a third returned back while another third remained in the host country and the final third chose the commuting option. I will first examine these processes, changes and influences by using quantitative questionnaires in order to obtain general information on demographic data, the social situation, and a self-assessment of linguistic skills. Secondly, I will use qualitative interviews to get in-depth information of the subjects’ life stories and language biographies. The results of this project are meant to deliver insight into different aspects that have not been looked at in detail to this point: which factors of the life stories of Italian workforce migrants, who decided to remain in Switzerland after retirement, influence the linguistic changes in general and the ones happening around retirement in particular.

Electrogram analysis and pacing are complimentary for recognition of abnormal conduction and far-field potentials during substrate mapping of infarct-related ventricular tachycardia.

BACKGROUND Mapping to identify scar-related ventricular tachycardia re-entry circuits during sinus rhythm focuses on sites with abnormal electrograms or pace-mapping findings of QRS morphology and long stimulus to QRS intervals. We hypothesized that (1) these methods do not necessarily identify the same sites and (2) some electrograms are far-field potentials that can be recognized by pacing. METHODS AND RESULTS From 12 patients with coronary disease and recurrent ventricular tachycardia undergoing catheter ablation, we retrospectively analyzed electrograms and pacing at 546 separate low bipolar voltage (<1.5 mV) sites. Electrograms were characterized as showing evidence of slow conduction if late potentials (56%) or fractionated potentials (76%) were present. Neither was present at (13%) sites. Pacing from the ablation catheter captured 70% of all electrograms. Higher bipolar voltage and fractionation were independent predictors for pace capture. There was a linear correlation between the stimulus to QRS duration during pacing and the lateness of a capturing electrogram (P<0.001), but electrogram and pacing markers of slow conduction were discordant at 40% of sites. Sites with far-field potentials, defined as those that remained visible and not captured by pacing stimuli, were identified at 48% of all pacing sites, especially in areas of low bipolar voltage and late potentials. Initial radiofrequency energy application rendered 74% of targeted sites electrically unexcitable. CONCLUSIONS Far-field potentials are common in scar areas. Combining analysis of electrogram characteristics and assessment of pace capture may refine identification of substrate targets for radiofrequency ablation.

Inflammation-associated autophagy-related programmed necrotic death of human neutrophils characterized by organelle fusion events

The most common form of neutrophil death, under both physiological and inflammatory conditions, is apoptosis. In this study, we report a novel form of programmed necrotic cell death, associated with cytoplasmic organelle fusion events, that occurs in neutrophils exposed to GM-CSF and other inflammatory cytokines upon ligation of CD44. Strikingly, this type of neutrophil death requires PI3K activation, a signaling event usually involved in cellular survival pathways. In the death pathway reported in this study, PI3K is required for the generation of reactive oxygen species, which somehow trigger the generation of large cytoplasmic vacuoles, generated by the fusion of CD44-containing endosomes with autophagosomes and secondary, but not primary, granules. Neutrophils demonstrating vacuolization undergo rapid cell death that depends on receptor-interacting protein 1 kinase activity and papain family protease(s), but not caspases, that are most likely activated and released, respectively, during or as a consequence of organelle fusion. Vacuolized neutrophils are present in infectious and autoimmune diseases under in vivo conditions. Moreover, isolated neutrophils from such patients are highly sensitive toward CD44-mediated PI3K activation, reactive oxygen species production, and cell death, suggesting that the newly described autophagy-related form of programmed neutrophil necrosis plays an important role in inflammatory responses.

HGF/c-Met related activation of ?-catenin in hepatoblastoma

Activation of beta-catenin is a hallmark of hepatoblastoma (HB) and appears to play a crucial role in its pathogenesis. While aberrant accumulation of the beta-catenin is a common event in HB, mutations or deletions in CTNNB1 (beta-catenin gene) do not always account for the high frequency of protein expression. In this study we have investigated alternative activation of beta-catenin by HGF/c-Met signaling in a large cohort of 98 HB patients enrolled in the SIOPEL-3 clinical trial.

Fate of individuals with ischemic amputations in the REACH Registry: Three-year cardiovascular and limb-related outcomes

To evaluate systemic and limb ischemic event rates of PAD patients with prior leg amputation and determine predictors of adverse outcomes.

Distress related to myocardial infarction and cardiovascular outcome: a retrospective observational study

Background During acute coronary syndromes patients perceive intense distress. We hypothesized that retrospective ratings of patients' MI-related fear of dying, helplessness, or pain, all assessed within the first year post-MI, are associated with poor cardiovascular outcome. Methods We studied 304 patients (61 ± 11 years, 85% men) who after a median of 52 days (range 12-365 days) after index MI retrospectively rated the level of distress in the form of fear of dying, helplessness, or pain they had perceived at the time of MI on a numeric scale ranging from 0 ("no distress") to 10 ("extreme distress"). Non-fatal hospital readmissions due to cardiovascular disease (CVD) related events (i.e., recurrent MI, elective and non-elective stent implantation, bypass surgery, pacemaker implantation, cerebrovascular incidents) were assessed at follow-up. The relative CVD event risk was computed for a (clinically meaningful) 2-point increase of distress using Cox proportional hazard models. Results During a median follow-up of 32 months (range 16-45), 45 patients (14.8%) experienced a CVD-related event requiring hospital readmission. Greater fear of dying (HR 1.21, 95% CI 1.03-1.43), helplessness (HR 1.22, 95% CI 1.04-1.44), or pain (HR 1.27, 95% CI 1.02-1.58) were significantly associated with an increased CVD risk without adjustment for covariates. A similarly increased relative risk emerged in patients with an unscheduled CVD-related hospital readmission, i.e., when excluding patients with elective stenting (fear of dying: HR 1.26, 95% CI 1.05-1.51; helplessness: 1.26, 95% CI 1.05-1.52; pain: HR 1.30, 95% CI 1.01-1.66). In the fully-adjusted models controlling for age, the number of diseased coronary vessels, hypertension, and smoking, HRs were 1.24 (95% CI 1.04-1.46) for fear of dying, 1.26 (95% CI 1.06-1.50) for helplessness, and 1.26 (95% CI 1.01-1.57) for pain. Conclusions Retrospectively perceived MI-related distress in the form of fear of dying, helplessness, or pain was associated with non-fatal cardiovascular outcome independent of other important prognostic factors.

Cascading climate effects and related ecological consequences during past centuries

The interface between climate and ecosystem structure and function is incompletely understood, partly because few ecological records start before the recent warming phase. Here, we analyse an exceptional 100-yr long record of the great tit (Parus major) population in Switzerland in relation to climate and habitat phenology. Using structural equation analysis, we demonstrate an uninterrupted cascade of significant influences of the large-scale atmospheric circulation (North-Atlantic Oscillation, NAO, and North-sea – Caspian Pattern, NCP) on habitat and breeding phenology, and further on fitness-relevant life history traits within great tit populations. We then apply the relationships of this analysis to reconstruct the circulation-driven component of fluctuations in great tit breeding phenology and productivity on the basis of new seasonal NAO and NCP indices back to 1500 AD. According to the structural equation model, the multi-decadal oscillation of the atmospheric circulation likely led to substantial variation in habitat phenology, productivity and consequently, tit population fluctuations with minima during the "Maunder Minimum" (∼ 1650–1720) and the Little Ice Age Type Event I (1810–1850). The warming since 1975 was not only related with a quick shift towards earlier breeding, but also with the highest productivity since 1500, and thus, the impact of the NAO and NCP has contributed to an unprecedented increase of the population. A verification of the structural equation model against two independent data series (1970–2000 and 1750–1900) corroborates that the retrospective model reliably depicts the major long-term NAO/NCP impact on ecosystem parameters. The results suggest a complex cascade of climate effects beginning at a global scale and ending at the level of individual life histories. This sheds light on how large-scale climate conditions substantially affect major life history parameters within a population, and thus influence key ecosystem parameters at the scale of centuries.

Regulation of endothelial cell cytoskeletal reorganization by a secreted frizzled-related protein-1 and frizzled 4- and frizzled 7-dependent pathway: role in neovessel formation

Consistent with findings of Wnt pathway members involved in vascular cells, a role for Wnt/Frizzled signaling has recently emerged in vascular cell development. Among the few Wnt family members implicated in vessel formation in adult, Wnt7b and Frizzled 4 have been shown as involved in vessel formation in the lung and in the retina, respectively. Our previous work has shown a role for secreted Frizzled-related protein-1 (sFRP-1), a proposed Wnt signaling inhibitor, in neovascularization after an ischemic event and demonstrated its role as a potent angiogenic factor. However the mechanisms involved have not been investigated. Here, we show that sFRP-1 treatment increases endothelial cell spreading on extracellular matrix as revealed by actin stress fiber reorganization in an integrin-dependent manner. We demonstrate that sFRP-1 can interact with Wnt receptors Frizzled 4 and 7 on endothelial cells to transduce downstream to cellular machineries requiring Rac-1 activity in cooperation with GSK-3beta. sFRP-1 overexpression in endothelium specifically reversed the inactivation of GSK-3 beta and increased neovascularization in ischemia-induced angiogenesis in mouse hindlimb. This study illustrates a regulated pathway by sFRP-1 involving GSK-3beta and Rac-1 in endothelial cell cytoskeletal reorganization and in neovessel formation.

CD34-related coexpression of MDR1 and BCRP indicates a clinically resistant phenotype in patients with acute myeloid leukemia (AML) of older age

Clinical resistance to chemotherapy in acute myeloid leukemia (AML) is associated with the expression of the multidrug resistance (MDR) proteins P-glycoprotein, encoded by the MDR1/ABCB1 gene, multidrug resistant-related protein (MRP/ABCC1), the lung resistance-related protein (LRP), or major vault protein (MVP), and the breast cancer resistance protein (BCRP/ABCG2). The clinical value of MDR1, MRP1, LRP/MVP, and BCRP messenger RNA (mRNA) expression was prospectively studied in 154 newly diagnosed AML patients >or=60 years who were treated in a multicenter, randomized phase 3 trial. Expression of MDR1 and BCRP showed a negative whereas MRP1 and LRP showed a positive correlation with high white blood cell count (respectively, p < 0.05, p < 0.001, p < 0.001 and p < 0.001). Higher BCRP mRNA was associated with secondary AML (p < 0.05). MDR1 and BCRP mRNA were highly significantly associated (p < 0.001), as were MRP1 and LRP mRNA (p < 0.001) expression. Univariate regression analyses revealed that CD34 expression, increasing MDR1 mRNA as well as MDR1/BCRP coexpression, were associated with a lower complete response (CR) rate and with worse event-free survival and overall survival. When adjusted for other prognostic actors, only CD34-related MDR1/BCRP coexpression remained significantly associated with a lower CR rate (p = 0.03), thereby identifying a clinically resistant subgroup of elderly AML patients.

Association of fatigue and psychological distress with quality of life in patients with a previous venous thromboembolic event

Health-related quality of life (QoL) has been associated with several social and medical conditions in patients with deep vein thrombosis (DVT) and pulmonary embolism (PE). To the best of our knowledge, there is no study investigating the relationship of QoL with psychological variables in this patient population. We assumed as a hypothesis an association between heightened levels of fatigue and psychological distress, as well as decreased QoL in patients with an objectively diagnosed venous thromboembolic event. Study participants were 205 consecutively enrolled out-patients (47.4 years, 54.6% men) with DVT and/or PE. Approximately 10 days before blood collection for thrombophilia work-up, QoL, fatigue, and psychological distress were assessed using the Short Form Health Survey (SF-12), the Multidimensional Fatigue Symptom Inventory Short Form (MFSI-SF) as well as the Hospitality Anxiety and Depression scale (HADS). After controlling for demographic and medical factors, fatigue (p < 0.01) but not psychological distress (p>0.05) was negatively associated with physical QoL, explaining 11.0% of the variance. Fatigue (p < 0.001) and psychological distress (p < 0.001) were significant predictors of mental QoL, explaining an additional 36.2% and 3.6% of the variance. Further analyses revealed that all subscales of the HADS (e.g. anxiety and depression) and of the MFSI-SF (e.g. general fatigue, physical fatigue, emotional fatigue, mental fatigue and vigor) were significant predictors of mental QoL. MFSI-SF subscales also predicted physical QoL. The findings suggest that fatigue and psychological distress substantially predict QoL in patients with a previous venous thromboembolic event above and beyond demographic factors.

CECOG experts' recommendations on the use of denosumab in the prevention of skeletal-related events in bone metastases of lung cancer

Purpose Skeletal-related events represent a substantial burden for patients with advanced cancer. Randomized, controlled studies suggested superiority of denosumab over zoledronic acid in the prevention of skeletal-related events in metastatic cancer patients, with a favorable safety profile. Experts gathered at the 2012 Skeletal Care Academy in Istanbul to bring forward practical recommendations, based on current evidence, for the use of denosumab in patients with bone metastases of lung cancer. Recommendations Based on current evidence, use of denosumab in lung cancer patients with confirmed bone metastases is recommended. It is important to note that clinical judgment should take into consideration the patient’s general performance status, overall prognosis, and live expectancy. Currently, the adverse event profile reported for denosumab includes hypocalcemia and infrequent occurrence of osteonecrosis of the jaw. Therefore, routine calcium and vitamin D supplementation, along with dental examination prior to denosumab initiation are recommended. There is no evidence for renal function impairment due to denosumab administration. At present, there is no rationale to discourage concomitant use of denosumab and surgery or radiotherapy.