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Cellular sulfation pathways rely on the activated sulfate 3'-phosphoadenosine-5'-phosphosulfate (PAPS). In humans, PAPS is exclusively provided by the two PAPS synthases PAPSS1 and PAPSS2. Mutations found in the PAPSS2 gene result in severe disease states such as bone dysplasia, androgen excess and polycystic ovary syndrome. The APS kinase domain of PAPSS2 catalyzes the rate-limiting step in PAPS biosynthesis. In this study, we show that clinically described disease mutations located in the naturally fragile APS kinase domain are associated either with its destabilization and aggregation or its deactivation. Our findings provide novel insights into possible molecular mechanisms that could give rise to disease phenotypes associated with sulfation pathway genes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Brylski, Shrestha, House, Gnutt, Mueller and Ebbinghaus.)

Context: PAPSS2 (PAPS synthase 2) provides the universal sulfate donor PAPS (3'-phospho-adenosine-5'-phosphosulfate) to all human sulfotransferases, including SULT2A1, responsible for sulfation of the crucial androgen precursor dehydroepiandrosterone (DHEA). Impaired DHEA sulfation is thought to increase the conversion of DHEA toward active androgens, a proposition supported by the previous report of a girl with inactivating PAPSS2 mutations who presented with low serum DHEA sulfate and androgen excess, clinically manifesting with premature pubarche and early-onset polycystic ovary syndrome., Patients and Methods: We investigated a family harboring two novel PAPSS2 mutations, including two compound heterozygous brothers presenting with disproportionate short stature, low serum DHEA sulfate, but normal serum androgens. Patients and parents underwent a DHEA challenge test comprising frequent blood sampling and urine collection before and after 100 mg DHEA orally, with subsequent analysis of DHEA sulfation and androgen metabolism by mass spectrometry. The functional impact of the mutations was investigated in silico and in vitro., Results: We identified a novel PAPSS2 frameshift mutation, c.1371del, p.W462Cfs*3, resulting in complete disruption, and a novel missense mutation, c.809G>A, p.G270D, causing partial disruption of DHEA sulfation. Both patients and their mother, who was heterozygous for p.W462Cfs*3, showed increased 5α-reductase activity at baseline and significantly increased production of active androgens after DHEA intake. The mother had a history of oligomenorrhea and chronic anovulation that required clomiphene for ovulation induction., Conclusions: We provide direct in vivo evidence for the significant functional impact of mutant PAPSS2 on DHEA sulfation and androgen activation. Heterozygosity for PAPSS2 mutations can be associated with a phenotype resembling polycystic ovary syndrome.

Androgens play an important role in regulation of body fat distribution in humans. They exert direct effects on adipocyte differentiation in a depot-specific manner, via the androgen receptor (AR), leading to modulation of adipocyte size and fat compartment expansion. Androgens also impact directly on key adipocyte functions including insulin signalling, lipid metabolism, fatty acid uptake and adipokine production. Androgen excess and deficiency have implications for metabolic health in both males and females, and these metabolic effects may be mediated through adipose tissue via effects on fat distribution, adipocyte function and lipolysis. Research into the field of androgen metabolism in human and animal adipose tissue has produced inconsistent results; it is important to take into account the sex-, depot- and organism-specific effects of androgens in fat. In general, studies point towards a stimulatory effect on lipolysis, with impairment of adipocyte differentiation, insulin signalling and adipokine generation. Observed effects are frequently gender-specific. Adipose tissue is an important organ of pre-receptor androgen metabolism, through which local androgen availability is rigorously controlled. Adipose androgen exposure is tightly controlled by isoenzymes of AKR1C, 5α-reductase and others, but regulation of the balance between generation and irreversible inactivation remains poorly understood. In particular, AKR1C2 and AKR1C3 are crucial in the regulation of local androgen bioavailability within adipose tissue. These isoforms control the balance between activation of androstenedione (A) to testosterone (T) by the 17β-hydroxysteroid dehydrogenase activity (17β-HSD) of AKR1C3, or inactivation of 5α-dihydrotestosterone (DHT) to 5α-androstane-3α,17β-diol by the 3α-hydroxysteroid dehydrogenase (3α-HSD) activity of AKR1C2. Most studies suggest that androgen inactivation is the predominant reaction in fat, particularly in the abdominal subcutaneous (SC) depot. Modulation of local adipose androgen availability may afford future therapeutic options to improve metabolic phenotype in disorders of androgen excess and deficiency., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The Community-Oriented Public Health Practice (COPHP) program, a 2-year in-residence MPH degree program in the University of Washington School of Public Health, has partnered with Public Health-Seattle & King County (PHSKC) since 2002 to create a mutually beneficial set of programs to improve teaching and address community-based public health problems in a practice setting. The COPHP program uses a problem-based learning approach that puts students in small groups to work on public health problems. Both University of Washington-based and PHSKC-based faculty facilitate the classroom work. In the first year for students, COPHP, in concert with PHSKC, places students in practicum assignments at PHSKC; in the second year, students undertake a master's project (capstone) in a community or public health agency. The capstone project entails taking on a problem in a community-based agency to improve either the health of a population or the capacity of the agency to improve population health. Both the practicum and the capstone projects emphasize applying classroom learning in actual public health practice work for community-based organizations. This partnership brings PHSKC and COPHP together in every aspect of teaching. In essence, PHSKC acts as the "academic health department" for COPHP. There are detailed agreements and contracts that guide all aspects of the partnership. Both the practicum and capstone projects require written contracts. The arrangements for getting non-University of Washington faculty paid for teaching and advising also include formal contracts.

Background: Telemedicine, based on the use of interactive video consultations, is being used more commonly in rural settings. This development is potentially important to rural patients because there are fewer physicians, particularly specialist physicians, in rural areas. Declining costs of telemedicine equipment and transmission have created increased access to these technologies for rural family physicians and their patients., Methods: This study considers satisfaction levels of rural family physicians, academic-based specialists, and rural patients in 130 consultations between rural physicians, rural patients, and urban academic specialists. To increase the practicability for rural use, low-cost equipment and low-bandwidth digital telephone transmission lines were utilized. Data were collected using questionnaires that were completed by patients, family physicians, and specialist consultants after each consultation., Results: All categories of participants noted very high levels of satisfaction., Conclusion: Telemedicine-based consultations are well accepted by rural patients, rural family physicians, and urban academic specialist consultants. This approach could offer a useful adjunct to rural health care.