STAR splicing mutations cause the severe phenotype of lipoid congenital adrenal hyperplasia: insights from a novel splice mutation and review of reported cases

OBJECTIVE The steroidogenic acute regulatory protein (StAR) transports cholesterol to the mitochondria for steroidogenesis. Loss of StAR function causes lipoid congenital adrenal hyperplasia (LCAH) which is characterized by impaired synthesis of adrenal and gonadal steroids causing adrenal insufficiency, 46,XY disorder of sex development (DSD) and failure of pubertal development. Partial loss of StAR activity may cause adrenal insufficiency only. PATIENT A newborn girl was admitted for mild dehydration, hyponatremia, hyperkalemia and hypoglycaemia and had normal external female genitalia without hyperpigmentation. Plasma cortisol, 17OH-progesterone, DHEA-S, androstendione and aldosterone were low, while ACTH and plasma renin activity were elevated, consistent with the diagnosis of primary adrenal insufficiency. Imaging showed normal adrenals, and cytogenetics revealed a 46,XX karyotype. She was treated with fluids, hydrocortisone and fludrocortisone. DESIGN, METHODS AND RESULTS Genetic studies revealed a novel homozygous STAR mutation in the 3' acceptor splice site of intron 4, c.466-1G>A (IVS4-1G>A). To test whether this mutation would affect splicing, we performed a minigene experiment with a plasmid construct containing wild-type or mutant StAR gDNA of exons-introns 4-6 in COS-1 cells. The splicing was assessed on total RNA using RT-PCR for STAR cDNAs. The mutant STAR minigene skipped exon 5 completely and changed the reading frame. Thus, it is predicted to produce an aberrant and shorter protein (p.V156GfsX19). Computational analysis revealed that this mutant protein lacks wild-type exons 5-7 which are essential for StAR-cholesterol interaction. CONCLUSIONS STAR c.466-1A skips exon 5 and causes a dramatic change in the C-terminal sequence of the protein, which is essential for StAR-cholesterol interaction. This splicing mutation is a loss-of-function mutation explaining the severe phenotype of our patient. Thus far, all reported splicing mutations of STAR cause a severe impairment of protein function and phenotype.

Learning to drive: learners' self-reported cognitive failure level predicts driving instructor's observation rating of driving performance

OBJECTIVES Evidence increases that cognitive failure may be used to screen for drivers at risk. Until now, most studies have relied on driving learners. This exploratory pilot study examines self-report of cognitive failure in driving beginners and error during real driving as observed by driving instructors. METHODS Forty-two driving learners of 14 driving instructors filled out a work-related cognitive failure questionnaire. Driving instructors observed driving errors during the next driving lesson. In multiple linear regression analysis, driving errors were regressed on cognitive failure with the number of driving lessons as an estimator of driving experience controlled. RESULTS Higher cognitive failure predicted more driving errors (p < .01) when age, gender and driving experience were controlled in analysis. CONCLUSIONS Cognitive failure was significantly associated with observed driving errors. Systematic research on cognitive failure in driving beginners is recommended.

Dirichlet-Neumann inverse spectral problem for a star graph of Stieltjes strings

We solve two inverse spectral problems for star graphs of Stieltjes strings with Dirichlet and Neumann boundary conditions, respectively, at a selected vertex called root. The root is either the central vertex or, in the more challenging problem, a pendant vertex of the star graph. At all other pendant vertices Dirichlet conditions are imposed; at the central vertex, at which a mass may be placed, continuity and Kirchhoff conditions are assumed. We derive conditions on two sets of real numbers to be the spectra of the above Dirichlet and Neumann problems. Our solution for the inverse problems is constructive: we establish algorithms to recover the mass distribution on the star graph (i.e. the point masses and lengths of subintervals between them) from these two spectra and from the lengths of the separate strings. If the root is a pendant vertex, the two spectra uniquely determine the parameters on the main string (i.e. the string incident to the root) if the length of the main string is known. The mass distribution on the other edges need not be unique; the reason for this is the non-uniqueness caused by the non-strict interlacing of the given data in the case when the root is the central vertex. Finally, we relate of our results to tree-patterned matrix inverse problems.

Partners for Life: A Brittle Star and Its Octocoral Host

Throughout the New England and Corner Rise seamounts of the western North Atlantic Ocean, several ophiuroid species are conspicuously epizoic on octocorals. One species, Ophiocreas oedipus, was found only on the chrysogorgiid octocoral Metallogorgia melanotrichos. Colonies of M. melanotrichos were collected from 11 seamounts during expeditions in 2003, 2004, and 2005 at depths between 1300 and 2200 m. O. oedipus is obligately associated with M. melanotrichos, leading a solitary existence on all octocorals observed. Evidence suggests that a young brittle star settles directly on a young octocoral and the 2 species then grow, mature, and senesce together. The brittle star benefits directly by being above the bottom for suspension feeding and is passively protected by the octocoral, but the latter, as far as we have been able to determine, Seems neither to benefit nor be disadvantaged by the relationship.

Improved star camera attitude data and their effect on the gravity field

Efforts are ongoing to decrease the noise of the GRACE gravity field models and hence to arrive closer to the GRACE baseline. The most significant error sources belong the untreated errors in the observation data and the imperfections in the background models. The recent study (Bandikova&Flury,2014) revealed that the current release of the star camera attitude data (SCA1B RL02) contain noise systematically higher than expected by about a factor 3-4. This is due to an incorrect implementation of the algorithms for quaternion combination in the JPL processing routines. Generating improved SCA data requires that valid data from both star camera heads are available which is not always the case because the Sun and Moon at times blind one camera. In the gravity field modeling, the attitude data are needed for the KBR antenna offset correction and to orient the non-gravitational linear accelerations sensed by the accelerometer. Hence any improvement in the SCA data is expected to be reflected in the gravity field models. In order to quantify the effect on the gravity field, we processed one month of observation data using two different approaches: the celestial mechanics approach (AIUB) and the variational equations approach (ITSG). We show that the noise in the KBR observations and the linear accelerations has effectively decreased. However, the effect on the gravity field on a global scale is hardly evident. We conclude that, at the current level of accuracy, the errors seen in the temporal gravity fields are dominated by errors coming from sources other than the attitude data.

Initiation of rivaroxaban in patients with nonvalvular atrial fibrillation at the primary care level:: The Swiss Therapy in Atrial Fibrillation for the Regulation of Coagulation (STAR) Study.

BACKGROUND Rivaroxaban has become an alternative to vitamin-K antagonists (VKA) for stroke prevention in non-valvular atrial fibrillation (AF) patients due to its favourable risk-benefit profile in the restrictive setting of a large randomized trial. However in the primary care setting, physician's motivation to begin with rivaroxaban, treatment satisfaction and the clinical event rate after the initiation of rivaroxaban are not known. METHODS Prospective data collection by 115 primary care physicians in Switzerland on consecutive nonvalvular AF patients with newly established rivaroxaban anticoagulation with 3-month follow-up. RESULTS We enrolled 537 patients (73±11years, 57% men) with mean CHADS2 and HAS-BLED-scores of 2.2±1.3 and 2.4±1.1, respectively: 301(56%) were switched from VKA to rivaroxaban (STR-group) and 236(44%) were VKA-naïve (VN-group). Absence of routine coagulation monitoring (68%) and fixed-dose once-daily treatment (58%) were the most frequent criteria for physicians to initiate rivaroxaban. In the STR-group, patient's satisfaction increased from 3.6±1.4 under VKA to 5.5±0.8 points (P<0.001), and overall physician satisfaction from 3.9±1.3 to 5.4±0.9 points (P<0.001) at 3months of rivaroxaban therapy (score from 1 to 6 with higher scores indicating greater satisfaction). In the VN-group, both patient's (5.4±0.9) and physician's satisfaction (5.5±0.7) at follow-up were comparable to the STR-group. During follow-up, 1(0.19%; 95%CI, 0.01-1.03%) ischemic stroke, 2(0.37%; 95%CI, 0.05-1.34%) major non-fatal bleeding and 11(2.05%; 95%CI, 1.03-3.64%) minor bleeding complications occurred. Rivaroxaban was stopped in 30(5.6%) patients, with side effects being the most frequent reason. CONCLUSION Initiation of rivaroxaban for patients with nonvalvular AF by primary care physicians was associated with a low clinical event rate and with high overall patient's and physician's satisfaction.