Tourette syndrome (TS) has been linked to reduced GABAergic inhibition, the so-called neural disinhibition, in the dorsal striatum. Dorsal striatal neural disinhibition in animal models, caused by local microinfusion of GABA-A receptor antagonists, produces striatal local field potential (LFP) spike-wave discharges and tic-like movements resembling motor tics. Here, we characterized further the neuro-behavioral impact of striatal disinhibition, by unilateral picrotoxin infusion into the anterior dorsal striatum, in adult male Lister hooded rats. In vivo electrophysiology under anesthesia revealed enhanced neuronal burst firing in the striatum, alongside spike-wave LFP discharges. In freely moving rats, striatal picrotoxin reliably induced tic-like movements, which mainly involved lifting of the contralateral forelimb and concomitant rotational movements of head and torso, as well as occasional rotations of the whole body around its long axis. Prepulse inhibition (PPI) of the acoustic startle response and startle were not affected. Both locomotor and nonambulatory movements, measured in photobeam cages, were increased. Our findings suggest that, apart from generating tic-like movements, dorsal striatal disinhibition may contribute to hyperactivity, which is often comorbid with TS. Enhanced striatal burst firing may be important for these behavioral effects. Our findings do not support that striatal disinhibition contributes to PPI disruption, which has been associated with TS and suggested to contribute to tic generation.

Tourette syndrome (TS) is a neurodevelopmental disorder of childhood onset characterised by vocal and motor tics and is associated with cortical-striatal-thalamic-cortical circuit [CSTC] dysfunction. TS often follows a developmental time course in which tics become increasingly more controlled during adolescence. However, many individuals continue to have debilitating tics into adulthood. This indicates that there may be important differences between adults with TS for whom the clinical phenotype is more stable, and children and adolescents with the disorder who may be undergoing developmental neuroplastic changes linked to the reduction of their tics. Previous studies have used transcranial magnetic stimulation (TMS) to investigate changes in cortical motor excitability in individuals with TS, including measurement of resting motor threshold (RMT). However, the findings from these studies have been mixed, have varied between adult and child samples, and have often been based on small sample sizes. Here we report a multi-centre, mega-analytic, study in which RMT data collected from children and adults with TS at multiple research centres was pooled for analysis. Results confirmed that mean RMT was significantly increased in individuals with TS compared to neurotypical controls. However, this result can be explained by the more important findings that: (a) RMT for adults with TS did not differ from that of neurotypical adults; and (b) the rate that RMT decreases with age during childhood and adolescence is reduced in individuals with TS compared to controls. Thus, while neurotypical individuals reach an adult RMT level by ~12-13 years of age, individuals with TS are substantially delayed in doing so, and do not reach an adult RMT level until much later, at ~24 years of age. We conclude therefore that differences in measures of cortical excitability between children and adolescents with TS and chronologically age-matched neurotypical controls may likely reflect a developmental delay in the maturation of functional brain networks in individuals with TS, which may normalise with age.

Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease that disproportionately affects women of reproductive age and is associated with substantial morbidity, premature mortality, and racial and ethnic disparities. Advances in diagnosis and immunosuppressive therapy have improved survival, yet patients remain at increased risk for kidney failure, cardiovascular disease, infection, pregnancy complications, and treatment related damage. Primary care and hospital-based clinicians are often the first point of contact and are central to early recognition, evaluation, and comorbidity management. Informed by a comprehensive literature review, this article links key SLE pathobiology to current therapies, including loss of immune tolerance to nuclear antigens, immune complex mediated tissue injury, and type I interferon driven inflammation. We outline a practical diagnostic approach that emphasizes pattern recognition across organ systems, judicious use and interpretation of antinuclear antibody testing, and timely referral to rheumatology. We highlight the distinction between disease activity and cumulative damage and describe a treat to target strategy focused on low disease activity or remission with minimal glucocorticoid exposure. Organ based sections address common renal, musculoskeletal, mucocutaneous, cardiopulmonary, hematologic, neuropsychiatric, and reproductive manifestations, with an emphasis on what clinicians should screen for, manage directly, and refer urgently. We review major comorbidities, including antiphospholipid syndrome, cardiovascular disease, osteoporosis, infection risk, and pediatric onset SLE, and address pregnancy and contraception. Throughout, we emphasize hydroxychloroquine as foundation therapy, a glucocorticoid sparing mindset, aggressive prevention of cardiovascular and bone disease, and structured collaboration between rheumatology and non-rheumatology clinicians to improve outcomes in SLE.

Treatments that deplete or modulate B cells are in use or being investigated for several immune-mediated glomerular diseases. Kidney Disease: Improving Global Outcomes (KDIGO) convened a Controversies Conference in Panama City, Panama, in June 2025 to review current evidence and identify key gaps in knowledge and research needs to effectively apply such therapies. Availability, effectiveness, and safety of B cell-targeted therapies vary substantially across glomerular diseases. In IgA nephropathy, anti-CD20 therapy (rituximab) has shown limited efficacy, although inhibitors of survival factors BAFF (B cell activating factor) and APRIL (a proliferation-inducing ligand) and anti-CD38 antibodies can lead to reduction in proteinuria and reduction in decline in estimated glomerular filtration rate. In contrast, for membranous nephropathy, anti-CD20 antibodies have become first-line therapy, achieving at least partial remission in most patients by 18 months. In steroid-dependent nephrotic syndrome, rituximab effectively prevents relapses, particularly in children, though benefits are transient. For lupus nephritis, newer approaches including obinutuzumab and chimeric antigen receptor (CAR) T cell therapy have shown promising results, with CAR T cells introducing the possibility of being free of disease activity and treatment for a prolonged time. In antineutrophil cytoplasmic antibody-associated glomerulonephritis, rituximab has proven effective for both induction and maintenance therapy, with ongoing trials investigating CAR T cell approaches. Safety considerations of B cell-targeting therapies vary by intensity of therapy, with conventional anti-CD20 therapy showing favorable safety profiles and CAR T cell therapy requiring careful patient selection because of the potential for cytokine release syndrome and other serious adverse events. Validating biomarkers for patient selection and monitoring is a critical research need, along with optimizing treatment protocols and determining optimal therapy duration.

Systemic nickel allergy syndrome (SNAS) is characterized by both cutaneous and extracutaneous symptoms following systemic exposure to nickel, most commonly through the ingestion of nickel-containing foods in individuals sensitized to nickel via skin contact. Patients with SNAS present with dermatitis in addition to gastrointestinal, neurologic, and other extracutaneous symptoms. The most widely implemented treatment is the low-nickel diet. The present authors saw a patient with a history of allergic contact dermatitis to nickel experience resolution of hand dermatitis, chronic pain (diagnosed as fibromyalgia), and chronic diarrhea (diagnosed as irritable bowel syndrome) with a low-nickel diet after just 1 month. She was diagnosed with SNAS, and this intriguing case prompted the review that follows.

Excessive RNA damage activates cellular stress responses, triggering cell death. However, pathways that negatively regulate RNA damage responses are largely uncharacterized. Using genetic screens, we find that the ubiquitin ligase RNF25 provides tolerance to RNA damage caused by the nucleoside analogue azacytidine, a chemotherapeutic agent used to treat acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Mechanistically, we show that azacytidine is incorporated into mRNA, where it causes lesions that stall elongating ribosomes, leading to cytotoxic activation of the GCN2-dependent integrated stress response (ISR). Furthermore, we establish that RNF25 prevents ISR hyperactivation by ubiquitylation of ribosomal protein eS31, thereby suppressing cell death upon azacytidine treatment. Our study reveals an mRNA damage tolerance mechanism that determines cellular survival in response to azacytidine, highlighting RNA damage-induced stress response as a potentially critical component of chemosensitivity in AML and MDS.

This chapter explores evidence for the effectiveness of noninvasive brain stimulation (NIBS) for tic disorders and explores what the future may hold for these approaches. NIBS can be achieved through several means, including electrical stimulation of peripheral nerves and transcranial cortical stimulation using electrical or magnetic stimulation. Each of these techniques will be discussed with a focus on current evidence of effectiveness in treating tics, benefits, limitations, and current unknowns.