Activin/myostatin signalling acts to induce skeletal muscle atrophy in adult mammals by inhibiting protein synthesis as well as promoting protein and organelle turnover. Numerous strategies have been successfully developed to attenuate the signalling properties of these molecules, which result in augmenting muscle growth. However, these molecules, in particular activin, play major roles in tissue homeostasis in numerous organs of the mammalian body. We have recently shown that although the attenuation of activin/myostatin results in robust muscle growth, it also has a detrimental impact on the testis. Here, we aimed to discover the long-term consequences of a brief period of exposure to muscle growth-promoting molecules in the testis. We demonstrate that muscle hypertrophy promoted by a soluble activin type IIB ligand trap (sActRIIB) is a short-lived phenomenon. In stark contrast, short-term treatment with sActRIIB results in immediate impact on the testis, which persists after the sessions of the intervention. Gene array analysis identified an expansion in aberrant gene expression over time in the testis, initiated by a brief exposure to muscle growth-promoting molecules. The impact on the testis results in decreased organ size as well as quantitative and qualitative impact on sperm. Finally, we have used a drug-repurposing strategy to exploit the gene expression data to identify a compound - N-6-methyladenosine - that may protect the testis from the impact of the muscle growth-promoting regime. This work indicates the potential long-term harmful effects of strategies aimed at promoting muscle growth by attenuating activin/myostatin signalling. Furthermore, we have identified a molecule that could, in the future, be used to overcome the detrimental impact of sActRIIB treatment on the testis.

Background Clinical studies indicate chemotherapy agents used in childhood cancer treatment regimens may impact future fertility. However, effects of individual agents on prepubertal human testis, necessary to identify later risk, have not been determined. The study aimed to investigate the impact of cisplatin, commonly used in childhood cancer, on immature (foetal and prepubertal) human testicular tissues. Comparison was made with carboplatin, which is used as an alternative to cisplatin in order to reduce toxicity in healthy tissues. Methods We developed an organotypic culture system combined with xenografting to determine the effect of clinically-relevant exposure to platinum-based chemotherapeutics on human testis. Human foetal and prepubertal testicular tissues were cultured and exposed to cisplatin, carboplatin or vehicle for 24 h, followed by 24-240 h in culture or long-term xenografting. Survival, proliferation and apoptosis of prepubertal germ stem cell populations (gonocytes and spermatogonia), critical for sperm production in adulthood, were quantified. Results Cisplatin exposure resulted in a significant reduction in the total number of germ cells (- 44%, p <0.0001) in human foetal testis, which involved an initial loss of gonocytes followed by a significant reduction in spermatogonia. This coincided with a reduction (- 70%, p <0.05) in germ cell proliferation. Cisplatin exposure resulted in similar effects on total germ cell number (including spermatogonial stem cells) in prepubertal human testicular tissues, demonstrating direct relevance to childhood cancer patients. Xenografting of cisplatin-exposed human foetal testicular tissue demonstrated that germ cell loss (- 42%, p <0.01) persisted at 12 weeks. Comparison between exposures to human-relevant concentrations of cisplatin and carboplatin revealed a very similar degree of germ cell loss at 240 h post-exposure. Conclusions This is the first demonstration of direct effects of chemotherapy exposure on germ cell populations in human foetal and prepubertal testis, demonstrating platinum-induced loss of all germ cell populations, and similar effects of cisplatin or carboplatin. Furthermore, these experimental approaches can be used to determine the effects of established and novel cancer therapies on the developing testis that will inform fertility counselling and development of strategies to preserve fertility in children with cancer.

Purpose: To evaluate short-term testicular outcome after torsion in children. Methods: Fifty-four children and adolescents were evaluated after 6 months of the operation for testicular torsion. Testicular volume was measured and circulating Inhibin B, FSH, LH and testosterone levels were checked. Results: Delay from the onset of symptoms to surgery was shorter in the orchidopexy group (n = 47), than in the orchiectomy group (n = 7, p = 0.001). In the orchidopexy group, the median volume of the affected testis was 83% (IQR 43-104) of the contralateral testis (p = 0.002). The plasma hormone levels in orchidopexy and orchiectomy groups were: 148 ng/l (IQR 108-208) vs. 129 ng/l (IQR, 123-138, p = 0.269) for Inhibin B; 4.5 IU/L (IQR2.6-6.9) vs. 11.7 IU/L (IQR 4.3-12.8, p = 0.037) for FSH; 2.9 IU/L (IQR 1.3-3.7) vs. 4.8 (IQR 3.0-5.6, p = 0.066) for LH; and 13.6 nM(IQR 6.5-18.0) vs. 14.5 nM(IQR 6.7-15.9, p = 0.834) for testosterone. The association between FSH, LH as well as testosterone levels was most clear with the volume of the contralateral testis (Rho = 0.574, p <0.001, Rho = 0.621, p = 0.001 and Rho 0.718, p <0.001 respectively). Conclusions: Testicular function is mainly dependent on the volume of contralateral testicle after testicular torsion. However, testis preserving surgery tends to maintain better function than orchiectomy. Type of study: Retrospective review. (c) 2019 Elsevier Inc. All rights reserved.

• Kaikukuvaus eli ultraäänitutkimus on usein ensisijainen kuvantamis¬ menetelmä lapsia tutkittaessa. • Näkyvyys on yleensä parempi kuin aikuisia tutkittaessa, eikä diagnoosiin pääsemiseksi välttämättä tarvita muita kuvantamismenetelmiä. • Lasten ultraäänidiagnostiikassa tarvitaan tietämystä eri kehitysvaiheissa ilmenevistä tyypillisistä sairauksista ja normaalilöydöksistä.