Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Phosphodiesterase-4 Inhibition in the Management of Psoriasis

Psoriasis is a common chronic immune-mediated disease with many comorbidities and impacts on quality of life. Among the treatments for psoriasis, phosphodiesterase-4 (PDE4) inhibitors are emerging with expanding options. PDE4 inhibitors play a pivotal role in the inflammatory cascade by degrading cyclic adenosine monophosphate (cAMP), contributing to pro-inflammatory mediator production. Apremilast, an oral PDE4 inhibitor, is approved for psoriasis. While effective, its adverse effects can limit its utility. Roflumilast, a topical PDE4 inhibitor, was also recently approved for psoriasis and shows promise in clinical trials. Crisaborole, a PDE4 inhibitor approved for atopic dermatitis, has also been studied in psoriasis. This review summarizes evidence from randomized clinical trials regarding the efficacy and safety of PDE4 inhibitors in psoriasis treatment. By highlighting their potential benefits and limitations, this review provides valuable insights for clinicians and researchers aiming to optimize psoriasis management.Medicine, Faculty ofNon UBCReviewedFacultyResearche

Hidradenitis suppurativa with SAPHO syndrome maintained effectively with adalimumab, methotrexate, and intralesional corticosteroid injections

Introduction: Hidradenitis suppurativa and synovitis, acne, pustulosis, hyperostosis, osteitis syndrome are chronic, debilitating diseases involving apocrine gland-bearing skin inflammation and bone inflammation, respectively. Although both often present with multiple comorbidities, single patient co-presentation is rare. Methods/Results: This study reports the 8-year treatment course of a 40-year-old man with hidradenitis suppurativa and synovitis, acne, pustulosis, hyperostosis, osteitis syndrome, and reviews relevant literature. Initial oral and topical antibiotics had little effect. Intralesional corticosteroid injections were effective for localized inflammatory lesions but insufficient for hidradenitis suppurativa control. Adalimumab initiation and local excision of a persistent HS lesion led to stabilization. Adalimumab provided dramatic back pain improvement. Synovitis, acne, pustulosis, hyperostosis, osteitis was diagnosed; adalimumab continuation with subsequent methotrexate addition resulted in hidradenitis suppurativa-synovitis, acne, pustulosis, hyperostosis, osteitis control. Conclusions: Literature regarding comorbid hidradenitis suppurativa and synovitis, acne, pustulosis, hyperostosis, osteitis syndrome therapy is scarce but growing. Adalimumab, methotrexate, intralesional corticosteroid, and lifestyle changes successfully maintained a severe hidradenitis suppurativa–synovitis, acne, pustulosis, hyperostosis, osteitis–syndrome case. Further studies beyond a case-based review could yield more definitive treatment plans

Acrodermatitis continua of Hallopeau successfully treated with adalimumab: A case report

Acrodermatitis continua of Hallopeau is a chronic, inflammatory, and relapsing condition that presents as pustules of the fingers and toes, often with nail involvement. This condition is infrequently reported, difficult to treat, and often misdiagnosed. Various anti-psoriatic therapies have been used, but literature is limited to case studies with equivocal results. Biological therapy is revolutionizing the management of many dermatologic conditions and is believed to be a promising option for acrodermatitis continua of Hallopeau patients who have failed conventional therapy. We report the 4-year treatment course of a 70-year-old woman with acrodermatitis continua of Hallopeau that was initially unsuccessful with conventional treatments but successfully treated with the tumor necrosis factor alpha inhibitor adalimumab, in combination with alitretinoin and clobetasol propionate. This case adds to the current understanding of acrodermatitis continua of Hallopeau and the potential of biological therapy, in our case, adalimumab, for acrodermatitis continua of Hallopeau management. Literature should continue growing to ascertain the safety and efficacy of biologic therapy for patients with acrodermatitis continua of Hallopeau

Weekend–weekday advances in sleep timing are associated with altered reward-related brain function in healthy adolescents

Sleep timing shifts later during adolescence, thus conflicting with early school start times. This can lead to irregular weekday-weekend schedules and circadian misalignment, which have been linked to depression and substance abuse, consistent with disruptions in the processing of rewards. We tested associations between weekend-weekday shifts in sleep timing and the neural response to monetary reward in healthy adolescents, using actigraphy and a functional magnetic resonance imaging paradigm. Region-of-interest analyses focused on the medial prefrontal cortex (mPFC) and striatum, both of which are implicated in reward function. Analyses adjusted for pubertal stage, sex, and total sleep time. Greater weekend-weekday advances in midsleep were associated with decreased mPFC and striatal reactivity to reward, which could reflect reduced regulatory response and reward sensitivity. We speculate that circadian misalignment associated with weekend shifts in sleep timing may contribute to reward-related problems such as depression and substance abuse

Mammalian Septins Are Required for Phagosome Formation

Septins are members of a highly conserved family of filamentous proteins that are required in many organisms for the completion of cytokinesis. In addition, septins have been implicated in a number of important cellular processes and have been suggested to have roles in regulating membrane traffic. Given the proposed role of septins in cell membrane dynamics, we investigated the function of septins during FcγR-mediated phagocytosis. We show that several septins are expressed in RAW264.7 and J774 mouse macrophage cell lines and that SEPT2 and SEPT11 are colocalized with submembranous actin-rich structures during the early stages of FcγR-mediated phagocytosis. In addition, SEPT2 accumulation is seen in primary human neutrophils and in nonprofessional phagocytes. The time course of septin accumulation mirrors actin accumulation and is inhibited by latrunculin and genistein, but not other inhibitors of phagocytosis. Inhibition of septin function by transient expression of the BD3 domain of BORG3, known to cause septin aggregation, or depletion of SEPT2 or SEPT11 by RNAi, significantly inhibited FcγR-mediated phagocytosis of IgG-coated latex beads. Interestingly, this occurred without affecting the accumulation of actin or the actin-associated protein coronin-1. These observations show that, although not necessary for actin recruitment, septins are required for efficient FcγR-mediated phagocytosis