Mindfulness and self-compassion in dermatological conditions: a systematic narrative review.

OBJECTIVE: People affected by chronic skin conditions suffer from elevated levels of psychological distress. There is a need for evidence-based treatments that integrate medical care. Mindfulness and Self-compassion programs (MCBPs) have proven effective in chronic diseases. This systematic review aims to narratively synthesize the literature on mindfulness and self-compassion as traits and interventions in chronic skin conditions. DESIGN: We searched four electronic databases for mindfulness and self-compassion trials and correlational studies in chronic skin conditions. We narratively synthetized results regarding the effects of mindfulness and self-compassion, both as traits and as interventions, on psychological and disease outcomes. RESULTS: Thirteen studies were included in our review. Evidence from cross-sectional studies suggest that mindfulness and self-compassion are linked to lower psychological distress and better adjustment to the disease. MCBPs appear feasible for this population and can lower psychological distress, reduce disease severity and improve quality of life. Methodological issues limit conclusions on MCBP efficacy. Based on our analysis, we propose possible mechanisms that future research could explore. CONCLUSIONS: The integration of MCBPs in the care process of chronic skin conditions appears promising. Definitive conclusions cannot be drawn due to a lack of strong evidence. Further studies with high methodological standards are needed.

European guideline for the diagnosis and treatment of insomnia

This European guideline for the diagnosis and treatment of insomnia was developed by a task force of the European Sleep Research Society, with the aim of providing clinical recommendations for the management of adult patients with insomnia. The guideline is based on a systematic review of relevant meta-analyses published till June 2016. The target audience for this guideline includes all clinicians involved in the management of insomnia, and the target patient population includes adults with chronic insomnia disorder. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) system was used to grade the evidence and guide recommendations. The diagnostic procedure for insomnia, and its co-morbidities, should include a clinical interview consisting of a sleep history (sleep habits, sleep environment, work schedules, circadian factors), the use of sleep questionnaires and sleep diaries, questions about somatic and mental health, a physical examination and additional measures if indicated (i.e. blood tests, electrocardiogram, electroencephalogram; strong recommendation, moderate- to high-quality evidence). Polysomnography can be used to evaluate other sleep disorders if suspected (i.e. periodic limb movement disorder, sleep-related breathing disorders), in treatment-resistant insomnia, for professional at-risk populations and when substantial sleep state misperception is suspected (strong recommendation, high-quality evidence). Cognitive behavioural therapy for insomnia is recommended as the first-line treatment for chronic insomnia in adults of any age (strong recommendation, high-quality evidence). A pharmacological intervention can be offered if cognitive behavioural therapy for insomnia is not sufficiently effective or not available. Benzodiazepines, benzodiazepine receptor agonists and some antidepressants are effective in the short-term treatment of insomnia (≤4 weeks; weak recommendation, moderate-quality evidence). Antihistamines, antipsychotics, melatonin and phytotherapeutics are not recommended for insomnia treatment (strong to weak recommendations, low- to very-low-quality evidence). Light therapy and exercise need to be further evaluated to judge their usefulness in the treatment of insomnia (weak recommendation, low-quality evidence). Complementary and alternative treatments (e.g. homeopathy, acupuncture) are not recommended for insomnia treatment (weak recommendation, very-low-quality evidence).

[Insomnia--state of the science]. / Insomnien--Stand der Forschung.

Diagnostic systems such as the international classification of diseases (ICD-10) or the diagnostic and statistical manual of mental disorders (DSM IV) have frequently been criticized as not adequately reflecting the complexity and heterogeneity of insomnia. Progress was made through the introduction of the international classification of sleep disorders (ICSD-2) and the research diagnostic criteria (RDC). The DSM-5 introduced the new category of insomnia disorder, thus relinquishing the traditional dichotomy of primary versus secondary insomnia. Recent basic research indicates that genetic and epigenetic factors are involved in the etiology of insomnia; the so-called three P model (i.e. predisposing, precipitating and perpetuating factors) and the hyperarousal concept have gained much attention in trying to explain the pathophysiology of insomnia. With respect to the cognitive-behavioral therapy of insomnia (CBT-I), a plethora of empirical evidence supports the first-line character of this type of treatment for insomnia. Unfortunately, CBT-I is still administered to only a minority of afflicted patients, probably due to a lack of resources in the healthcare system. As a consequence, stepped-care models to improve insomnia therapy encompass self-help programs, internet-based treatment avenues, community-centered activities (specially trained nurses) and as a last resort medical specialists/psychotherapists and sleep experts to deal with insomnia.

REM sleep instability--a new pathway for insomnia?

Chronic insomnia afflicts approximately 10% of the adult population and is associated with daytime impairments and an elevated risk for developing somatic and mental disorders. Current pathophysiological models propose a persistent hyperarousal on the cognitive, emotional and physiological levels. However, the marked discrepancy between minor objective alterations in standard parameters of sleep continuity and the profound subjective impairment in patients with insomnia is unresolved. We propose that "instability" of REM sleep contributes to the experience of disrupted and non-restorative sleep and to the explanation of this discrepancy. This concept is based on evidence showing increased micro- and macro-arousals during REM sleep in insomnia patients. As REM sleep represents the most highly aroused brain state during sleep it seems particularly prone to fragmentation in individuals with persistent hyperarousal. The continuity hypothesis of dream production suggests that pre-sleep concerns of patients with insomnia, i. e., worries about poor sleep and its consequences, dominate their dream content. Enhanced arousal during REM sleep may render these wake-like cognitions more accessible to conscious perception, memory storage and morning recall, resulting in the experience of disrupted and non-restorative sleep. Furthermore, chronic fragmentation of REM sleep might lead to dysfunction in a ventral emotional neural network, including limbic and paralimbic areas that are specifically activated during REM sleep. This dysfunction, along with attenuated functioning in a dorsal executive neural network, including frontal and prefrontal areas, might contribute to emotional and cognitive alterations and an elevated risk of developing depression.

[Lack of sleep and insomnia. Impact on somatic and mental health]. / Schlafmangel und Insomnie. Einfluss auf die körperliche und psychische Gesundheit.

Lack of sleep and insomnia need to be viewed differently. Lack of sleep implies a shortening of the habitual sleep duration due to external circumstances or motivational factors. Insomnia, in contrast, is defined as a sleep disorder due to unknown reasons for the afflicted subjects. People with insomnia suffer from being unable to sleep, in spite of adequate external circumstances. Research on lack of sleep/shortened sleep duration has focused on relationships with somatic and mental health. Longitudinal studies revealed that a shortening of sleep duration (< 6 h) is associated with an increased risk for the metabolic syndrome and cardiovascular diseases. For sleep duration and mortality, a U-shaped relationship was found, indicating that both shortened (< 6 h) and prolonged sleep durations (> 8 h) are associated with increased mortality. Similar, albeit weaker, correlations were described for insomnia and somatic health. In addition, insomnia is a risk factor for the development of mental disorders, especially depression. These relationships suggest that the area of sleep and sleep disorders should be integrated into everyday medical practice and that preventive approaches to somatic and mental disorders should encompass the topic of sleep to a much stronger extent than currently practiced.

Degradation of unstable interleukin-1 alpha mRNA in a rabbit reticulocyte cell-free system. Localization of an instability determinant to a cluster of AUUUA motifs.

Labeled transcripts of interleukin-1 alpha (IL-1 alpha) cDNA were rapidly degraded in incubations with rabbit reticulocyte lysate (RRL). In contrast, a transcript of superoxide dismutase cDNA was stable in control incubations. A transcript of the 3'-untranslated region (UTR) of IL-1 alpha was rapidly degraded while that of the 5'-UTR and coding region was stable. This degradative activity was present in the post-ribosomal supernatant. Degradation of the 3'-UTR transcript was inhibited by the addition of a large excess of an 80-base RNA containing four AUUUA repeats, but not by the same RNA without such repeats. This suggested that AUUUA motifs were responsible for the instability of the 3'-UTR transcript. The 80-base RNA did not act as a competitive substrate for a nuclease since it was not degraded. Partial transcripts of IL-1 alpha 3'-UTR were incubated with RRL to localize instability determinants. Transcripts containing at least three clustered AUUUA motifs were rapidly degraded, while transcripts containing four scattered AUUUA motifs were stable. To study the mechanism of RNA degradation, the RRL was passed through an affinity column that retained AUUUA-binding proteins. The flow-through or the fraction eluted from such a column were inactive, but the two fractions together degraded the 3'-UTR transcript. This indicated that proteins bound by the affinity column did not have nuclease activity but targeted this RNA for degradation.

Expression of interleukin-1 alpha and beta in early passage fibroblasts from aging individuals.

Human diploid fibroblasts (HDFs) from newborn foreskin constitutively express interleukin-1 (IL-1) mRNA and protein after completing at least 70% (approximately 40 population doublings) of their in vitro life span. This IL-1 in turn induces the synthesis of specific proteins in aging HDFs. To determine whether IL-1 expression may be promoted by in vivo aging, we analyzed the expression of IL-1 and of inducible mRNAs in HDFs from two normal individuals 55 and 92 years old and in HDFs from a patient with premature aging caused by Werner's syndrome. By reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), we detected expression of IL-1 alpha and beta mRNA and protein in early passage HDFs from both normal individuals and the Werner's syndrome patient. These HDFs also expressed the IL-1-inducible mRNAs for stromelysin, plasminogen activator inhibitor type 2, manganous superoxide dismutase, and collagenase. These results suggest that an age-dependent expression of IL-1 occurs either in vivo or after a few cell divisions in vitro. Therefore, the fibroblast phenotype is modified by the expression of IL-1-inducible genes during aging.

Differential induction and decay of manganese superoxide dismutase mRNAs.

Human manganese superoxide dismutase (MnSOD) is encoded by two mRNAs of 4 and 1 kb, respectively. These mRNAs are transcribed from the same gene and have an identical coding sequence, but differ in the 3' untranslated sequence because of alternate polyadenylation. Tumor necrosis factor-alpha (TNF) induced both 4- and 1-kb mRNAs in all the human cell lines examined. However, the relative expression of these mRNAs varied significantly among different cell lines after an 8-h treatment with TNF. Therefore, the time course of induction by TNF and the decay of MnSOD mRNAs after TNF removal were analyzed. The rate of accumulation of the 4-kb mRNA was initially much greater than that of the 1-kb mRNA, suggesting that the 4-kb mRNA was produced faster than the 1-kb mRNA. The rapid accumulation of the 4-kb mRNA was offset after a few hours by an enhanced rate of decay. The half-life of the 4-kb mRNA was approximately 2-4 h in different cells while that of the 1-kb mRNA was approximately 10-12 h. This different half-life of mRNAs that encode the same protein suggests that their relative expression is also regulated by a post-transcriptional mechanism affecting their turnover. Additional evidence supporting the differential decay of the two MnSOD mRNAs was obtained by incubation in a rabbit reticulocyte cell-free system; the 4-kb mRNA decayed rapidly while the 1-kb mRNA appeared to be stable.

Tumor necrosis factor increases stability of interleukin-1 mRNA by activating protein kinase C.

The mRNAs coding for interleukin-1 alpha (IL-1 alpha) and IL-1 beta are constitutively transcribed but do not accumulate in human diploid fibroblasts and in fibrosarcoma cells. Treatment of these cells with tumor necrosis factor (TNF) induces accumulation of IL-1 mRNA by an unknown mechanism. This induction of IL-1 mRNA was investigated in HT-1080 cells. The induction was quite fast, with maximum levels of IL-1 alpha and beta mRNA reached 4 h after addition of TNF. Nuclear run-off experiment showed that TNF did not increase the rate of transcription of IL-1 mRNA. This mRNA was apparently unstable in untreated cells, but it accumulated in cycloheximide-treated cells. Phorbol esters induced IL-1 mRNA, suggesting that activation of protein kinase C was responsible for the accumulation of this mRNA. This hypothesis was confirmed by experiments with the PKC inhibitors staurosporine and calphostin C, which prevented the induction of IL-1 mRNA by TNF and accelerated the decay of this mRNA in cells pretreated with TNF. Both IL-1 alpha and IL-1 beta were detected in TNF-treated cells by Western blot analysis and enzyme-linked immunosorbent assay. These results indicate that the TNF-mediated induction of IL-1 can be entirely accounted for by stabilization of this mRNA.

Expression of messenger RNAs for complement inhibitors in human tissues and tumors.

The mRNAs coding for three complement inhibitors produced by human cells, complement cytolysis inhibitor (CLI), decay-accelerating factor (DAF), and CD59, are characteristically distributed among normal tissues. High levels of CLI mRNA are expressed in tissues that express low levels of DAF mRNA and vice versa. Therefore, the expression of these mRNAs shows a mutually exclusive relationship, with the possible exception of the lung, where all these mRNAs are expressed. In contrast, CD59 mRNA is rather uniformly expressed in all tumor cell lines examined, whereas the mRNA for either of the two other complement inhibitors is overexpressed in some specific tumor cells, e.g., HeLa cells overexpress DAF mRNA, while A172 cells overexpress CLI mRNA. These two cell lines were resistant to antibody-dependent complement cytotoxicity. Expression of CLI and DAF mRNA was induced in cells treated with the antitumor drug N-(chloroetyl)-N'-cyclohexyl-N-nitrosourea; these cells became resistant to complement cytotoxicity. A similar pattern of expression was detected in tumor samples obtained during surgery, with a relatively uniform expression of CD59 mRNA and occasional overexpression of CLI or DAF mRNA. These findings suggest that overexpression of complement inhibitors mRNA and of the corresponding proteins may contribute to tumor cell resistance to complement-mediated cytotoxicity.

Expression of interleukin 1-inducible genes and production of interleukin 1 by aging human fibroblasts.

The interleukin 1 (IL-1)-inducible mRNAs for plasminogen activator inhibitor type 2, manganese superoxide dismutase, and urokinase are overexpressed in old (greater than 70% of life-span completed) but not in young (less than 40% of life-span completed) human foreskin fibroblasts. Furthermore, the activity of this superoxide dismutase is greater in old than in young fibroblasts. IL-1 beta mRNA is detected by Northern blot analysis in old fibroblasts and its expression is further enhanced by a treatment with IL-1 alpha. IL-1 alpha and IL-1 beta mRNAs are detected in old foreskin and lung fibroblasts by a sensitive reverse transcription-PCR assay. IL-1 mRNA is consistently expressed after fibroblasts have completed 85% of their in vitro life-span; an assay with specific antibodies shows that IL-1 alpha is present in these fibroblasts. Prolonged treatment with IL-1 receptor antagonist decreases the levels of IL-1 alpha and of IL-1 alpha and IL-1 beta mRNAs. This observation suggests that IL-1 receptor antagonist inhibits an autocrine loop responsible for IL-1 expression. IL-1 mRNA accumulates in young fibroblasts treated with cycloheximide, suggesting that it is transcribed but unstable in these cells; accumulation of IL-1 mRNA in old fibroblasts may be due at least in part to increased stability. IL-1 alpha stimulates DNA synthesis in young fibroblasts but has progressively less effect as the cells age in culture. These data indicate that IL-1 is "constitutively" produced by aging fibroblasts and that IL-1 induces the expression of specific proteins in these cells. The mechanism for this constitutive production of IL-1 is explored in this paper.

Expression of porcine complement cytolysis inhibitor mRNA in cultured aortic smooth muscle cells. Changes during differentiation in vitro.

Porcine smooth muscle cells (SMC) grown to a high density monolayer culture undergo a morphological transition in which the cells draw away from the substrate and form multicellular nodules. The cells within the nodule resemble SMC in the aortic media and in some atherosclerotic plaques. The process of nodule formation is associated with the enhanced production of a secreted 38-kDa glycoprotein. To characterize the 38-kDa protein and its expression, a cDNA clone (pc38K) was isolated by immunological screening of an expression library. The 1646-base pair cDNA contains a single open reading frame encoding 446 amino acids. This sequence shows 72% homology with the human complement cytolysis inhibitor (CLI), also called serum protein-40,40, and 68% identity with rat sulfated glycoprotein-2. Based on this homology, we refer to the protein encoded by pc38K as CLI. This polypeptide includes a potential signal sequence, seven glycosylation sites and 10 cysteines in two clusters of five each. Southern blot analysis reveals that a single copy gene encoding CLI is present in mammals and chicken. In Northern blot analysis of SMC RNA, pc38K hybridizes to a mRNA of about 1.9 kilobases that is preferentially expressed in nodular SMC. The steady state level of this mRNA increases as the cultures begin to form multilayered regions. High levels of the mRNA persist after the cells are trypsin-dissociated. Culture medium conditioned by nodular SMC also induces an increase of CLI mRNA. Analysis of RNA extracted from porcine tissues show the highest levels of CLI mRNA in brain and liver; lower levels are detected in other tissues, including the aorta. Possible functions for the CLI are discussed.

Reduced expression of manganese superoxide dismutase in cells resistant to cytolysis by tumor necrosis factor.

Tumor necrosis factor (TNF) induces synthesis of manganese superoxide dismutase (MnSOD). It was previously shown that overexpression of MnSOD protected some mammalian cells from TNF cytotoxicity. The purpose of this study was to establish whether MnSOD was increased in cells selected for resistance to cytolysis by TNF in combination with cycloheximide. Melanoma SK-MEL-109 and HeLa cell-resistant variants were selected by repeated treatments with TNF and cycloheximide. The SK-MEL-109 variants had relatively low levels of MnSOD that were inducible by TNF. Surprisingly, the HeLa variants had very low levels of MnSOD that were poorly inducible by either TNF or interleukin-1 alpha. Therefore, an elevated level of MnSOD was not required to protect these cells from TNF-mediated cytolysis. The HeLa variants were more sensitive than parental cells to superoxide radical (O2-) generating compounds, such as paraquat or xanthine/xanthine oxidase. Pretreatment of these variants with TNF did not provide protection against damage by superoxide radicals.

Protection from tumor necrosis factor-mediated cytolysis by overexpression of plasminogen activator inhibitor type-2.

Pretreatment of HT-1080 fibrosarcoma cells with tumor necrosis factor (TNF) induced resistance to the cytolytic activity of this cytokine in combination with cycloheximide. This resistance correlated with the synthesis of plasminogen activator inhibitor type-2 (PAI-2). HT-1080 cells were transfected with a PAI-2 expression vector in both sense and antisense orientation. The resistance to TNF-mediated cytolysis of transfected cell clones was correlated with the level of PAI-2 expression. Cells expressing antisense PAI-2 RNA showed reduced expression of PAI-2 and increased sensitivity to TNF-mediated cytolysis. Cells expressing constitutively PAI-2 were treated with TNF and cycloheximide to select cells with increased resistance to cytolysis and enhanced PAI-2 expression. PAI-2 gradually disappeared during a treatment with TNF and cycloheximide. This finding suggested that PAI-2 formed a complex with a target proteinase, which could be involved in mediating the cytolytic activity of TNF.

Modulation of neurite outgrowth in neuroblastoma cells by protein kinase C and platelet-activating factor.

Previous reports have shown that thrombin and activators of protein kinase C (PKC) inhibit neurite outgrowth (NOG) in neuroblastoma cells cultured in serum-free medium. Therefore, we tested the hypothesis that PKC activation mediates the effect of thrombin on NOG in murine neuroblastoma NB-2a cells. After 2 h in serum-free medium, 70% of the cells displayed neurites; addition of 300 ng/ml thrombin reduced NOG to 24% within 1 h. This inhibition was reduced after NB-2a cells were pretreated for 24 h with 200 nM phorbol dibutyrate down-regulate PKC. Thrombin and phorbol 12-myristate 13-acetate inhibited NOG in an additive way and the protein kinase inhibitors H-7, H-8, and HA1004 reversed the effect of thrombin on NOG with a rank order of activity consistent with PKC inhibition. Furthermore, PKC was translocated from the cytosol to a membrane-bound form 5 to 10 min after addition of thrombin. These findings indicate that thrombin inhibits NOG through a PKC-dependent pathway. Thrombin stimulates the synthesis of the phospholipid platelet-activating factor (PAF) in some cells. However, NOG was markedly stimulated when PAF or its analogue carbamyl-PAF were added to NB-2a cells in medium with serum. Furthermore, the PAF receptor antagonist SRI 63072 inhibited NOG in NB-2a cells in serum-free medium. These cells accumulated PAF with kinetics similar to that of NOG inducPAF was synthesized by the de novo pathway, as shown by the incorporation of [3H]choline. These findings suggest that PAF is a mediator of NOG in NB-2a cells. Thrombin neither stimulates nor inhibits PAF synthesis in these cells.

Inhibition of the synthesis of platelet-activating factor by anti-inflammatory peptides (antiflammins) without methionine.

Antiflammins are synthetic peptides corresponding to a region of similarity between uteroglobin and lipocortin I. These peptides inhibit synthesis of platelet-activating factor and release of arachidonic acid from neutrophils and macrophages stimulated by phagocytosis or tumor necrosis factor. Antiflammins containing methionine are inactivated readily in the absence of reducing agents. Novel antiflammins containing alanine or norleucine in place of methionine are inhibitory without added reducing agents, but only when stock solutions are heated to 45 degrees C. Heating may favor hydrophobic interactions between peptide molecules, thereby activating the antiflammins. These peptides are less inhibitory when added after cell stimulation, suggesting that they interfere with the activation of phospholipase A2.

Deadenylation and turnover of interferon-beta mRNA.

The pathway of degradation of human interferon-beta (IFN-beta) mRNA was examined in murine C127 cells that carry an expression vector for this mRNA. The IFN-beta mRNA decayed with a half-life of approximately 45 min in actinomycin D-treated cells and became gradually shorter. This mRNA was superinduced in cycloheximide-treated cells, but it also became gradually shorter. However, apparently full-length species of IFN-beta mRNA accumulated after prolonged incubation with cycloheximide. The shortened IFN-beta mRNA species were partially deadenylated and less stable than full-length species. These findings suggest that at least two nuclease activities are involved in degrading IFN-beta mRNA; one deadenylates this mRNA and decays in cycloheximide-treated cells, while the other apparently breaks down deadenylated mRNA.

Posttranscriptional regulation of interferon mRNA levels in peritoneal macrophages.

Low levels of beta interferon (IFN) mRNA are transcribed in freshly explanted murine peritoneal macrophages. Nuclear runoff transcription assays show that this "constitutive" IFN-beta-mRNA transcription does not increase in macrophages treated either with lipopolysaccharide or with IFN-gamma, which induce a marked accumulation of this mRNA and greatly increase IFN secretion. Therefore, these agents promote accumulation of IFN-beta mRNA by posttranscriptional mechanisms. The IFN-alpha 2 gene is also constitutively transcribed by macrophages, but the corresponding mRNA does not accumulate in lipopolysaccharide-treated cells.