Parenting in times of war: A meta-analysis and qualitative synthesis of war-exposure, parenting, and child adjustment

This mixed-methods systematic review and meta-analysis sheds more light on the role parenting practices play in children’s adjustment after war exposure. Specifically, we quantitatively examined how war exposure shapes parenting behavior, and whether parenting behavior explains some of the well-known associations between war exposure and children’s adjustment. In addition, we meta-synthesized the qualitative evidence answering when and why parenting practices might change for war-affected families. We searched nine electronic databases and contacted experts in the field for relevant studies published until March 2018, identifying 4,147 unique publications that were further screened by title and abstract, resulting in 158 publications being fully screened. By running a meta-analytic structural equation model (MASEM) with 38 quantitative studies (N = 54,372, Mage = 12.00, SDage = 3.54), we found that war-exposed parents showed less warmth and more harshness towards their children, which partly mediated the association between war exposure and child adjustment, i.e., more post-traumatic stress symptoms, depression and anxiety, social problems, externalizing behavior, and lower positive outcomes. War exposure was not associated with parents’ exercise of behavioral control. Through meta-synthesizing ten qualitative studies (N = 1,042, age range = 0-18), we found that the nature of war-related trauma affected parenting differently. That is, parents showed harshness, hostility, inconsistency and less warmth in highly dangerous settings, and more warmth and overprotection when only living under threat. We conclude that it is not only how much but also what families have seen that shape parenting in times of war

Role of the Pituitary-Adrenal Axis in G-CSF Therapy after Neonatal Hypoxia-Ischemia

Several reports indicate that the activity of the hypothalamic-pituitary-adrenal axis (HPA) as measured by the increased level of adrenocorticotropic hormone (ACTH), and corticosterone is increased after a brain insult. These hormones are the effectors secreted respectively by the pituitary and adrenal glands. It has been shown that the down-regulation of corticosterone levels can improve detrimental outcomes associated with ischemic brain injuries. Neonatal hypoxia-ischemia (HI) is a devastating perinatal event with a grim prognosis and limited therapeutic strategies. In recent studies, granulocyte-colony stimulating factor (G-CSF) has shown promise in neonatal HI investigations by improving neuromotor function and reducing apoptosis in the brain. Furthermore, G-CSF is shown in the naïve rat to regulate hormones of the HPA axis. Therefore we hypothesized that G-CSF may in part confer its neuroprotective properties by influencing the pituitary-adrenal response after neonatal HI. To test our hypothesis, metyrapone was administered to inhibit the release of rodent specific glucocorticoid, corticosterone, at the adrenal level. Dexamethasone, a synthetic glucocorticoid, was administered to agonize the effects of corticosterone. Following the Rice-Vannucci model, seven-day old rats (P7) were subjected to unilateral carotid ligation followed by 2.5 hours of hypoxia. Our results show that both G-CSF and metyrapone significantly reduced infarct volume via anti-apoptotic properties but lost its protective effect when combined with dexamethasone. Additionally, G-CSF suppressed the increase of corticosterone in the blood after HI. To investigate the mechanism by which G-CSF modulated corticosterone synthesis, we evaluated its effect in adrenal cortical cells in vitro. Our results indicate that G-CSF activated the JAK/PI3K/Akt/PDE3B pathway, which in turn inhibited corticosterone synthesis. The inhibitors of JAK/PI3K/PDE3B respectively Tyrphostin AG490, LY-294002, and 3-isobutyl-1methylxanthine reversed the inhibitory effect of G-CSF on corticosterone synthesis. We report that G-CSF was neuroprotective in neonatal HI by reducing infarct volume, by suppressing the HIinduced increase of the Bax/Bcl-2 ratio, and by decreasing corticosterone at the adrenal level via the JAK/PI3K/PDE3B pathway. Metyrapone was able to confer similar neuroprotection as G-CSF while dexamethasone reversed the effects of G-CSF. In conclusion, we show that reducing corticosterone was neuroprotective after neonatal HI, which can be achieved by administering G-CSF

HiJAKing innate lymphoid cells?

The family of innate lymphoid cells (ILCs) consists of a heterogeneous group of cytokine-producing cells that have features in common with adaptive T helper (Th) cells. Cytokines acting through the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways are key players in both Th and ILC biology. Observations in animal models, supported by evidence from humans, have highlighted the importance of the downstream events evoked by the cytokines that signal through the common IL-2 γ-chain receptor. Similarly, it is reasonable to assume that therapeutic targeting of this signaling cascade will also modulate ILC effector function in disease. Since a major limitation of gene knockout studies in mice is the complete loss of ILC populations, including NK cells, we believe that an attractive, alternative, strategy would be to study the role of cytokine signaling in the regulation of ILC function by pharmacological manipulation of these pathways instead. Here, we discuss the potential of JAK inhibitors as a drug class to elucidate mechanisms underlying ILC biology and to inform the design of new therapeutic strategies for inflammatory and autoimmune disorders

Emerging Topical and Systemic JAK Inhibitors in Dermatology

Accumulating data on cellular and molecular pathways help to develop novel therapeutic strategies in skin inflammation and autoimmunity. Examples are psoriasis and atopic dermatitis, two clinically and immunologically well-defined disorders. Here, the elucidation of key pathogenic factors such as IL-17A/IL-23 on the one hand and IL-4/IL-13 on the other hand profoundly changed our therapeutic practice. The knowledge on intracellular pathways and governing factors is shifting our attention to new druggable molecules. Multiple cytokine receptors signal through Janus kinases (JAKs) and associated signal transducer and activators of transcription (STATs). Inhibition of JAKs can simultaneously block the function of multiple cytokines. Therefore, JAK inhibitors (JAKi) are emerging as a new class of drugs, which in dermatology can either be used systemically as oral drugs or locally in topical formulations. Inhibition of JAKs has been shown to be effective in various skin disorders. The first oral JAKi have been recently approved for the treatment of rheumatoid arthritis and psoriatic arthritis. Currently, multiple inhibitors of the JAK/STAT pathway are being investigated for skin diseases like alopecia areata, atopic dermatitis, dermatomyositis, graft-versus-host-disease, hidradenitis suppurativa, lichen planus, lupus erythematosus, psoriasis, and vitiligo. Here, we aim to discuss the immunological basis and current stage of development of JAKi in dermatology

JAK3 as an emerging target for topical treatment of inflammatory skin diseases

The recent interest and elucidation of the JAK/STAT signaling pathway created new targets for the treatment of inflammatory skin diseases (ISDs). JAK inhibitors in oral and topical formulations have shown beneficial results in psoriasis and alopecia areata. Patients suffering from other ISDs might also benefit from JAK inhibition. Given the development of specific JAK inhibitors, the expression patterns of JAKs in different ISDs needs to be clarified. We aimed to analyze the expression of JAK/STAT family members in a set of prevalent ISDs: psoriasis, lichen planus (LP), cutaneous lupus erythematosus (CLE), atopic dermatitis (AD), pyoderma gangrenosum (PG) and alopecia areata (AA) versus healthy controls for (p) JAK1, (p) JAK2, (p) JAK3, (p) TYK2, pSTAT1, pSTAT2 and pSTAT3. The epidermis carried in all ISDs, except for CLE, a strong JAK3 signature. The dermal infiltrate showed a more diverse expression pattern. JAK1, JAK2 and JAK3 were significantly overexpressed in PG and AD suggesting the need for pan-JAK inhibitors. In contrast, psoriasis and LP showed only JAK1 and JAK3 upregulation, while AA and CLE were characterized by a single dermal JAK signal (pJAK3 and pJAK1, respectively). This indicates that the latter diseases may benefit from more targeted JAK inhibitors. Our in vitro keratinocyte psoriasis model displayed reversal of the psoriatic JAK profile following tofacitinib treatment. This direct interaction with keratinocytes may decrease the need for deep skin penetration of topical JAK inhibitors in order to exert its effects on dermal immune cells. In conclusion, these results point to the important contribution of the JAK/STAT pathway in several ISDs. Considering the epidermal JAK3 expression levels, great interest should go to the investigation of topical JAK3 inhibitors as therapeutic option of ISDs