Deficiency of macrophage PHACTR1 impairs efferocytosis and promotes atherosclerotic plaque necrosis

Efferocytosis, the process through which apoptotic cells (ACs) are cleared through actin-mediated engulfment by macrophages, prevents secondary necrosis, suppresses inflammation, and promotes resolution. Impaired efferocytosis drives the formation of clinically dangerous necrotic atherosclerotic plaques, the underlying etiology of coronary artery disease (CAD). An intron of the gene encoding PHACTR1 contains rs9349379 (A>G), a common variant associated with CAD. As PHACTR1 is an actin-binding protein, we reasoned that if the rs9349379 risk allele G causes lower PHACTR1 expression in macrophages, it might link the risk allele to CAD via impaired efferocytosis. We show here that rs9349379-G/G was associated with lower levels of PHACTR1 and impaired efferocytosis in human monocyte–derived macrophages and human atherosclerotic lesional macrophages compared with rs9349379-A/A. Silencing PHACTR1 in human and mouse macrophages compromised AC engulfment, and Western diet–fed Ldlr^–/– mice in which hematopoietic Phactr1 was genetically targeted showed impaired lesional efferocytosis, increased plaque necrosis, and thinner fibrous caps — all signs of vulnerable plaques in humans. Mechanistically, PHACTR1 prevented dephosphorylation of myosin light chain (MLC), which was necessary for AC engulfment. In summary, rs9349379-G lowered PHACTR1, which, by lowering phospho-MLC, compromised efferocytosis. Thus, rs9349379-G may contribute to CAD risk, at least in part, by impairing atherosclerotic lesional macrophage efferocytosis.     

Self-rated health as a predictor of return to work among employees on long-term sickness absence

Aims.?The aim of the present study is to identify self-rated health predictors of return to work (RTW) within the study population as a whole as well as in three subgroups, namely musculoskeletal complaints, other physical health complaints, and psychological complaints.

Methods.?The study was based on a sample of 862 employees on sickness absence (maximum duration of 12 weeks). The employees filled out a baseline questionnaire and were subsequently followed until the tenth month after listing sick. Cox proportional hazards regression analyses were used to identify determinants of RTW.

Results.?For the study population as a whole type of complaint, earlier sickness absence, subjective severity of complaints and several RAND-36 subscales were predictive of RTW. Furthermore, the RAND-36 subscales physical functioning, physical role limitations, mental health, and health change were predictive of RTW among employees with musculoskeletal complaints. For employees with other physical health problems subjective severity of complaints and the RAND-36 subscales physical and social functioning, general health perception, and health change were associated with RTW. Finally, with regard to the group with psychological complaints the RAND-36 subscales mental health and general health perception predicted RTW.

Conclusion.?Several aspects of self-rated health predict RTW for employees on long-term sickness absence. Variables related to functional status predict RTW for employees with physical complaints in contrast to psychological problems.     

Internet use and cognitive frailty in older adults: a large-scale multidimensional approach

Although research on sociodemographic correlates of internet use in older adults without and with pronounced cognitive impairment is already quite extensive, much less is known about the relationship between cognitive frailty (CF) and this behaviour. As CF is associated to multidimensional frailty aspects, this study explored the relationship between internet use and CF, operationalised as Subjective Cognitive Impairment, in older adults by means of a comprehensive explanatory model including sociodemographic factors and multiple frailty measures. The dataset included a sample of community-dwelling 60 + older adults that were included in the Belgian Ageing Studies (BAS) and that completed survey questions on (i) internet use frequency and (ii) internet activities. Multidimensional frailty was measured with the CFAI-Plus. The analysis comprised a structural equation modelling (SEM) procedure. Internet use was frequent; however, it became less frequent with higher CF. Moreover, the latter used less tablets as compared to the no-low CF group. Navigating the web, sharing email and online banking were the most frequently reported activities. Tele-communicating with Skype, online shopping and using e-government services were the least frequent. Age, female gender, lower income and living with a partner were also negatively associated with internet use. To conclude, CF, along with other frailty and sociodemographic factors, was negatively related to internet use in older adults. Future research should focus, amongst others, on the dynamic processes underlying internet use in the population of older adults affected by CF.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10433-022-00686-2.     

Attitude towards pre-implantation genetic diagnosis for hereditary cancer

The use of pre-implantation genetic diagnosis (PGD) for hereditary cancer is subject to on-going debate, particularly among professionals. This study evaluates the attitude towards PGD and attitude-associated characteristics of those concerned: family members with a hereditary cancer predisposition. Forty-eight Von Hippel-Lindau and 18 Li–Fraumeni Syndrome families were identified via the 9 family cancer clinics in the Netherlands. In total, 216 high risk family members and partners were approached, of whom 179 (83%) completed a self-report questionnaire. Of the high risk family members, 35% expressed a positive attitude towards PGD. Those with a current desire to have children were significantly more likely to have a positive attitude: 48% would consider the use of PGD. No other sociodemographic, medical or psychosocial variables were associated significantly with a positive attitude. The most frequently reported advantage of PGD is the avoidance of a possible pregnancy termination. Uncertainty about late effects was the most frequently reported disadvantage. These results indicate that approximately half of those contemplating a future pregnancy would consider the use of PGD. The actual uptake, however, is expected to be lower. There is no indication that psychosocial factors affect interest in PGD.     

Trunk sway in patients with spinocerebellar ataxia.

We investigated whether quantified measurements of trunk sway during stance and gait tests in patients with autosomal dominant spinocerebellar ataxia (SCA) could be a useful approach to assess ataxia, which is highly relevant for adequate follow-up and future intervention studies. Examined were 11 SCA patients and 11 age-matched, healthy controls. Postural and balance control were quantified using peak-to-peak measurements of trunk angle and angular velocity, in the roll (lateral) and pitch (anterior-posterior) directions, during a battery of stance and gait tasks. In all stance tasks, trunk angle displacement and angular velocity in both the pitch and roll planes were significantly larger in the SCA group compared with the control group. Among the ataxia patients instability was more increased in the pitch than in the roll direction for two-legged stance tasks, especially when standing on foam, with pronounced oscillations in the pitch plane at 1.4 and 2.5 Hz. A similar dominance of pitch over roll instability was also observed in most gait tasks, especially for tandem gait and while walking with simultaneous head rotations. Trunk sway measurements were effective in detecting and quantifying the gait and balance abnormalities in SCA patients, suggesting that this method might be used for follow-up studies of SCA patients. Furthermore, the method might help to identify early symptomatic individuals and those patients at risk of falling. The postural instability in SCA was found to be multidirectional, although there is generally more pitch than roll instability corresponding with predominant involvement of the spinocerebellum.     

Flat penile lesions: the infectious "invisible" link in the transmission of human papillomavirus

Although it has been widely accepted that high-risk human papillomavirus (hrHPV) is sexually transmitted, limited insight is available about the clinical manifestations of hrHPV infection in men and their contribution in the viral spread. Here, we reviewed the literature on the relationship between hrHPV and the presence of penile lesions. Flat penile lesions have similar predilection sites as HPV, often contain hrHPV as identified by DNA in situ hybridization in biopsy specimens, show a high association with hrHPV as identified by PCR in penile scrapes of lesional sites and are associated with high viral copy numbers. Absence of flat lesions is generally associated with very low HPV copy numbers or absence of HPV. Therefore, we argue that these lesions form the reservoir of hrHPV in men and contribute to the viral spread. Their bare visibility with the naked eye and their high degree of spontaneous healing explain why flat penile lesions have slipped the attention of the clinician. Combining an HPV DNA test with a visual inspection after acetic acid application offers a more reliable interpretation of a positive HPV test in men, as it helps to distinguish positivity that is very likely to reflect a productive HPV infection from potentially HPV infections with very low copy numbers or HPV contamination by the sex partner. Future trials of HPV vaccines in men should take into account not only the presence of penile HPV but also the presence of flat penile lesions as an outcome measure for the efficacy of a vaccine.     

Decision-making in palliative care practice and the need for moral deliberation: a qualitative study

The development of palliative care is increasing the interest in the moral problems that arise in the practice of palliative care. It is not clear how caregivers deal with these moral problems. In this article, we focus on the decision whether to continue treatment or to withhold it, and discuss the way caregivers deal with this question amongst themselves and in communication or consultation with the patient. We look at moral deliberation, the process of identifying the crucial arguments for this decision in palliative care.     

Intravenous adenosine protects the myocardium primarily by activation of a neurogenic pathway

Endogenous adenosine is a trigger for ischemic myocardial preconditioning (IPC). Although intravascular administration of adenosine has been used to further unravel the mechanism of protection by IPC, it is questionable whether adenosine and IPC employ the same signaling pathways to exert cardioprotection. We therefore investigated whether the active metabolic barrier of the endothelium prevents an increase in myocardial interstitial adenosine concentrations by intravenous adenosine, using microdialysis, and also the role of NO and activation of a neurogenic pathway in the cardioprotection by adenosine. In pentobarbital-anesthetized rats, area at risk and infarct size (IS) were determined 120 min after a 60-min coronary artery occlusion (CAO), using trypan blue and nitro-blue-tetrazolium staining, respectively. IPC with a single 15-min CAO and a 15-min adenosine infusion (ADO, 200 microg min(-1) i.v.) limited IS to the same extent (IS = 41 +/- 6% and IS = 40 +/- 4%, respectively) compared to control rats (IS = 63 +/- 3%, both P < 0.05). However, IPC increased myocardial interstitial adenosine levels seven-fold from 4.3 +/- 0.7 to 27.1 +/- 10.0 microM (P < 0.05), while ADO had no effect on interstitial adenosine (4.1 +/- 1.2 microM), or any of the other purines. The NO synthase inhibitor N(omega)-nitro-L-arginine (LNNA), which did not affect IS (IS = 62 +/- 3%), attenuated the protection by ADO (IS = 56 +/- 3%; P < 0.05 vs ADO, P = NS vs LNNA). The ganglion blocker hexamethonium, which had also no effect on IS (IS = 66 +/- 3%), blunted the protection by ADO (IS = 55 +/- 4%; P < 0.05 vs ADO and vs hexamethonium). These observations demonstrate that cardioprotection by ADO is dependent on NO, and is primarily mediated by activation of a neurogenic pathway.