Obedience-disobedience dynamic and the role of responsibility

Obedience has been thoroughly studied in social psychology, both in its positive and negative aspects. Nevertheless, in these empirical studies disobedience has been considered to be the opposite of obedience and indeed its negation. Instead, some recent studies suggest that if obedience to authority is important in ensuring the continuity of social and group life, disobedience is crucial, under some circumstances, in stopping the authority relationship from degenerating into an authoritarian relationship. In this perspective, disobedience may be conceived of as a protest undermining the legitimacy of authority, or else it can represent an instrument of the community for controlling the legitimacy of the authority's demands, becoming a factor safeguarding against authoritarianism. The aim of the present study was to empirically verify the dynamics existing between disobedience and obedience. The results show that people who attach importance to both obedience and disobedience in the relationship between the individual and society recognize the importance of democratic values and consider themselves responsible for the defence of human rights. Instead, people who only recognize the value of obedience and consider disobedience as a threat to the status quo are more authoritarian, individualistic people.

Uncovering a role for micro-RNAs in sleep homeostasis and energy metabolism

Micro-RNAs (miRNAs) are key, post-transcriptional regulators of gene expression and have been implicated in almost every cellular process investigated thus far. However, their role in sleep, in particular the homeostatic aspect of sleep control, has received little attention. We here assessed the effects of sleep deprivation on the brain miRNA transcriptome in the mouse. Sleep deprivation affected miRNA expression in a brain-region specific manner. The forebrain expression of the miRNA miR-709 was affected the most and in situ analyses confirmed its robust increase throughout the brain, especially in the cerebral cortex and the hippocampus. The hippocampus was a major target of the sleep deprivation affecting 37 miRNAs compared to 52 in the whole forebrain. Moreover, independent from the sleep deprivation condition, miRNA expression was highly region-specific with 45% of all expressed miRNAs showing higher expression in hippocampus and 55% in cortex. Next we demonstrated that down-regulation of miRNAs in Com/c2o-expressing neurons of adult mice, through a conditional and inducible Dicer knockout mice model (cKO), results in an altered homeostatic response after sleep deprivation eight weeks following the tamoxifen-induced recombination. Dicer cKO mice showed a larger increase in the electro-encephalographic (EEG) marker of sleep pressure, EEG delta power, and a reduced Rapid Eye Movement sleep rebound, compared to controls, highlighting a functional role of miRNAs in sleep homeostasis. Beside a sleep phenotype, Dicer cKO mice developed an unexpected, severe obesity phenotype associated with hyperphagia and altered metabolism. Even more surprisingly, after reaching maximum body weight 5 weeks after tamoxifen injection, obese cKO mice spontaneously started losing weight as rapidly as it was gained. Brain transcriptome analyses in obese mice identified several obesity-related pathways (e.g. leptin, somatostatin, and nemo-like kinase signaling), as well as genes involved in feeding and appetite (e.g. Pmch, Neurotensin). A gene cluster with anti-correlated expression in the cerebral cortex of post-obese compared to obese mice was enriched for synaptic plasticity pathways. While other studies have identified a role for miRNAs in obesity, we here present a unique model that allows for the study of processes involved in reversing obesity. Moreover, our study identified the cortex as a brain area important for body weight homeostasis. Together, these observations strongly suggest a role for miRNAs in the maintenance of homeostatic processes in the mouse, and support the hypothesis of a tight relationship between sleep and metabolism at a molecular - Les micro-ARNS (miARNs) sont des régulateurs post-transcriptionnels de l'expression des gènes, impliqués dans la quasi-totalité des processus cellulaires. Cependant, leur rôle dans la régulation du sommeil, et en particulier dans le maintien de l'homéostasie du sommeil, n'a reçu que très peu d'attention jusqu'à présent. Dans cette étude, nous avons étudié les conséquences d'une privation de sommeil sur l'expression cérébrale des miARNs chez la souris, et observé des changements dans l'expression de nombreux miARNs. Dans le cerveau antérieur, miR-709 est le miARN le plus affecté par la perte de sommeil, en particulier dans le cortex cérébral et l'hippocampe. L'hippocampe est la région la plus touchée avec 37 miARNs changés comparés à 52 dans le cerveau entier. Par ailleurs, indépendamment de la privation de sommeil, certains miARNs sont spécifiquement enrichis dans certaines aires cérébrales, 45% des miARNs étant surexprimés dans l'hippocampe contre 55% dans le cortex. Dans une seconde étude, nous avons observé que la délétion de DICER, enzyme essentielle à la biosynthèse des miARNs, et la perte subséquente des miARNs dans les neurones exprimant la protéine CAMK2a altère la réponse homéostatique à une privation de sommeil, 8 semaines après l'induction de la recombinaison génétique par le tamoxifen. Les souris sans Dicer (cKO) ont une plus large augmentation de l'EEG delta power, le principal marqueur électro-encéphalographique du besoin de sommeil, comparée aux contrôles, ainsi qu'un rebond en sommeil paradoxal plus petit. De façon surprenante, les souris Dicer cKO développent une obésité rapide, sévère et transitoire, associée à de l'hyperphagie et une altération de leur métabolisme énergétique. Après avoir atteint un pic maximal d'obésité, les souris cKO entrent spontanément dans une période de perte de poids rapide. L'analyse du transcriptome cérébral des souris obèses nous a permis d'identifier des voies associées à l'obésité (leptine, somatostatine et nemo-like kinase), et à la prise alimentaire (Pmch, Neurotensin), tandis que celui des souris post-obèses a révélé un groupe de gènes liés à la plasticité synaptique. Au-delà des nombreux modèles d'obésité existant chez la souris, notre étude présente un modèle unique permettant d'étudier les mécanismes sous-jacent la perte de poids. De plus, nous avons mis en évidence un rôle important du cortex cérébral dans le maintien de la balance énergétique. En conclusion, toutes ces observations soutiennent l'idée que les miARNs sont des régulateurs cruciaux dans le maintien des processus homéostatiques et confortent l'hypothèse d'une étroite relation moléculaire entre le sommeil et le métabolisme.

Role of defensins and cathelicidin LL37 in auto-immune and auto-inflammatory diseases.

Defensins and cathelicidins are anti-microbial peptides (AMPs) that act as natural antibiotics and are part of the innate immune defence in many species. We consider human defensins and LL37, the only human member of the cathelicidin family. In particular, we refer to the human alpha-defensins called human neutrophil peptides (HNP1 through 4), which are produced by neutrophils, HD5 and HD6, mainly expressed in Paneth cells of intestine, the human beta-defensins HBD1, HBD2 and HBD3, synthesized by epithelial cells and LL37, which is located in granulocytes, but is also produced by epithelial cells of the skin, lungs, and gut. In the last years, the study of AMPs activity and regulation has allowed to understand the important role of these peptides not only in the innate defence mechanisms against bacteria, viruses, fungi, but also in the regulation of immune cell activation and migration. Complementary studies have disclosed a role for AMPs in modulating many physiological processes that involve non-immune cells, such as activation of wound healing, angiogenesis, cartilage remodeling. Due to the pleiotropic tasks of these peptides, many of them are now being discovered to contribute to immune pathology of chronic diseases that affect skin, gut, joints; this is supported by many examples of immune-mediated pathologies in which their expression is disregulated. In this article we review the current literature that suggests a role for human defensins and LL37 in pathogenic mechanisms of several chronic diseases that are considered of auto-immune or auto-inflammatory origin.

Proteomics fingerprinting of phagosome maturation and evidence for the role of a Galpha during uptake.

Phagocytosis, whether of food particles in protozoa or bacteria and cell remnants in the metazoan immune system, is a conserved process. The particles are taken up into phagosomes, which then undergo complex remodeling of their components, called maturation. By using two-dimensional gel electrophoresis and mass spectrometry combined with genomic data, we identified 179 phagosomal proteins in the amoeba Dictyostelium, including components of signal transduction, membrane traffic, and the cytoskeleton. By carrying out this proteomics analysis over the course of maturation, we obtained time profiles for 1,388 spots and thus generated a dynamic record of phagosomal protein composition. Clustering of the time profiles revealed five clusters and 24 functional groups that were mapped onto a flow chart of maturation. Two heterotrimeric G protein subunits, Galpha4 and Gbeta, appeared at the earliest times. We showed that mutations in the genes encoding these two proteins produce a phagocytic uptake defect in Dictyostelium. This analysis of phagosome protein dynamics provides a reference point for future genetic and functional investigations.

Expansion of intraocular gas bubbles due to altitude: do meteorological factors play a role?

BACKGROUND: Intraocular gas bubbles expand as patients move up to higher altitude. This may cause an acute intraocular pressure (IOP) rise with associated vascular obstructions and visual loss. MATERIALS AND METHODS: Two pseudophakic patients underwent a pars plana vitrectomy and 23% SF6 gas tamponade for a pseudophakic retinal detachment. During the immediate post-operative phase, the patients travelled daily up to their domicile, which was situated approximately 600 m higher than the level where they had been operated on. These travels were always without any pain or visual loss. However 1 week after surgery both patients developed severe ocular pain, and one patient had complete temporary loss of vision after ascending to altitude levels, which had previously presented no problem. Both episodes occurred in parallel with a change in barometric pressure. RESULTS: Treatment with acetazolamide reduced the increased IOP to normal levels, and visual acuity recovered. CONCLUSIONS: Although the post-operative size of an intraocular gas bubble decreases progressively over time, problems with bubble expansion may still occur even at a late stage if meteorological factors, that may increase the bubble size, change.

Renal protection with calcium antagonists: the role of lercanidipine.

Abstract Background: Clinical research in the field of hypertension is now increasingly focusing on the potential effects of antihypertensive treatments that may go beyond the reduction of blood pressure (BP). In particular, renal protection appears as a desirable goal, especially considering that hypertension is associated with an increased risk of developing kidney damage, which may eventually lead to end-stage renal disease and a higher mortality. Dihydropyridine calcium channel blockers (CCBs) are widely used in the field of hypertension therapy but the different renal effects of the various CCBs have been poorly explored to date. Scope: This review will discuss available evidence on the renal effects of two calcium channel blockers: amlodipine and lercanidipine, on the basis of clinical data. Methods: MEDLINE and EMBASE were searched for inclusion of relevant studies. No limitations in time were considered. Results: Results from preclinical and clinical studies suggest that amlodipine is overall less effective in terms of renal protection when compared with other antihypertensive tested agents. Its beneficial effect in retarding the progression of renal disease is achievable only when combined with a blocker of the renin-angiotensin system. Conversely lercanidipine seems to provide renal protection in a similar way to ACE inhibitors, probably thanks to its mechanism of action which acts directly on the afferent and efferent renal arterioles. Conclusions: Treatment of hypertension with CCBs should take into consideration the special effects of each single agent at different levels; lercanidipine for example may play a useful role in the management not only of hypertension but also in renal protection of hypertensive patients.

Dermatologie esthétique et correctrice: applications cliniques et rôle social [Esthetic and corrective dermatology: clinical applications and social role].

Skin diseases may have severe aesthetic and psychological repercussions leading sometimes to discriminations and social isolation. Dermatologists have contributed to the development of many cosmetic procedures: peelings, botulinum toxin or hyaluronic acid injections, lasers, blepharoplasty, facelift, etc. Many of these treatments have interesting clinical applications and may help numerous patients with skin diseases to return to a normal social life.

Role of disease activity for decision making ability in early multiple sclerosis

Background and purpose: Decision making (DM) has been defined as the process through which a person forms preferences, selects and executes actions, and evaluates the outcome related to a selected choice. This ability represents an important factor for adequate behaviour in everyday life. DM impairment in multiple sclerosis (MS) has been previously reported. The purpose of the present study was to assess DM in patients with MS at the earliest clinically detectable time point of the disease. Methods: Patients with definite (n=109) or possible (clinically isolated syndrome, CIS; n=56) MS, a short disease duration (mean 2.3 years) and a minor neurological disability (mean EDSS 1.8) were compared to 50 healthy controls aged 18 to 60 years (mean age 32.2) using the Iowa Gambling Task (IGT). Subjects had to select a card from any of 4 decks (A/B [disadvantageous]; C/D [advantageous]). The game consisted of 100 trials then grouped in blocks of 20 cards for data analysis. Skill in DM was assessed by means of a learning index (LI) defined as the difference between the averaged last three block indexes and first two block indexes (LI=[(BI-3+BI-4+BI-5)/3-(BI-1+B2)/2]). Non parametric tests were used for statistical analysis. Results: LI was higher in the control group (0.24, SD 0.44) than in the MS group (0.21, SD 0.38), however without reaching statistical significance (p=0.7). Interesting differences were detected when MS patients were grouped according to phenotype. A trend to a difference between MS subgroups and controls was observed for LI (p=0.06), which became significant between MS subgroups (p=0.03). CIS patients who confirmed MS diagnosis by presenting a second relapse after study entry showed a dysfunction in the IGT in comparison to the other CIS (p=0.01) and definite MS (p=0.04) patients. In the opposite, CIS patients characterised by not entirely fulfilled McDonald criteria at inclusion and absence of relapse during the study showed an normal learning pattern on the IGT. Finally, comparing MS patients who developed relapses after study entry, those who remained clinically stable and controls, we observed impaired performances only in relapsing patients in comparison to stable patients (p=0.008) and controls (p=0.03). Discussion: These results raise the assumption of a sustained role for both MS relapsing activity and disease heterogeneity (i.e. infra-clinical severity or activity of MS) in the impaired process of decision making.

No Role for Cerebrospinal Fluid Myelin Basic Protein Levels in Patients Treated for Childhood Acute Lymphoblastic Leukemia.

INTRODUCTION: Central nervous system prophylaxis of childhood acute lymphoblastic leukemia has dropped rates of relapses but has been associated with neurotoxicity and imaging abnormalities. Predictors of neurotoxicity are lacking, because of inconsistency between clinical symptoms and imaging. Some have suggested that cerebrospinal fluid myelin basic protein (MBP) levels to be of potential interest. A retrospective analysis of MBP levels in correlation with clinical and radiologic data is presented. MATERIALS AND METHODS: MBP levels obtained at the time of intrathecals, charts, and neuroradiology reports were retrospectively analyzed. Academic achievement data were obtained from phone contacts with patients and families. RESULTS: We retrieved 1248 dosages of MBP in 83 patients, 381 neurologic examinations in 34 patients and 69 neuroradiologic investigations in 27 patients. Fifty-two patients had abnormal MBP levels. Radiologic anomalies were present in 47% of those investigated, 14% of them having school difficulties. Proportions of patients with school difficulties in the groups with abnormal MBP levels but no radiologic anomalies or with no radiologic investigations were 0% and 3%, respectively, which was lower than in the group of patients with normal MBP levels (100%, 22%, and 5%, respectively). DISCUSSION: Notwithstanding the retrospective character of our study, we conclude that there is limited usefulness of systematic dosage of MBP as indicator of treatment-induced neurotoxicity in acute lymphoblastic leukemia patients.

The role of neutralizing antibodies for mouse mammary tumor virus transmission and mammary cancer development.

Mouse mammary tumor virus (MMTV) infection establishes chronic germinal centers and a lifelong neutralizing Ab response. We show that removal of the draining lymph node after establishment of the germinal center reaction led to complete loss of neutralizing Abs despite comparable infection levels in peripheral lymphocytes. Importantly, in the absence of neutralization, only the exocrine organs mammary gland, salivary gland, pancreas, and skin showed strikingly increased infection, resulting in accelerated mammary tumor development. Induction of stronger neutralization did not influence chronic infection levels of peripheral lymphoid organs but strongly inhibited mammary gland infection and virus transmission to the next generation. Taken together, we provide evidence that a tight equilibrium in virus neutralization allows limited infection of exocrine organs and controls cancer development in susceptible mouse strains. These experiments show that a strong neutralizing Ab response induced after infection is not able to control lymphoid MMTV infection. Strong neutralization, however, is capable of blocking amplification of mammary gland infection, tumor development, and virus transmission to the next generation. The results also indicate a role of neutralization in natural resistance to MMTV infection.

The dermatologists' role in managing psoriatic arthritis: results of a swiss delphi exercise intended to improve collaboration with rheumatologists.

BACKGROUND: Psoriatic arthritis (PsA) substantially impacts the management of psoriatic disease. OBJECTIVE: This study aimed to generate an interdisciplinary national consensus on recommendations of how PsA should be managed. METHODS: Based on a systematic literature search, an interdisciplinary expert group identified important domains and went through 3 rounds of a Delphi exercise, followed by a nominal group discussion to generate specific recommendations. RESULTS: A strong consensus was reached on numerous central messages regarding the impact of PsA, screening procedures, organization of the interaction between dermatologists and rheumatologists, and treatment goals. CONCLUSION: These recommendations can serve as a template for similar initiatives in other countries. At the same time, they highlight the need to take into account the impact of the respective national health care system. © 2015 S. Karger AG, Basel.