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Studies of androgen receptor gene mutations in patients phenotypically ranging from complete androgen insensitivity to men with preserved fertility
No full textThe androgen insensitivity syndrome (AIS) is the single most common cause of male pseudohermaphroditism, i. e., deficient masculinization which is not explained by disturbed testis development. In its most severe form it affects at least 1/20 000 newborn 46, XY males. This X-linked recessive disorder is caused by mutations in the androgen receptor (AR) gene, and has classically been divided into two subgroups according to severity; complete (CAIS) and partial androgen insensitivity syndrome (PAIS). In the complete form, the 46, XY individual presents as a phenotypically normal girl, except for absence of sexual hair. These patients have intraabdominal testes and, due to regression of Müllerian ducts, a short vagina, no uterus and lack oviducts. Partial forms of AIS present as varying degrees of undermasculinization, ranging from a predominantly female phenotype to boys with genital malformations, such as hypospadias or cryptorchidism. It has also been speculated, that subtle androgen receptor defects could cause impaired spermatogenesis without genital malformations. In the present work 13 missense mutations are described, identified in the AR gene of patients phenotypically ranging from complete androgen insensitivity to men with preserved fertility at the other end of the spectrum. The functional properties of 10 mutations have been characterized, using the approaches of site-directed mutagenesis, transient expression in COS-1 cells, and transactivation assays using an androgen sensitive reporter gene. Hormone binding assays in transfected COS-1 cells and genital skin fibroblasts from some patients were also performed.With a few exceptions, the degrees of impairment of mutant ARs in vitro were roughly in agreement with the severity of symptoms seen in the patients. Mutation A596T was an exception. A596T was functionally normal at high concentrations of androgens in vitro, although it was found in two newborns with PAIS. In accordance with this finding, treatment of the two boys with high doses of androgens resulted in a positive response.When this study was initiated, there was no molecular evidence for involvement of the AR in infertility. However, an elongated CAG repeat in exon I of the AR was known to be associated with dysfunctional sperm production in Kennedy's disease. Therefore, the length of the CAG-repeat of 33 infertile men was determined and compared to the CAG-repeats of 294 normal men. We found no difference in repeat lengths between the two groups. On the other hand, two missense mutations, N233K and N756S, were identified in two out of ten cases of infertility, selected due to elevated levels of LH and testosterone as well as azoo- or oligozoospermia. In both men, in vitro studies showed reduced transactivational capacity as compared to wild type AR. The patient carrying the N233K mutation displayed additional symptoms not generally seen in patients with AIS; he suffered from musculoskeletal and urogenital pain. He reported a remarkable relief upon high-dose androgen treatment. We speculate, that these symptoms result from abnormal protein- protein interactions arising as a consequence of the mutation, which is located in the transactivating domain of the AR where very few mutations previously have been found.Mutations in the AR gene have not been considered to be compatible with fertility. The Q824K mutation was found in three individuals of a family who complained of gynecomastia and showed hormonal levels indicating AIS. The mutant AR showed slight functional impairment in vitro. The patients had inherited the mutation from their grandfathers through their mothers, and one of them has fathered a daughter. The E653K mutation was found in a father of two daughters, who were affected with congenital adrenal hyperplasia due to 2 1 -hydroxylase deficiency. The daughters, who were heterozygous for the mutation, showed unusually mild signs of androgen excess, but in vitro assays of the E653K mutant failed to detect any functional abnormality.In conclusion, mutations in the AR gene have been found in patients covering the whole range of clinical phenotypes of androgen insensitivity. We confirm that the syndrome can be classified into three entities; CAIS, PAIS, and minimal androgen insensitivity (MAIS), where MAIS is defined as biochemical signs of AIS, gynecomastia and / or infertility, but without genital malformations.List of scientific papersI. Lundberg Giwercman Y, Nikoshkov A, Lindsten K, Byström B, Pousette Å, Chibalin AV, Arvidsson S, Tiulpakov A, Semitcheva TV, Peterkova V, Hagenfeldt K, Ritzén EM, Wedell A (1998). "Functional characterisation of mutations in the ligand-binding domain of the androgen receptor gene in patients with androgen insensitivity syndrome" Hum Genet 103(4): 529-531 https://pubmed.ncbi.nlm.nih.gov/99072324II. Lundberg Giwercman Y, Nikoshkov A, Lindsten K, Byström B, Pousette Å, Knudtzon J, Alm J, Wedell A (2000). "Response to Treatment in Patients with Partial Androgen Insensitivity due to Mutations in the DNA-Binding Domain of the Androgen Receptor" Horm Res 53(2): 83-88III. Giwercman YL, Xu C, Arver S, Pousette Å, Reneland R (1998). "No association between the androgen receptor gene CAG repeat and impaired sperm production in Swedish men" Clin Genet 54(5): 435-436 https://pubmed.ncbi.nlm.nih.gov/99057132IV. Lundberg Giwercman Y, Nikoshkov A, Byström B, Arver S, Pousette Å, Wedell A (2000). "A novel mutation (N233K) in the transactivating domain and the N7556S mutation in the ligand binding domain of the androgen receptor gene are associated with male infertility" (Submitted)V. Giwercman A, Kledal T, Schwartz M, Giwercman YL, Leffers H, Zazzi H, Wedell A, Skakkebaek NE (2000). "Preserved male fertility despite decreased androgen sensitivity caused by a mutation in the ligand-binding domain of the androgen receptor gene" J Clin Endocrinol Metab 85(6): 2253-2259 https://pubmed.ncbi.nlm.nih.gov/20309299VI. Lundberg Giwercman Y, Nikoshkov A, Byström B, Nordenskjöld A, Pousette Å, Wedell A (2000). "An androgen receptor variant in a family with congenital adrenal hyperplasia" (Manuscript)</p
Cadmium may impair prostate function as measured by Prostate Specific Antigen in semen: a cross-sectional study among European and Inuit men.
No full textWe investigated the association between cadmium in blood and the concentration of the prostate specific antigen (PSA) in semen, including the modifying effects of zinc or the CAG polymorphism in the androgen receptor (AR). Blood and semen samples were collected from 504 partners of pregnant women in Greenland, Poland and Ukraine. We found an inverse trend between cadmium and PSA (log (ß)= -0.121, 95% Confidence Interval (CI):-0.213; -0.029, P=0.0103) in Greenlandic men. Similar results were observed in men with a high number of CAG repeats (CAG 24) (log (ß)=-0.231, 95% CI:-0.363; -0.098, P=0.0009). Inverse trends between cadmium and PSA were found when semen zinc concentrations were below the median value for men from Ukraine and Greenland. These outcomes suggest that cadmium may impair prostate function, as measured by PSA in semen, while high zinc levels and a low number of CAG repeats protects against this action
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
No full text“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Androgen receptor gene CAG repeat length as a modifier of the association between persistent organohalogen pollutant exposure markers and semen characteristics.
No full textObjectives Exposure to persistent organohalogen pollutants was suggested to impair male reproductive function. A gene-environment interaction has been proposed. No genes modifying the effect of persistent organohalogen pollutants on reproductive organs have yet been identified. We aimed to investigate whether the CAG and GGN polymorphisms in the androgen receptor gene modify the effect of persistent organohalogen pollutant exposure on human sperm characteristics. Methods Semen and blood from 680 men [mean (SD) age 34 (10) years] from Greenland, Sweden, Warsaw (Poland) and Kharkiv (Ukraine) were collected. Persistent organohalogen pollutant exposure was assessed by measuring serum levels of 2,2,4,4,5,5'-hexachlorobiphenyl (CB-153) and dichlorodiphenyl dichloroethene (p,p'-DDE). Semen characteristics (volume, sperm concentration, total count proportion of progressively motile and morphology) and DNA fragmentation index (DFI) were determined. CAG and GGN repeat lengths were determined by direct sequencing of leukocyte DNA. Results A statistically significant interaction was found between the CB-153 group and CAG repeat category in relation to sperm concentration and total sperm count (P=0.03 and 0.01, respectively). For p,p'-DDE, in the European cohorts a significant interaction was found in relation to DFI (P=0.01). For CAG<20, sperm concentration and total sperm count were 35 and 42% lower, respectively, when the group with CB-153 exposure above median was compared with that below the median. DF1 was 40% higher in the high p,p'-DDE exposure group for CAG < 21. Conclusions This study indicated that the androgen receptor CAG repeat length might modify the susceptibility of an individual to the adverse effects of persistent organohalogen pollutant exposure on semen quality. Other studies regarding this matter are warranted
Appropriate Similarity Measures for Author Cocitation Analysis
No full textWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Are sex disparities in COVID-19 a predictable outcome of failing men’s health provision?
No full textThe COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus, has taken a catastrophic toll on society, health-care systems and the economy. Notably, COVID-19 has been shown to be associated with a higher mortality rate in men than in women. This disparity is likely to be a consequence of a failure to invest in men’s health, as it has also been established that men have a lower life expectancy and poorer outcomes from non-communicable diseases than women. A variety of biological, social and economic factors have contributed to the sex disparities in mortality from COVID-19. A streamlined men’s health programme — with the urologist as the gatekeeper of men’s health — is needed to help prevent future tragedies of this nature
Dispelling the Myths Behind First-author Citation Counts
No full textWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
Training in andrology: the level 1 programme of the European Academy of Andrology (EAA) and of the European Society for Andrological Urology (ESAU)
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