The oncogene Gankyrin is expressed in testicular cancer and contributes to cisplatin sensitivity in embryonal carcinoma cells

BACKGROUND: Testicular germ cell cancer (TGCC) develops from pre-malignant germ neoplasia in situ (GCNIS) cells. GCNIS originates from fetal gonocytes (POU5F1+/MAGE-A4-), which fail to differentiate to pre-spermatogonia (POU5F1-/MAGE-A4+) and undergo malignant transformation. Gankyrin is an oncogene which has been shown to prevent POU5F1 degradation and specifically interact with MAGE-A4 in hepatocellular carcinoma (HCC) cells. We aimed to investigate the role of Gankyrin in progression from gonocyte to pre-invasive GCNIS and subsequent invasive TGCC. METHODS: We determined Gankyrin expression in human fetal testicular tissue (gestational weeks 9-20; n = 38), human adult testicular tissue with active spermatogenesis (n = 9), human testicular tissue with germ cell maturation delay (n = 4), testicular tissue from patients with pre-invasive GCNIS (n = 6), and invasive TGCC including seminoma (n = 6) and teratoma (n = 7). Functional analysis was performed in-vitro by siRNA knock-down of Gankyrin in the NTera2 cells (derived from embryonal carcinoma). RESULTS: Germ cell expression of Gankyrin was restricted to a sub-population of prespermatogonia in human fetal testes. Nuclear Gankyrin was also expressed in GCNIS cells of childhood and adult pre-invasive TGCC patients, and in GCNIS from seminoma and non-seminoma patients. Cytoplasmic expression was observed in seminoma tumour cell

Experimentally-induced ‘Testicular dysgenesis syndrome’ originates in the masculinization programming window

The testicular dysgenesis syndrome (TDS) hypothesis, which proposes that common reproductive disorders of newborn and adult human males may have a common fetal origin, is largely untested. We tested this hypothesis using a rat model involving gestational exposure to dibutyl phthalate (DBP), which suppresses testosterone production by the fetal testis. We evaluated if induction of TDS via testosterone suppression is restricted to the “masculinization programming window” (MPW), as indicated by reduction in anogenital distance (AGD). We show that DBP suppresses fetal testosterone equally during and after the MPW, but only DBP exposure in the MPW causes reduced AGD, focal testicular dysgenesis, and TDS disorders (cryptorchidism, hypospadias, reduced adult testis size, and compensated adult Leydig cell failure). Focal testicular dysgenesis, reduced size of adult male reproductive organs, and TDS disorders and their severity were all strongly associated with reduced AGD. We related our findings to human TDS cases by demonstrating similar focal dysgenetic changes in testes of men with preinvasive germ cell neoplasia (GCNIS) and in testes of DBP-MPW animals. If our results are translatable to humans, they suggest that identification of potential causes of human TDS disorders should focus on exposures during a human MPW equivalent, especially if negatively associated with offspring AGD

Ease and difficulty of pre-hospital airway management in 425 paediatric patients treated by a helicopter emergency medical service: a retrospective analysis

BACKGROUND: Pre-hospital paediatric airway management is complex. A variety of pitfalls need prompt response to establish and maintain adequate ventilation and oxygenation. Anatomical disparity render laryngoscopy different compared to the adult. The correct choice of endotracheal tube size and depth of insertion is not trivial and often challenged due to the initially unknown age of child. METHODS: Data from 425 paediatric patients (<17 years of age) with any airway manipulation treated by a Swiss Air-Ambulance crew between June 2010 and December 2013 were retrospectively analysed. Endpoints were: 1) Endotracheal intubation success rate and incidence of difficult airway management in primary missions. 2) Correlation of endotracheal tube size and depth of insertion with patient's age in all (primary and secondary) missions. RESULTS: In primary missions, the first laryngoscopy-guided endotracheal intubation attempt was successful in 95.3% of cases, with an overall success rate of 98.6%. Difficult airway management was reported in 10 (4.7%) patients. Endotracheal tube size was frequently chosen inadequately large (overall 50 of 343 patients: 14.6%), especially and statistically significant in the age group below 1 year (19 of 33 patients; p < 0.001). Tubes were frequently and distinctively more deeply inserted (38.9%) than recommended by current formulae. CONCLUSION: Difficult airway management, including cannot intubate and cannot ventilate situations during pre-hospital paediatric emergency treatment was rare. In contrast, the success rate of endotracheal intubation at the first attempt was very high. High numbers of inadequate endotracheal tube size and deep placement according to patient age require further analysis. Practical algorithms need to be found to prevent potentially harmful treatment

Specialist advice may improve patient selection for decompression therapy following diving accidents: a retrospective observational study

Abstract Background Even in a landlocked country like Switzerland recreational diving is becoming more and more popular. Smaller lakes in the Alps are located at an altitude of 2500 m above sea level. The incidence of diving accidents among all helicopter emergency service missions and the consecutive medical knowledge about decompression injuries is low. Thus, a collaboration between the Swiss Air-Ambulance (Rega) and the divers alert network (DAN) was initiated to improve patient treatment and identification of decompression injury and necessity of hyperbaric oxygen therapy (HBO). Methods Retrospective observational study that includes all patients treated by the Rega which have been classified to have had a diving accident from 2005 to 2014. Patient and diving epidemiology was assessed and the impact of DAN collaboration on patient selection and identification of patients needing transport to HBO facilities were analysed. Results In the 10-year observational period 116 patients with diving accidents were treated by Rega. Mean patient age was 40 (SD 11) years and 95 (82%) were male. If the Rega emergency physician suspected a decompression injury (DCI), without DAN contact 27/28 (96%) of these patients were transported directly to a HBO facility, whereas with DAN contact only 53/63 (84%) needed transport to a HBO facility. DAN was involved in 66/96 (69%) of the cases with suspected DCI on scene, with a significant increase over time (p = 0.001). Mean flight time to HBO facilities was significantly longer (28.9, SD 17.7 min.), compared to non-HBO facilities (7.1, SD 3.2 min., p < 0.001). Due to specialist advice, patients may have been selected who finally did not need a transport to a HBO facility, although DCI was primarily suspected by the emergency physician on the scene. These patients experienced a significantly reduced flight time to the (non-HBO) hospital of 25.6 (SD 6.5) min. (p < 0.001). Discussion Collaboration of DAN and Rega may allow a safe patient selection and a consecutive reduction of flight time and costs. Due to international collaborations, evacuation to HBO-facilities for acute recompression therapy can be provided by HEMS within less than 30 min all over Switzerland. Conclusions For diving accidents among HEMS missions, specialist advice by diving medicine specialists (DAN) appears mandatory to accurately identify and transport patients with decompression injury, as exposure of emergency physicians towards diving accidents and the diagnosis of DCI is low

Advanced airway management in an anaesthesiologist-staffed Helicopter Emergency Medical Service (HEMS): A retrospective analysis of 1047 out-of-hospital intubations

INTRODUCTION Airway management in the out-of-hospital emergency setting is challenging. Failed and even prolonged airway management is associated with serious clinical consequences, such as desaturation, bradycardia, airway injuries, or aspiration. The overall success rate of tracheal intubation ranges between 77% and 99%, depending on the level of experience of the provider. Therefore, advanced airway management should only be performed by highly-skilled and experienced providers. METHODS 9765 patients were treated in the out-of-hospital emergency setting by the anaesthesiologist-staffed Helicopter Emergency Medical Services (HEMS) between 2002 and 2014. Patients successfully intubated upon the first attempt were compared to patients who required more than one intubation attempts regarding several potential confounding factors such as age, gender, on-going CPR, NACA Score, initial GCS, prior administration of anaesthetic drugs, neuromuscular blocking agents, and vasopressors. RESULTS 1573 out of 9765 patients (16.1%) required advanced airway management. 459 patients had already been intubated upon arrival of the HEMS, whereas 1114 patients (11.4%) underwent advanced airway management by the HEMS physician. 67 patients had to be excluded. Data for the remaining 1047 patients (790 males and 257 females) were analyzed further. Primary use of an alternative airway device was reported in 59 patients (5.6%), whereas 988 patients (94.4%) underwent laryngoscopy-guided tracheal intubation. 952 patients (96.4%) could be intubated upon the first attempt and overall intubation success was 99.5% (983 out of 988). CONCLUSION Our study demonstrates that HEMS physicians performed airway management frequently and that both the first attempt as well as the overall success rate of tracheal intubation was high. Together with the fact that all failed and difficult intubations were successfully recognized and handled and that no surgical airway had to be established, the current study once more underlines the importance of proper training of HEMS care providers regarding airway management