a b s t r a c tIn higher vertebrates, in response to stress, the hypothalamus produces corticotropin-releasing hormone (CRH), which stimulates cells in the anterior pituitary to produce adrenocorticotropic hormone (ACTH), which in turn stimulates production of either cortisol (F) or corticosterone (B) by the adrenal tissues. In lampreys, however, neither of these steroids is present. Instead, it has been proposed that the stress steroid is actually 17,21-dihydroxypregn-4-ene-3,20-dione (11-deoxycortisol; S). However, there have been no studies yet to determine its mechanism of regulation or site of production. Here we demonstrate that (1) intraperitoneal injections of lamprey-CRH increase plasma S in a dose dependent manner, (2) intraperitoneal injections of four lamprey-specific ACTH peptides at 100 lg/kg, did not induce changes in plasma S concentrations in either males or females; (3) two lamprey-specific gonadotropin-releasing hormones (GnRH I and III) and arginine-vasotocin (AVT), all at single doses, stimulated S production as well as, or to an even greater extent than CRH; (4) sea lamprey mesonephric kidneys, in vitro, converted tritiated 17a-hydroxyprogesterone (17a-P) into a steroid that had the same chromatographic properties (on HPLC and TLC) as S; (5) kidney tissues released significantly more immunoassayable S into the incubation medium than gill, liver or gonad tissues. One interpretation of these results is that the corticosteroid production of the sea lamprey, one of the oldest extant vertebrates, is regulated through multiple pathways rather than the classical HPI-axis. However, the responsiveness of this steroid to the GnRH peptides means that a reproductive rather than a stress role for this steroid cannot yet be ruled out.

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BackgroundAlthough uncommon, the most feared adverse event of urate-lowering drugs (ULDs) is allopurinol hypersensitivity syndrome (AHS), primarily manifesting as Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN). HLA-B*5801 allele carriage (a strong determinant of AHS) varies substantially among races, which may lead to major racial disparities in the risk of SJS/TEN in the context of ULD adverse events (ULDAEs). Such information could immediately help risk stratification to prevent these severe ULDAEs.ObjectivesTo examine potential racial disparities in the risk of SJS/TEN in the context of ULDAEs in a large, racially diverse, and generalizable population.MethodsUsing the Nationwide Inpatient Sample (NIS, 2009–2013), a database representative of all US hospitalizations, we examined the racial distribution of hospitalized SJS/TEN (principal discharge diagnosis) as ULDAEs (ICD-9-CM Classification of External Causes); this combination implicates allopurinol, which is the only ULD established to cause SJS/TEN. Our reference groups were the US Census population, US allopurinol users (from the NHANES), and ULDAE hospitalizations without SJS/TEN (from the NIS).ResultsWe identified 606 patients hospitalized for SJS/TEN as ULDAEs meeting our criteria between 2009–2013 (mean age, 68 years; 44% male). Of these 606 patients, there was a substantial over-representation of Asians (27%) and Blacks (26%), and an under-representation of Whites (29%) and Hispanics (% too-low-to-report), compared with the US Census population (5%, 12%, 67%, and 15%, respectively). The hospitalization rate ratios for SJS/TEN among Asians, Blacks, and Whites were 11.9, 5.0, and 1.0 (referent), respectively. These associations persisted using other national referents (allopurinol users and ULDAE cases without SJS/TEN).ConclusionsThese national data indicate that Asians and Blacks have a substantially higher risk of SJS/TEN as ULDAEs than Whites (or Hispanics), correlating well with corresponding frequencies of HLA-B*5801 in the US population (i.e.,7.4%, 4%, 1%, and 1% among Asians, Blacks, and Whites, Hispanics, respectively). As no other ULDs available in the US have been established to cause SJS/TEN, these findings support the use of vigilance in these minorities when considering allopurinol.Disclosure of InterestNone declared