RESUMO
BACKGROUND: Atypical hemolytic uremic syndrome is a rare group of disorders that have in common underlying complement amplifying conditions. These conditions can accelerate complement activation that results in a positive feedback cycle. The known triggers for complement activation can be diverse and include, infection, autoimmune disease, and malignancy. Recent reports suggest that certain autoimmune and rheumatological triggers of complement activation may result in atypical hemolytic uremic syndrome that does not resolve despite treating the underlying disorder. Specifically, patients with systemic lupus erythematosus and microangiopathic hemolysis may not respond to treatment of their underlying rheumatological trigger but responded to complement blockade. CASE PRESENTATIONS: We report two patients with inflammatory bowel disease complicated by development of atypical hemolytic uremic syndrome. In both cases, patients were on treatment for inflammatory bowel disease, that was not well controlled/flaring at the time. The first patient is a male who developed Crohn's disease and microangiopathic hemolysis at age 5 and was treated with eculizumab successfully. Discontinuation of the medication led to multiple relapses, and the patient currently is being treated with eculizumab and has normal hematological and stable renal parameters. The second patient is a 49-year-old female with Ulcerative Colitis treated with 6-Mercaptopurine. She developed acute kidney injury and microangiopathic hemolysis. Prompt diagnosis and treatment with eculizumab resulted in the recovery of kidney injury along with a complete hematological response. CONCLUSIONS: These two cases are the fifth and sixth patients to be published in the literature with atypical hemolytic uremic syndrome and inflammatory bowel disease treated with complement blockade. This confirms that C5 complement blockade is effective in treating complement mediated thrombotic microangiopathy/atypical hemolytic uremic syndrome when it is triggered in patients with inflammatory bowel disease.
RESUMO
Excessive, binge alcohol drinking is a potent and pernicious obstacle to treating alcohol use disorder (AUD), and heavy-drinking humans are responsible for much of the substantial costs and harms of AUD. Thus, identifying key mechanisms that drive intake in higher-drinking individuals may provide important, translationally useful therapeutic interventions. Orexin-1-receptors (Ox1Rs) promote states of high motivation, and studies with systemic Ox1R inhibition suggest a particular role in individuals with higher intake levels. However, little has been known about circuits where Ox1Rs promote pathological intake, especially excessive alcohol consumption. We previously discovered that binge alcohol drinking requires Ox1Rs in medial nucleus accumbens shell (Shell), using two-bottle-choice Drinking-in-the-Dark (2bc-DID) in adult, male C57BL/6 mice. Here, we show that Shell Ox1Rs promoted intake during intermittent-access alcohol drinking as well as 2bc-DID, and that Shell inhibition with muscimol/baclofen also suppressed 2bc-DID intake. Importantly, with this large data set, we were able to demonstrate that Shell Ox1Rs and overall activity were particularly important for driving alcohol consumption in higher-drinking individuals, with little overall impact in moderate drinkers. Shell inhibition results were compared with control data combined from drug treatments that did not reduce intake, including NMDAR or PKC inhibition in Shell, Ox1R inhibition in accumbens core, and systemic inhibition of dopamine-1 receptors; these were used to understand whether more specific Shell Ox1R contributions in higher drinkers might simply result from intrinsic variability in mouse drinking. Ineffectiveness of Shell inhibition in moderate-drinkers was not due to a floor effect, since systemic baclofen reduced alcohol drinking regardless of basal intake levels, without altering concurrent water intake or saccharin consumption. Finally, alcohol intake in the first exposure predicted consumption levels weeks later, suggesting that intake level may be a stable trait in each individual. Together, our studies indicate that Shell Ox1Rs are critical mediators of binge alcohol intake in higher-drinking individuals, with little net contribution to alcohol drinking in more moderate bingers, and that targeting Ox1Rs may substantially reduce AUD-related harms.