TNFR2 induced priming of the inflammasome leads to a RIPK1-dependent cell death in the absence of XIAP.

The pediatric immune deficiency X-linked proliferative disease-2 (XLP-2) is a unique disease, with patients presenting with either hemophagocytic lymphohistiocytosis (HLH) or intestinal bowel disease (IBD). Interestingly, XLP-2 patients display high levels of IL-18 in the serum even while in stable condition, presumably through spontaneous inflammasome activation. Recent data suggests that LPS stimulation can trigger inflammasome activation through a TNFR2/TNF/TNFR1 mediated loop in xiap-/- macrophages. Yet, the direct role TNFR2-specific activation plays in the absence of XIAP is unknown. We found TNFR2-specific activation leads to cell death in xiap-/- myeloid cells, particularly in the absence of the RING domain. RIPK1 kinase activity downstream of TNFR2 resulted in a TNF/TNFR1 cell death, independent of necroptosis. TNFR2-specific activation leads to a similar inflammatory NF-kB driven transcriptional profile as TNFR1 activation with the exception of upregulation of NLRP3 and caspase-11. Activation and upregulation of the canonical inflammasome upon loss of XIAP was mediated by RIPK1 kinase activity and ROS production. While both the inhibition of RIPK1 kinase activity and ROS production reduced cell death, as well as release of IL-1β, the release of IL-18 was not reduced to basal levels. This study supports targeting TNFR2 specifically to reduce IL-18 release in XLP-2 patients and to reduce priming of the inflammasome components

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

Policies and practices regarding students with accents in speech-language pathology training programs.

Speech-language pathology (SLP) training programs are the initial gateway for non-native speakers of English to join the SLP profession. An anonymous web-based survey in New York State examined policies and practices implemented when SLP students have foreign accents in English or in other languages. Responses were elicited from 530 students and 28 clinic and program directors. Few policies delineated criteria for determining how native-like or intelligible students’ speech needed to be in order for them to work effectively or for determining when accent modification was required. Students with foreign accents in English were asked more often to undergo accent modification than were students with foreign accents in Spanish or other languages. Strategies for practices regarding SLP students with accents are proposed

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

Beliefs regarding the impact of accent within speech-language pathology practice areas

With the demographic shifts in the U.S., it is increasingly the case that speech-language pathologists (SLPs) come from different language backgrounds from those of their clients and have non-native accents in their languages of service. An anonymous web-based survey was completed by students and clinic directors in SLP training programs in New York State regarding their beliefs about the appropriate scope of practice of SLPs with accents in English and other languages. Responses were received from 28 directors and 530 students. Perceived appropriateness of service by accented clinicians depended on particular disorders serviced and degree of accent, with phonologically-based services believed by the greatest number of respondents to require more native-like speech than other areas. Further efforts must be made to research effects of SLPs’ accents on service delivery and plan strategies, if needed, for successful service provision in SLPs’ diverse areas of practice when mismatches in language backgrounds occur

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

A longitudinal study of e-cigarette, cigarette, and marijuana use sequence in youth.

OBJECTIVE: There is evidence linking youth use of electronic (e-) cigarettes to subsequent cigarette and marijuana use, raising public health concerns. We examined the sequence of use of e-cigarettes, conventional cigarettes, and marijuana in a longitudinal sample of adolescents, to determine if use of e-cigarettes often preceded use of other substances. METHODS: We collected self-reports from 1123 Oregon adolescents (52% female; 37% Hispanic) longitudinally from 8 to 11 grade (8 total surveys) regarding their lifetime (ever use) and current use (last 30 days) of e-cigarettes, cigarettes, and marijuana. If applicable, students also reported the delivery method of their current marijuana use. RESULTS: Almost 10% of adolescents reported using e-cigarettes prior to use of cigarettes or marijuana, and the majority of these youth initiated use of marijuana, cigarettes, or both by 11 grade. More youth transitioned from e-cigarette use to marijuana use then from e-cigarettes to use of conventional cigarettes. Participants who were co-using e-cigarettes and marijuana in 11 grade had an increased likelihood of consuming marijuana via vaping, dabbing, and edibles, compared to those who were only using marijuana. DISCUSSION: E-cigarettes were often the first substance used in this longitudinal sample, and more of these youth subsequently used marijuana compared to cigarettes. While research has focused on the progression from e-cigarettes to cigarettes in youth, these findings indicate that more attention should be focused on the subsequent initiation of marijuana

The clinical education of students with non-native accents

This Professional Issues Statement was developed by a Subcommittee of a former American Speech-Language-Hearing Association Executive Board working group on language proficiency. Members of the group were Catherine J. Crowley, Erika S. Levy, Nidhi Mahendra, and Vicki R. Deal-Williams (ex officio). Julie B. Noel, ASHA vice president for speech-language pathology practice (2009–2011), served as the monitoring officer. This document was approved by the ASHA Board of Directors (BOD 31-2011). ASHA members must consider all applicable local, state, and federal requirements when applying the information in this policy

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