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textabstractWe examined the occurrence of faking on a rating situational judgment test (SJT) by comparing SJT scores and response styles of the same individuals across two natu‐ rally occurring situations. An SJT for medical school selection was administered twice to the same group of applicants (N = 317) under low‐stakes (T1) and high‐stakes (T2) circumstances. The SJT was scored using three different methods that were differ‐ entially affected by response tendencies. Applicants used significantly more extreme responding on T2 than T1. Faking (higher SJT score on T2) was only observed for scoring methods that controlled for response tendencies. Scoring methods that do not control for response tendencies introduce systematic error into the SJT score, which may lead to inaccurate conclusions about the existence of faking.

To maintain a thermal balance when experiencing cold, humans reduce heat loss and enhance heat production. A potent and rapid mechanism for heat generation is shivering. Research has shown that women prefer a warmer environment and feel less comfortable than men in the same thermal condition. Using the Blanketrol® III, a temperature management device commonly used to study brown adipose tissue activity, we tested whether the experimental temperature (TE) at which men and women start to shiver differs. Twenty male and 23 female volunteers underwent a cooling protocol, starting at 24 °C and gradually decreasing by 1–2 °C every 5 min until an electromyogram detected the shivering or the temperature reached 9 °C. Women started shivering at a higher TE than men (11.3 ± 1.8 °C for women vs 9.6 ± 1.8 °C for men, P = 0.003). In addition, women felt cool, scored by a visual analogue scale, at a higher TE than men (18.3 ± 3.0 °C for women vs 14.6 ± 2.6 °C for men, P < 0.001). This study demonstrates a sex difference in response to cold exposure: women require shivering as a source of heat production earlier than men. This difference could be important and sex should be considered when using cooling protocols in physiological studies.

Background The proportion of medical doctors involved in research activities is declining. Undergraduate medical research programs are positively associated with medical students’ research interest. Scientific pre-university programs (SPUPs) outside the medical domain are also positively associated with research interest, but have not been related to the shortage of clinician-scientists. This study examined the effect of an SPUP on medical students’ research interest. Methods This study was conducted at a Dutch medical school. Medical students in all years who had participated in an SPUP and first-year master students who had not participated in an SPUP were invited to fill out an online survey on extracurricular activities and future career interests. SPUP participants were compared with three groups of non-participants: (i) an unmatched group, (ii) a group matched on gender and pre-university Grade Point Average (pu-GPA) and (iii) a group matched on gender and first-year GPA, one to five years after finishing the SPUP. Participants evaluated the SPUP through ratings of statements about the program. Results Two-hundred forty medical students, including 71 SPUP participants responded to the survey. SPUP participants participated significantly more often in the Honors class (i.e., extracurricular educational program for high-performing students), gained significantly more often extracurricular research experience, enrolled significantly more often in the Research master (i.e., research training program parallel to the clinical master program) and obtained significantly more often a scholarship than unmatched non-SPUP participants. Using a non-SPUP group matched on gender and pu-GPA reduced the effect size of the significant differences in Honors class participation, Research master participation and scholarship obtainment. Using a non-SPUP group matched on gender and first-year GPA rendered the significant difference in Research master participation and scholarship obtainment insignificant. Significantly more SPUP participants than unmatched non-SPUP participants preferred a combination of clinical care and research in their future career. Using a non-SPUP group matched on gender and either pu-GPA or first-year GPA did not change the effect size of this significant difference. Conclusions These findings demonstrate the potential value of an SPUP in increasing the number of medical students with research interest and as a policy measure to help to alleviate the shortage of clinician-scientists. Electronic supplementary material The online version of this article (10.1186/s12909-017-0990-4) contains supplementary material, which is available to authorized users.

de Leng et al. argue that feedback communicators can be made more comfortable delivering unpleasant messages if clinical training settings promote trainees’ learning‐goal orientation.

Not all students cope successfully with the demands of medical school, and students' struggles may result in study delay or dropout. To prevent these outcomes, medical schools need to identify students who are experiencing academic difficulties and provide them with timely interventions through access to support programs. Although the importance of early identification and intervention is well recognized, less is known about successful strategies for identifying and supporting struggling students.Building on the literature and their own empirical findings, the authors propose an integrated, school-wide model for medical student success comprising a continuum of academic and behavioral support. This Four-Tier Continuum of Academic and Behavioral Support (4T-CABS) model focuses on improving both academic and behavioral outcomes by offering support for students at four levels, which range from adequate instruction for all, to targeted small-group interventions, to individualized support, and also include exit support for students who might be better off in another degree program.Additionally, medical schools should provide both academic and behavioral support; set high, yet realistic expectations and clearly communicate these to students; and intervene early, which requires timely identification of at-risk students who would benefit from the different types and tiers of support. Finally, interventions should be evidence based and fit the needs of the identified groups of students. The authors argue that adopting the core principles of the 4T-CABS model will enable medical schools to maximize academic engagement and performance for all students.

Several medical schools include candidates' extracurricular activities in their selection procedure, with promising results regarding their predictive value for achievement during the clinical years of medical school. This study aims to reveal whether the better achievement in clinical training of students selected on the basis of their extracurricular activities could be explained by persistent participation in extracurricular activities during medical school (msECAs). Lottery-admitted and selected student admission groups were compared on their participation in three types of msECAs: (1) research master, (2) important board positions or (3) additional degree programme. Logistic regression was used to measure the effect of admission group on participation in any msECA, adjusted for pre-university GPA. Two-way ANCOVA was used to examine the inter-relationships between admission group, participation in msECAs and clerkship grade, with pre-university GPA as covariate. Significantly more selected students compared to lottery-admitted students participated in any msECA. Participation in msECAs was associated with a higher pre-university GPA for lottery-admitted students only, whereas participation in msECAs was associated with higher clerkship grades for selected students only. These results suggest that persistent participation in extracurricular activities of selected students favours better clinical achievement, supporting the inclusion of ECAs in the selection procedure. More insight in the rationale behind participation in extracurricular activities during medical school may explain differences found between lottery-admitted and selected students.

SummaryObjective The objective of this study was to determine the aetiological spectrum of disorders of sex development (DSD) in a large cohort of underprivileged and undiagnosed patients from Indonesia. Methods A total of 286 patients with atypical external and/or internal genitalia were evaluated using clinical, hormonal, molecular genetic and histological parameters. Results The age (years) at presentation was 0–0·5 in 41 (14·3%), >0·5–12 in 181 (63·3%) and >12 in 64 cases (22·4%). 46,XY DSD was most common (68·2%, n = 195), 46,XX DSD was found in 23·4% (n = 67) and sex chromosomal DSD in 8·4% (n = 24). In 61·2% of 46,XX DSD patients, 17·9% of 46,XY DSD patients and all sex chromosome DSD patients (29·4% in total), a final diagnosis was reached based on genetic or histological gonadal tissue evaluation. 17-hydroxyprogesterone and androstenedione levels were the most distinctive parameters in 46,XX DSD patients. In 46,XY DSD, diagnostic groups were identified based on the external masculinization score: androgen action disorder (AAD), unknown male undermasculinization (UMU), and gonadal dysgenesis (GD). LH, FSH and testosterone levels were most informative especially in the older age group. HCG tests were of no additional value as no patients with androgen synthesis disorders were found. Hormonal profiles of patients with sex chromosome DSD and a Y-chromosome sequence containing karyotype showed high levels of LH and FSH, and low levels of AMH, inhibin B and testosterone compared with the normal male range. Gene mutations were found in all patients with CAH, but in only 24·5% and 1·8% of patients with AAD and UMU. In 32% of 46,XY GD patients, copy number variants of different genes were found. Conclusion A stepwise diagnostic approach led to a molecularly or histologically proven final diagnosis in 29·4% of the patients. The most informative parameters were serum levels of 17-hydroxyprogesterone and androstenedione in 46,XX DSD patients, and serum LH, FSH and testosterone levels in 46,XY DSD patients.

Medical schools are increasingly faced with a more diverse student population. Generally, ethnic minority students are reported to underperform compared with those from the ethnic majority. However, there are inconsistencies in findings in different types of examinations. Additionally, little is known about the performance of first-generation university students and about performance differences across ethnic minority groups. This study aimed to investigate underperformance across ethnic minority groups and by first-generation university students in different types of written tests and clinical skills examinations during pre-clinical training. A longitudinal prospective cohort study of progress on a 3-year Dutch Bachelor of Medicine course was conducted. Participants included 2432 students who entered the course over a consecutive 6-year period (2008-2013). Compared with Dutch students, the three non-Western ethnic minority groups (Turkish/Moroccan/African, Surinamese/Antillean and Asian) underperformed in the clinical problem solving tests, the language test and the OSCEs. Findings on the theoretical end-of-block tests and writing skills tests, and results for Western minority students were less consistent. Age, gender, pre-university grade point average and additional socio-demographic variables (including first-generation university student, first language, and medical doctor parent) could explain the ethnicity-related differences in theoretical examinations, but not in language, clinical and writing skills examinations. First-generation university students only underperformed in the language test. Apparently, underperformance differs both across ethnic subgroups and between different types of written and clinical examinations. Medical schools should ensure their assessment strategies create a level playing field for all students and explore reasons for underperformance in the clinical and writing skills examinations.

Society expects physicians to always improve their competencies and to be up to date with developments in their field. Therefore, an important aim of medical schools is to educate future medical doctors to become self-regulated, lifelong learners. However, it is unclear if medical students become better self-regulated learners during the pre-clinical stage of medical school, and whether students develop self-regulated learning skills differently, dependent on the educational approach of their medical school. In a cross-sectional design, we investigated the development of 384 medical students' self-regulated learning skills with the use of the Self-Regulation of Learning Self-Report Scale. Next, we compared this development in students who enrolled in two distinct medical curricula: a problem-based curriculum and a lectured-based curriculum. Analysis showed that more skills decreased than increased during the pre-clinical stage of medical school, and that the difference between the curricula was mainly caused by a decrease in the skill evaluation in the lecture-based curriculum. These findings seem to suggest that, irrespective of the curriculum, self-regulated learning skills do not develop during medical school.

Context Ethnicity‐related differences in clinical grades exist. Broad sampling in assessment of clinical competencies involves multiple assessments used by multiple assessors across multiple moments. Broad sampling in assessment potentially reduces irrelevant variances and may therefore mitigate ethnic disparities in clinical grades. Objectives Research question 1 (RQ1): to assess whether the relationship between students’ ethnicity and clinical grades is weaker in a broadly sampled versus a global assessment. Research question 2 (RQ2): to assess whether larger ethnicity‐related differences in grades occur when supervisors are given the opportunity to deviate from the broadly sampled assessment score. Methods Students’ ethnicity was classified as Turkish/Moroccan/African, Surinamese/Antillean, Asian, Western, and native Dutch. RQ1: 1667 students (74.3% native Dutch students) were included, who entered medical school between 2002 and 2004 (global assessment, 818 students) and between 2008 and 2010 (broadly sampled assessment, 849 students). The main outcome measure was whether or not students received ≥3 times a grade of 8 or higher on a scale from 1 to 10 in five clerkships. RQ2: 849 students (72.4% native Dutch students) were included, who were assessed by broad sampling. The main outcome measure was the number of grade points by which supervisors had deviated from broadly sampled scores. Both analyses were adjusted for gender, age, (im)migration status and average bachelor grade. Results Research question 1: ethnicity‐related differences in clinical grades were smaller in broadly sampled than in global assessment, and this was also seen after adjustments. More specifically, native Dutch students had reduced probabilities (0.87–0.65) in broadly sampled as compared with global assessment, whereas Surinamese (0.03–0.51) and Asian students (0.21–0.30) had increased probabilities of having ≥3 times a grade of 8 or higher in five clerkships. Research question 2: when supervisors were allowed to deviate from original grades, ethnicity‐related differences in clinical grades were reintroduced. Conclusions Broadly sampled assessment reduces ethnicity‐related differences in grades., van Andel et al. demonstrate that ethnicity‐related differences in clinical grades can be reduced using multiple assessors, multiple assessments and multiple evaluation moments.

Objective Brown adipose tissue (BAT) can generate heat by burning fatty acids, a process mediated by uncoupling protein 1 (UCP1). White adipose tissue (WAT) depots can gain BAT-like properties, and various studies have suggested that females have more active BAT or BAT-like WAT. We studied sex differences in BAT-like properties of human perirenal adipose tissue. Methods Perirenal and subcutaneous adipose tissue was obtained from 20 male and 24 female healthy live kidney donors. Mesenchymal stem cells (MSCs), adipocyte precursor cells, were isolated from these depots to study whether intrinsic factors control BAT-like properties of the adipose tissue depots. Results When average outside temperature a week before harvesting was below 11C, brown-like adipocytes expressing UCP1 were present in perirenal adipose tissue of women, but not of men. MSCs derived from perirenal adipose tissue expressed significantly more UCP1 when from female origin compared to male origin (P = 0.009). However, UCP1 protein content and oxygen consumption rate did not differ between adipocytes derived from male and female perirenal MSCs. Conclusions Female perirenal adipose tissue has a higher potency to gain BAT-like properties than male perirenal adipose tissue. The degree of gaining BAT-like properties depends on sex-specific intrinsic factors and environmental triggers such as temperature.

Background This study examined the influence of two Situational Judgement Test (SJT) design features (response instructions and response format) on applicant perceptions. Additionally, we investigated demographic subgroup differences in applicant perceptions of an SJT. Methods Medical school applicants (N = 372) responded to an online survey on applicant perceptions, including a description and two example items of an SJT. Respondents randomly received one of four SJT versions (should do-rating, should do-pick-one, would do-rating, would do-pick-one). They rated overall favourability and items on four procedural justice factors (face validity, applicant differentiation, study relatedness and chance to perform) and ease-of-cheating. Additionally, applicant perceptions were compared for subgroups based on gender, ethnic background and first-generation university status. Results Applicants rated would-do instructions as easier to cheat than should-do instructions. Rating formats received more favourable judgements than pick-one formats on applicant differentiation, study-relatedness, chance to perform and ease of cheating. No significant main effect for demographic subgroup on applicant perceptions was found, but significant interaction effects showed that certain subgroups might have more pronounced preferences for certain SJT design features. Specifically, ethnic minority applicants – but not ethnic majority applicants – showed greater preference for should-do than would-do instructions. Additionally, first-generation university students – but not non-first-generation university students – were more favourable of rating formats than of pick-one formats. Conclusions Findings indicate that changing SJT design features may positively affect applicant perceptions by promoting procedural justice factors and reducing perceived ease of cheating and that response instructions and response format can increase the attractiveness of SJTs for minority applicants. Electronic supplementary material The online version of this article (10.1186/s12909-018-1390-0) contains supplementary material, which is available to authorized users.

Cold exposure of mice is a common method to stimulate brown adipose tissue (BAT) activity and induce browning of white adipose tissue (WAT) that has beneficial effects on whole-body lipid metabolism, including reduced plasma triglyceride (TG) concentrations. The liver is a key regulatory organ in lipid metabolism as it can take up as well as oxidize fatty acids. The liver can also synthesize, store and secrete TGs in VLDL particles. The effects of cold exposure on murine hepatic lipid metabolism have not been addressed. Here, we report the effects of 24-h exposure to 4°C on parameters of hepatic lipid metabolism of male C57BL/6J mice. Cold exposure increased hepatic TG concentrations by 2-fold (P Cyp7a1encoding the rate-limiting enzyme in the classical bile acid (BA) synthesis pathway was increased by 4.3-fold (P P P

Many different medical school selection processes are used worldwide. In this paper, we examine the effect of (1) participation, and (2) selection in a voluntary selection process on study performance. We included data from two cohorts of medical students admitted to Erasmus MC, Rotterdam and VUmc, Amsterdam, The Netherlands and compared them to previously published data from Groningen medical school, The Netherlands. All included students were admitted based on either (1) a top pre-university grade point average, or (2) a voluntary selection process, or (3) weighted lottery. We distinguished between lottery-admitted students who had participated in the voluntary selection process and had been rejected, and lottery-admitted students who had not participated. Knowledge test scores, study progress, and professionalism scores were examined using ANCOVA modelling, logistic regression, and Bonferroni post hoc multiple-comparison tests, controlling for gender and cohort. For written test grades, results showed a participation effect at Groningen medical school and Erasmus MC (p

Context Despite their widespread use in medical school selection, there remains a lack of clarity on exactly what situational judgement tests (SJTs) measure. Objectives We aimed to develop an SJT that measures integrity by combining critical incident interviews (inductive approach) with an innovative deductive approach. The deductive approach guided the development of the SJT according to two established theoretical models, of which one was positively related to integrity (honesty–humility [HH]) and one was negatively related to integrity (cognitive distortions [CD]). The Integrity SJT covered desirable (HH‐based) and undesirable (CD‐based) response options. We examined the convergent and discriminant validity of the Integrity SJT and compared the validity of the HH‐based and CD‐based subscores. Methods The Integrity SJT was administered to 402 prospective applicants at a Dutch medical school. The Integrity SJT consisted of 57 scenarios, each followed by four response options, of which two represented HH facets and two represented CD categories. Three SJT scores were computed, including a total, an HH‐based and a CD‐based score. The validity of these scores was examined according to their relationships with external integrity‐related measures (convergent validity) and self‐efficacy (discriminant validity). Results The three SJT scores correlated significantly with all integrity‐related measures and not with self‐efficacy, indicating convergent and discriminant validity. In addition, the CD‐based SJT score correlated significantly more strongly than the HH‐based SJT score with two of the four integrity‐related measures. Conclusions An SJT that assesses the ability to correctly recognise CD‐based response options as inappropriate (i.e. what one should not do) seems to have stronger convergent validity than an SJT that assesses the ability to correctly recognise HH‐based response options as appropriate (i.e. what one should do). This finding might be explained by the larger consensus on what is considered inappropriate than on what is considered appropriate in a challenging situation. It may be promising to focus an SJT on the ability to recognise what one should not do., The authors demonstrate that an SJT score based on recognizing what not to do has stronger convergent validity than an SJT score based on recognizing what to do.

Brown adipose tissue (BAT) and brown-like cells in white adipose tissue (WAT) can dissipate energy through thermogenesis, a process mediated by uncoupling protein 1 (UCP1). We investigated whether stress hormones ACTH and corticosterone contribute to BAT activation and browning of WAT. ACTH and corticosterone were studied in male mice exposed to 4 or 23 degrees C for 24 h. Direct effects were studied in T37i mouse brown adipocytes and primary cultured murine BAT and inguinal WAT (iWAT) cells. In vivo effects were studied using F-18-deoxyglucose positron emission tomography. Cold exposure doubled serum ACTH concentrations (P=0.03) and fecal corticosterone excretion (P=0.008). In T37i cells, ACTH dose-dependently increased Ucp1 mRNA (EC50=1.8 nM) but also induced Ucp1 protein content 88% (P=0.02), glycerol release 32% (P=0.03) and uncoupled respiration 40% (P=0.003). In cultured BAT and iWAT, ACTH elevated Ucp1 mRNA by 3-fold (P=0.03) and 3.7-fold (P=0.01), respectively. In T37i cells, corticosterone prevented induction of Ucp1 mRNA and Ucp1 protein by both ACTH and norepinephrine in a glucocorticoid receptor (GR)-dependent fashion. ACTH and GR antagonist RU486 independently doubled BAT F-18-deoxyglucose uptake (P=0.0003 and P=0.004, respectively) in vivo. Our results show that ACTH activates BAT and browning of WAT while corticosterone counteracts this.Van den Beukel, J. C., Grefhorst, A., Quarta, C., Steenbergen, J., Mastroberardino, P. G., Lombes, M., Delhanty, P. J., Mazza, R., Pagotto, U., van der Lely, A. J., Themmen, A. P. N. Direct activating effects of adrenocorticotropic hormone (ACTH) on brown adipose tissue are attenuated by corticosterone.

Situational Judgment Tests (SJTs) are increasingly used for medical school selection. Scoring an SJT is more complicated than scoring a knowledge test, because there are no objectively correct answers. The scoring method of an SJT may influence the construct and concurrent validity and the adverse impact with respect to non-traditional students. Previous research has compared only a small number of scoring methods and has not studied the effect of scoring method on internal consistency reliability. This study compared 28 different scoring methods for a rating SJT on internal consistency reliability, adverse impact and correlation with personality. The scoring methods varied on four aspects: the way of controlling for systematic error, and the type of reference group, distance and central tendency statistic. All scoring methods were applied to a previously validated integrity-based SJT, administered to 931 medical school applicants. Internal consistency reliability varied between .33 and .73, which is likely explained by the dependence of coefficient alpha on the total score variance. All scoring methods led to significantly higher scores for the ethnic majority than for the non-Western minorities, with effect sizes ranging from 0.48 to 0.66. Eighteen scoring methods showed a significant small positive correlation with agreeableness. Four scoring methods showed a significant small positive correlation with conscientiousness. The way of controlling for systematic error was the most influential scoring method aspect. These results suggest that the increased use of SJTs for selection into medical school must be accompanied by a thorough examination of the scoring method to be used.

Background The thermoneutral zone (TNZ) is a species-specific range of ambient temperature (T a), at which mammals can maintain a constant body temperature with the lowest metabolic rate. The TNZ for an adult mouse is between 26 and 34 °C. Interestingly, female mice prefer a higher T a than male mice although the underlying mechanism for this sex difference is unknown. Here, we tested whether gonadal hormones are dominant factors controlling temperature preference in male and female mice. Methods We performed a temperature preference test in which 10-week-old gonadectomized and sham-operated male and female C57BL/6J mice were allowed to choose to reside at the thermoneutral cage of 29 °C or an experimental cage of 26, 29, or 32 °C. Results All mice preferred a T a higher than 26 °C, especially in the inactive phase. Choosing between 29 and 32 °C, female mice resided more at 32 °C while male mice had no preference between the temperatures. Hence, the preferred T a for female mice was significantly higher (0.9 ± 0.2 °C) than that for male mice. However, gonadectomy did not influence the T a preference. Conclusions Female mice prefer a warmer environment than male mice, a difference not affected by gonadectomy. This suggests that thermal-sensing mechanisms may be influenced by sex-specific pathways other than gonadal factors or that the thermoregulatory set point has already been determined prior to puberty. Electronic supplementary material The online version of this article (doi:10.1186/s13293-017-0145-7) contains supplementary material, which is available to authorized users.

Medical Education 2012: 46:575585 Context Research from numerous medical schools has shown that students from ethnic minorities underperform compared with those from the ethnic majority. However, little is known about why this underperformance occurs and whether there are performance differences among ethnic minority groups. Objectives This study aimed to investigate underperformance across ethnic minority groups in undergraduate pre-clinical and clinical training. Methods A longitudinal prospective cohort study of progress on a 6-year undergraduate medical course was conducted in a Dutch medical school. Participants included 1661 Dutch and 696 non-Dutch students who entered the course over a consecutive 6-year period (20022007). Main outcome measures were performance in Year 1 and in the pre-clinical and clinical courses. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated by logistic regression analysis for ethnic subgroups (Surinamese/Antillean, Turkish/Moroccan/African, Asian, Western) compared with Dutch students, adjusted for age, gender, pre-university grade point average (pu-GPA), additional socio-demographic variables (first-generation immigrant, urban background, first-generation university student, first language, medical doctor as parent) and previous performance at medical school. Results Compared with Dutch students, Surinamese and Antillean students specifically underperformed in the Year 1 course (pass rate: 37% versus 64%; adjusted OR 0.40, 95% CI 0.270.60) and the pre-clinical course (pass rate: 19% versus 41%; adjusted OR 0.57, 95% CI 0.350.93). On the clinical course all non-Dutch subgroups were less likely than Dutch students to receive a grade of = 8.0 (at least three of five grades: 5477% versus 88%; adjusted ORs: 0.170.45). Conclusions Strong ethnic disparities exist in medical school performance even after adjusting for age, gender, pu-GPA and socio-demographic variables. More subjective grading cannot be ruled out as a cause of lower grades in clinical training, but other possible explanations should be studied further to mitigate the disparities.

Primary ovarian insufficiency (POI), also known as premature ovarian failure, is a disorder of infertility characterized by amenorrhoea, low estrogen levels and increased gonadotropin levels in women aged

With great interest we have read the recent Show and Tell article The binding study advice in medical education: a 2-year experience by Eijsvogels et al. [1]. Their results largely confirm our own previous findings that the implementation of the binding study advice (or academic dismissal policy as we called it) did not lead to earlier dropout, higher completion rates or an improved study rate during the first 2 years at our medical school [2]. To explain the limited impact of the binding study advice on the study outcomes in medical faculties, Eijsvogels et al. propose a ‘ceiling effect’ rather than a ‘threshold effect’: it is not so much that students reduce their study efforts after having obtained enough ECTS credits, but due to the already high performance level of medical students there is little room for improvement. Although this explanation sounds plausible, we are not sure whether we totally agree. The reason for this is that we wonder what the effect would be of raising the standards. We believe that in particular non-struggling students may be expected to demonstrate the ability to improve their study progress if they are encouraged to do so. Indeed, Eijsvogels et al. find that more students obtained access to the second year of the study programme after the implementation of the binding study advice. The ultimate example of standard raising is to set the minimum equal to the maximum, or–put differently–to expect students to obtain all 60 first-year ECTS credits within one year. A couple of years ago this so-called nominal = normal policy was implemented at the Erasmus University Rotterdam and more recently (September 2014) also at the Erasmus MC Medical School. A prerequisite for introducing such a system is that medical schools encourage and facilitate students to meet the standard by providing feasible study programmes, student-centred learning and timely feedback on examinations, and allow compensation between exam scores. Although the effect of the nominal = normal policy on study outcomes of our medical students is not yet known, it provides a strong incentive to students whose study progress is not optimal to obtain all first-year credits within one year. Ideally, it becomes just natural to have an optimal study rate and focusing on the minimum standards required becomes pointless.

Medical Education 2011: 45: 1032–1040 Objectives A recent controlled study by our group showed that the dropout rate in the first 2 years of study of medical students selected for entry by the assessment of a combination of non-cognitive and cognitive abilities was 2.6 times lower than that of a control group of students admitted by lottery. The aim of the present study was to compare the performance of these two groups in the clinical phase. Methods A prospective cohort study was performed to compare the performance of 389 medical students admitted by selection with that of 938 students admitted by weighted lottery between 2001 and 2004. Follow-up of these cohorts lasted 5.5–8.5 years. The main outcome measures were the mean grade obtained on the first five discipline-specific clerkships by all cohorts and the mean grade achieved on all 10 clerkships by the cohorts of 2001 and 2002. Results Selected students obtained a significantly higher mean grade during their first five clerkships than lottery-admitted students (mean ± standard error [SE] 7.95 ± 0.03, 95% confidence interval [CI] 7.90–8.00 versus mean ± SE 7.84 ± 0.02, 95% CI 7.81–7.87; p

CONTEXT Medical students often fail to finish medical school within the designated time. An academic dismissal (AD) policy aims to enforce satisfactory progress and to enable early identification and timely support or referral of struggling students. In this study, we assessed whether the implementation of an AD policy improved study progress in the first 2 years of medical school. Additionally, we analysed its effect on the help-seeking behaviour of struggling students. METHODS We compared two AD cohorts (entering in 2005 and 2006, respectively) and two non-AD cohorts (entering in 2003 and 2004, respectively) on dropout rates, Year 1 curriculum completion rates and the percentage of students with an optimal study rate (i.e. all modules completed) at 1 and 2 years after enrolment. We also measured the effect on study progress of attending the support meetings offered. RESULTS The AD (n = 809) and non-AD cohorts (n = 809) did not differ significantly in dropout rate at 5 months, in Year 1 completion rate at 2 years and in the percentage of optimally performing students at 1 year after enrolment. At 2 years after enrolment, more students from the AD cohorts had left and more non-AD students demonstrated optimal performance, but effect sizes (ESs) for these differences were small. Voluntary support at 4 months was attended by AD students more often than by non-AD students (68.9% versus 39.8%; chi(2)((1)) = 43.95, p

OBJECTIVE: To describe changes of anti-Müllerian hormone (AMH) and inhibin B during low-dose gonadotropin ovulation induction (OI) treatment in women with polycystic ovary syndrome (PCOS), and thus disturbed selection of the dominant follicle.DESIGN: Observational study.SETTING: A referral fertility clinic.PATIENT(S): Women with PCOS (n = 48) and normo-ovulatory women (n = 23).INTERVENTION(S) AND MAIN OUTCOME MEASURE(S): Serum AMH, inhibin B, FSH, and E(2) concentrations were measured at start of stimulation, on the day of follicle selection, and at administration of hCG during OI cycles and were compared with concentration measured during the normal menstrual cycle.RESULT(S): Development of a single dominant follicle was observed in 92% of all OI cycles, reflected by similar E(2) concentrations compared with those in spontaneous cycles. AMH concentrations were constant during low-dose ovarian stimulation. Inhibin B concentrations remained elevated in patients with PCOS, suggesting prolonged survival of small antral follicles, whereas in controls inhibin B concentrations declined during the late follicular phase.CONCLUSION(S): The lack of change in AMH and inhibin B concentrations suggest that follicle dynamics during low-dose stimulation seem different from those during controlled ovarian hyperstimulation. In addition, constant AMH and inhibin B levels suggest that neither AMH nor inhibin B is an accurate marker of ovarian response after low-dose gonadotropin OI in patients with PCOS.

Context: Germline and somatic activating mutations in the LH receptor (LHR) gene have been reported.Objective: Our objective was to perform mutation analysis of the LHR gene of patients with Leydig cell adenoma or hyperplasia. Functional studies were conducted to compare the D578H-LHR mutant with the wild-type (WT)-LHR and the D578G-LHR mutant, a classic cause of testotoxicosis. The three main signal transduction pathways in which LHR is involved were studied.Patients: We describe eight male patients with gonadotropin-independent precocious puberty due to Leydig cell adenoma or hyperplasia.Results: The D578H-LHR mutation was found in the adenoma or nodule with hyperplasia in all but two patients. D578H-LHR displayed a constitutively increased but noninducible production of cAMP, led to a very high production of inositol phosphates, and induced a slight phosphorylation of p44/42 MAPK in the absence of human chorionic gonadotropin. The D578G-LHR showed a response intermediate between WT-LHR and the D578H-LHR. Subcellular localization studies showed that the WT-LHR was almost exclusively located at the cell membrane, whereas the D578H-LHR showed signs of internalization. D578H-LHR was the only receptor to colocalize with early endosomes in the absence of human chorionic gonadotropin.Conclusions: Although several LHR mutations have been reported in testotoxicosis, the D578H-LHR mutation, which has been found only as a somatic mutation, appears up until now to be specifically responsible for Leydig cell adenomas. This is reflected by the different activation of the signal transduction pathways, when compared with the WT-LHR or D578G-LHR, which may explain the tumorigenesis in the D578H mutant. (J Clin Endocrinol Metab 96: E1197-E1205, 2011)

Delhanty PJ, van Kerkwijk A, Huisman M, van de Zande B, Verhoef-Post M, Gauna C, Hofland L, Themmen AP, van der Lely AJ. Unsaturated fatty acids prevent desensitization of the human growth hormone secretagogue receptor by blocking its internalization. Am J Physiol Endocrinol Metab 299: E497-E505, 2010. First published June 29, 2010; doi:10.1152/ajpendo.00414.2009.-The composition of the plasma membrane affects the responsiveness of cells to metabolically important hormones such as insulin and vasoactive intestinal peptide. Ghrelin is a metabolically regulated hormone that activates the G protein-coupled receptor GH secretagogue receptor type 1a (GHSR) not only in the pituitary gland but also in peripheral tissues such as the pancreas, stomach, and T cells in the circulation. We have investigated the effects of lipids and altered plasma membrane composition on GHSR activation. Oligounsaturated fatty acids (OFAs) disrupt the structure of membranes and make them more fluid. Prolonged (96 h), but not acute, treatment of the GHSR cells with the 18C OFAs oleic and linoleic acid caused a significant increase in sensitivity of the receptor to ghrelin (EC50 reduced by a factor of 2.4 and 2.9 at 60 and 120 mu M OFAs, respectively). OFAs were found to block the inhibitory effects of ghrelin pretreatment on subsequent ghrelin responsiveness, suggesting that OFAs suppress desensitization of GHSR. Radioligand displacement studies did not show a significant shift in receptor binding after incubation with OFAs. However, it was found that OFA treatment suppressed GHSR internalization, likely explaining OFA-induced refractoriness to ligand-induced desensitization. The involvement of lipid rafts in this process was indicated by the altered responsiveness of GHSR under conditions that alter membrane cholesterol. In conclusion, our findings demonstrate the importance of membrane composition for GHSR activation and desensitization and indicate at least part of the mechanism through which OFAs and cholesterol could affect ghrelin's activity in vivo.

ObjectiveAberrant adrenal expression of various hormone receptors has been identified in ACTH-independent macronodular adrenal hyperplasia (AIMAH) causing cortisol hypersecretion regulated by hormones other than ACTH. We aimed to determine aberrant expression of multiple hormone receptors in vivo and in vitro in adrenal tissue of a patient with AIMAH.DesignThe design of the study includes clinical case description, and biochemical and immunohistochemical analysis to demonstrate aberrant expression of multiple hormone receptors in AIMAH.MethodsThe subject of the study is a male diagnosed with Cushing's syndrome because of AIMAH. Directly after laparoscopic removal of the adrenals, adrenal tissue was incubated with and without test substances (ACTH, forskolin, arginine vasopressin (AVP), desmopressin, epinephrine, norepinephrine, purified human chorionic gonadotropin (hCG), metoclopramide and the combinations of AVP with ACTH, epinephrine and metoclopramide). LH/hCG-receptor (hCG-R) immunohistochemistry and RT-PCR analyses were performed to demonstrate aberrant expression of LH/hCG-R and V1–3-AVPR.ResultsAIMAH was characterized by in vivo cortisol responsiveness to AVP and in vitro cortisol responses to AVP, hCG, epinephrine, and norepinephrine suggesting aberrant adrenal expression of the receptors for AVP (the V1–3-AVPRs), catecholamines (the β-AR), and LH (the LH/hCG-R). Incubation with combinations of AVP and ACTH and of AVP with epinephrine induced a stronger cortisol response compared with incubation with the individual agents. Moreover, we demonstrated adrenal V1–3-AVPR and LH/hCG-R expression.ConclusionsAIMAH tissue may simultaneously express multiple aberrant hormone receptors, and individual ligands may potentiate each other regarding cell proliferation and cortisol production.

Objective: To evaluate serum anti-Müllerian hormone (AMH) in well-characterized men with normal and reduced sperm concentration and in men with a history of or persistent maldescended testes as a possible clinical marker of male factor infertility and/or maldescended testes. Design: Retrospective analysis of 199 men selected from our database (Androbase). Setting: The university-based Institute of Reproductive Medicine. Patient(s): One hundred eight men with normal and 60 men with reduced sperm concentration without known cause of infertility and additionally 31 infertile men with current or former maldescended testes were evaluated. Intervention(s): Serum AMH was analyzed by an in-house ELISA. Main Outcome Measure(s): Hormone and semen parameters were compared and correlated with AMH. Result(s): No significant differences were found in AMH levels. Only in men with maldescended testes did AMH correlate negatively with FSH and positively with testicular volume and sperm concentration. No correlations between AMH and LH or testosterone (T) were found. Conclusion(s): Anti-Müllerian hormone serum levels are not significantly affected by impaired spermatogenesis in general but are correlated with spermatogenic parameters in men with current or former maldescended testes. Therefore, AMH measurement does not improve clinical routine diagnostics but should be evaluated further in patients with maldescended testes. Anti-Müllerian hormone might serve as a marker of Sertoli cell number, function, and/or maturation in these men.

Contains fulltext : 80097.pdf (Publisher’s version ) (Open Access) CONTEXT: Ovarian dysfunction is classically categorized on the basis of cycle history, FSH, and estradiol levels. Novel ovarian markers may provide a more direct insight into follicular quantity in hypergonadotropic women. OBJECTIVE: The objective of the study was to investigate the distribution of novel ovarian markers in young hypergonadotropic women as compared with normogonadotropic regularly menstruating women. DESIGN: This was a nationwide prospective cohort study. SETTING: The study was conducted at 10 hospitals in The Netherlands. PATIENTS: Women below age 40 yr with regular menses and normal FSH (controls; n = 83), regular menstrual cycles and elevated FSH [incipient ovarian failure (IOF); n = 68]; oligomenorrhea and elevated FSH [referred to as transitional ovarian failure (TOF); n = 79]; or at least 4 months amenorrhea together with FSH levels exceeding 40 IU/liter [premature ovarian failure (POF); n = 112]. MAIN OUTCOME Measures: Serum levels of anti-Mullerian hormone (AMH), inhibin B, and antral follicle count (AFC) was measured. RESULTS: All POF patients showed AMH levels below the fifth percentile (p(5)) of normoovulatory women. Normal AMH levels (>p(5)) could be identified in 75% of IOF, 33% of TOF patients, and 98% of controls. AFC and AMH levels changed with increasing age (P < 0.0001), whereas inhibin B did not (P = 0.26). AMH levels were significantly different between TOF and IOF over the entire age range, whereas AFC became similar for TOF and IOF at higher ages. CONCLUSIONS: Compared with inhibin B and AFC, AMH was more consistently correlated with the clinical degree of follicle pool depletion in young women presenting with elevated FSH levels. AMH may provide a more accurate assessment of the follicle pool in young hypergonadotropic patients, especially in the clinically challenging subgroups of patients with elevated FSH and regular menses (i.e. IOF) and in hypergonadotropic women with cycle disturbances not fulfilling the POF diagnostic criteria (i.e. TOF).

Objectives We aimed to discover, through a controlled experiment, whether cognitive and non-cognitive assessment would select higher-achieving applicants to medical school than selection by lottery. Methods We carried out a prospective cohort study to compare 389 medical students who had been admitted by selection and 938 students who had been admitted by weighted lottery, between 2001 and 2004. Main outcome measures were dropout rates, study rate (credits per year) and mean grade per first examination attempt per year. Study rates in the 4 pre-clinical years of medical school were used to categorise students' performance as average or optimal. Results Pre-admission variables did not differ between the two groups. The main outcome of the selection experiment was that relative risk for dropping out of medical school was 2.6 times lower for selected students than for lottery-admitted controls (95% confidence interval 1.59-4.17). Significant differences between the groups in the percentage of optimally performing students and grade point average for first examination attempts were found only in the 2001 cohort, when results favoured the selected group. The results of the selection process took into account both the assessment procedure involved and the number of students who withdrew voluntarily. Conclusions This is the first controlled study to show that assessing applicants' non-cognitive and cognitive abilities makes it possible to select students whose dropout rate will be lower than that of students admitted by lottery. The dropout rate in our overall cohort was 2.6 times lower in the selected group.

Methods to predict numbers of healthy oocytes in the ovaries of young adults could have important diagnostic relevance in family planning and animal agriculture. We have observed that peak antral follicle count (AFC) determined by serial ovarian ultrasonography during follicular waves is very highly reproducible within individual young adult cattle, despite 7-fold variation among animals. Herein, we tested the hypothesis that AFC is positively associated with the number of morphologically healthy oocytes and follicles in ovaries and with serum concentrations of anti-Mullerian hormone (AMH), an indirect marker for number of healthy follicles and oocytes in ovaries. In the present study, age-matched young adult cattle (12-18 mo old) were subjected to serial ultrasonography to identify animals with a consistently high (> or =25 follicles that were > or =3 mm in diameter) or low (< or =15 follicles) AFC during follicular waves. Differences in serum AMH concentrations, ovary weight, and number of morphologically healthy and atretic follicles and oocytes were determined. The phenotypic classifications of cattle based on AFC during follicular waves or AMH concentrations both predict reliably the relative number of morphologically healthy follicles and oocytes in ovaries of age-matched young adult cattle.

BACKGROUND: Polycystic ovaries display an increased number of pre-antral and antral follicles compared with normal ovaries, suggesting that early and late follicle development are disturbed. The pathophysiology of this process is poorly understood. Since the transforming growth factor β family members, anti-Mullerian hormone (AMH) and bone morphogenetic proteins (BMPs), inhibit FSH sensitivity, their signalling may contribute to the aberrant follicle development in these women. Here, we investigated the role of ALK2, a type I receptor for AMH/BMP signalling, in PCOS using a genetic approach. METHODS: Seven single nucleotide polymorphisms in the ACVR1 gene, encoding ALK2, were genotyped in 359 PCOS patients and 30 normo-ovulatory and 3543 population-based control women, and haplotypes were determined. Subsequently, the association of ACVR1 variants with ovarian parameters and hormone levels was investigated. RESULTS: The polymorphisms rs1220134, rs10497189 and rs2033962 and their corresponding haplotypes did not show different frequencies from controls, but were associated with AMH levels in PCOS women (P = 0.001, P = 0.002 and P = 0.007, respectively). Adjustment for follicle number revealed that the association with AMH levels was, in part, independent from follicle number, suggesting that variants in ACVR1 also influence AMH production per follicle. CONCLUSIONS: Genetic variation within ACVR1 is associated with AMH levels and follicle number in PCOS women, suggesting that ALK2 signalling contributes to the disturbed folliculogenesis in PCOS patients.

Objective To compare in an integral way the value of the basal serum anti-Mullerian hormone (AMH) level with most of the established ovarian reserve tests. Design Prospective randomized controlled trial. Setting Fertility center of a university hospital in the Netherlands. Patient(s) One hundred ten patients undergoing their first IVF cycle who were randomized, by a computer-designed four-block system, into two groups. Intervention(s) Fifty-six patients underwent a clomiphene citrate challenge test (CCCT), and 54 patients underwent an exogenous FSH ovarian reserve test (EFORT). In all patients, basal AMH, basal FSH, basal inhibin B, antral follicle count (AFC), and basal volume of the ovaries were measured. In all patients, the test was followed by a standard IVF treatment. Main Outcome Measure(s) Ovarian response after ovarian hyperstimulation in an IVF treatment, expressed as the total number of stimulated follicles, retrieved oocytes, and ongoing pregnancies. Result(s) The best prediction of ovarian reserve (Y) was seen in a multiple regression prediction model that simultaneously included AFC, inhibin B increment in the EFORT, and basal volume of the ovaries. Univariate logistic regression showed that the best predictors for poor response were AMH, the CCCT, basal FSH, and the AFC. For hyperresponse, univariate logistic regression showed that the best predictor was AFC. Multiple logistic regression analysis did not produce a better model in terms of improving the prediction of poor response or hyperresponse. The best predictors for the prediction of non-pregnancy were the CCCT and the E 2 increment in the EFORT. Conclusion(s) Anti-Mullerian hormone is comparable with other commonly used ovarian reserve tests but is probably most applicable in general practice.

Background: Serum antimüllerian hormone (AMH) levels are highly correlated with antral follicle counts, while being menstrual cycle independent and easily measurable. However, AMH, unlike antral follicle counts, has not been tested as yet as a predictor of reproductive status. By relating AMH levels to the age distribution of reproductive events like onset of menopause, we tested this hypothesis. Methods: AMH levels were measured in 144 fertile normal volunteers and used to determine an estimate of mean AMH as a function of age. Data on the onset of menopause were obtained from the population-based Prospect-European Prospective Investigation into Cancer and Nutrition [Prospect-EPIC] cohort. Estimation of an AMH threshold to predict menopause was done by maximum likelihood using the observed (Prospect-EPIC) distribution of age at menopause and the predictive distribution from this AMH threshold. Predictions of age at menopause follow from an individual woman’s AMH relative to percentiles of the distribution of AMH for a given age, and the corresponding percentiles of the predictive distribution of age at menopause. Results: There was good conformity between the observed distribution of age at menopause and that predicted from declining AMH levels. Conclusions: The similarity between observed and predictive distributions of age at menopause supports the hypothesis that AMH levels are related to onset of menopause. Results of this study suggest that AMH is able to specify a woman’s reproductive age more realistically than chronological age alone.

A chemically induced model of ovarian failure has been developed in rodents, and was used to test whether or not anti-Mullerian hormone (AMH) can be used as a non-invasive measure of primordial follicle numbers. Repeated exposures of mice to 4-vinylcyclohexene diepoxide (VCD) induce loss of primordial and earliest growing ovarian follicles. An accelerated exposure regimen was used to eliminate small ovarian follicles in C57BL6/J mice (240 mg VCD/kg/day, 5 days, i.p.). Follicle populations were determined and correlated with circulating AMH levels. Exposures decreased only primordial and small primary follicles by 96% on day 16 after initiating exposures, followed by almost complete follicle elimination on days 37-100. AMH levels in VCD-exposed mice were similar to vehicle-treated mice on day 16, but became significantly lower or undetectable at later time points. Thus, AMH correlated well with growing follicle numbers. AMH only correlated with primordial follicles at time points after ovarian insult at which their loss led to decreased growing follicle numbers. (C) 2008 Elsevier Inc. All rights reserved

The luteinizing hormone (LH) receptor plays an essential role in male and female gonadal function. Together with the follicle-stimulating hormone (FSH) and thyroid stimulating hormone (TSH) receptors, the LH receptor forms the family of glycoprotein hormone receptors. All glycoprotein hormone receptors share a common modular topography, with an N-terminal extracellular ligand binding domain and a C-terminal seven-transmembrane transduction domain. The ligand binding domain consists of 9 leucine-rich repeats, flanked by N- and C-terminal cysteine-rich regions. Recently, crystal structures have been published of the extracellular domains of the FSH and TSH receptors. However, the C-terminal cysteine-rich region (CCR), also referred to as the “hinge region,” was not included in these structures. Both structure and function of the CCR therefore remain unknown. In this study we set out to characterize important domains within the CCR of the LH receptor. First, we mutated all cysteines and combinations of cysteines in the CCR to identify the most probable disulfide bridges. Second, we exchanged large parts of the LH receptor CCR by its FSH receptor counterparts, and characterized the mutant receptors in transiently transfected HEK 293 cells. We zoomed in on important regions by focused exchange and deletion mutagenesis followed by alanine scanning. Mutations in the CCR specifically decreased the potencies of LH and hCG, because the potency of the low molecular weight agonist Org 41841 was unaffected. Using this unbiased approach, we identified Asp330 and Tyr331 as key amino acids in LH/hCG mediated signaling.

Aim: Dietary restriction (DR) and fasting (FA) induce robust protection against the detrimental effects of renal ischemia-reperfusion injury (I/RI). Several mechanisms of protection have been proposed, such as hormesis. Hormesis is defined as a life-supporting beneficial effect resulting from the cellular responses to single or multiple rounds of (mild) stress. The cold exposure (CE) model is a stress model similar to DR, and has been shown to have hormetic effects and has proved to increase longevity. CE is considered to be the most robust method to increase metabolism through activation of brown adipocytes. BAT has been considered important in etiology of obesity and its metabolic consequences. Materials and methods: Since DR, FA, and CE models are proposed to work through hormesis, we investigated physiology of adipose tissue and effect on BAT in these models and compared them to ad libitum (AL) fed mice. We also studied the differential effect of these stress models on immunological changes, and effect of CE on renal I/RI. Key findings: We show similar physiological changes in adiposity in male C57Bl/6 mice due to DR, FA and CE, but the CE mice were not protected against renal I/RI. The immunophenotypic changes observed in the CE mice were similar to the AL animals, in contrast to FA mice, that showed major immunophenotypic changes in the B and T cell development stages in primary and secondary lymphoid organs. Significance: Our findings thus demonstrate that DR, FA and CE are hormetic stress models. DR and FA protect against renal I/IR, whereas CE could not. (C) 2015 Elsevier Inc. All rights reserved.

Content: Medical schools aim to graduate medical doctors who are able to self-regulate their learning. It is therefore important to investigate whether medical students' self-regulated learning skills change during medical school. In addition, since these skills are expected to be helpful to learn more effectively, it is of interest to investigate whether these skills are related to academic performance.Methods: In a cross-sectional design, the Self-Regulation of Learning Self-Report Scale (SRL-SRS) was used to investigate the change in students' self-regulated learning skills. First and third-year students (N=949, 81.7%) SRL-SRS scores were compared with ANOVA. The relation with academic performance was investigated with multinomial regression analysis.Results: Only one of the six skills, reflection, significantly, but positively, changed during medical school. In addition, a small, but positive relation of monitoring, reflection, and effort with first-year GPA was found, while only effort was related to third-year GPA.Conclusions: The change in self-regulated learning skills is minor as only the level of reflection differs between the first and third year. In addition, the relation between self-regulated learning skills and academic performance is limited. Medical schools are therefore encouraged to re-examine the curriculum and methods they use to enhance their students' self-regulated learning skills. Future research is required to understand the limited impact on performance.

Recent findings demonstrate that the effects of ghrelin can be abrogated by co-administered unacylated ghrelin (UAG). Since the general consensus is that UAG does not interact with the type 1a growth hormone secretagogue receptor (GHS-R), a possible mechanism of action for this antagonistic effect is via another receptor. However, functional antagonism of the GHS-R by UAG has not been explored extensively. In this study we used human GHS-R and aequorin expressing CHO-K1 cells to measure [Ca(2+)](i) following treatment with UAG. UAG at up to 10(-5)M did not antagonize ghrelin induced [Ca(2+)](i). However, UAG was found to be a full agonist of the GHS-R with an EC(50) of between 1.6 and 2 microM using this in vitro system. Correspondingly, UAG displaced radio-labeled ghrelin from the GHS-R with an IC(50) of 13 microM. In addition, GHS-R antagonists were found to block UAG induced [Ca(2+)](i) with approximately similar potency to their effect on ghrelin activation of the GHS-R, suggesting a similar mode of action. These findings demonstrate in a defined system that UAG does not antagonize activation of the GHS-R by ghrelin. But our findings also emphasize the importance of assessing the concentration of UAG used in both in vitro and in vivo experimental systems that are aimed at examining GHS-R independent effects. Where local concentrations of UAG may reach the high nanomolar to micromolar range, assignment of GHS-R independent effects should be made with caution.

Background: Anti-Müllerian hormone (AMH) inhibits primordial follicle recruitment in the mouse ovary. We hypothesize that in women AMH signaling also regulates the usage of the primordial follicle pool and hence influences the onset of menopause. Since age at menopause has a strong genetic component, we investigated the role of AMH signaling using a candidate gene approach. Methods: In two large population-based cohorts of Dutch post-menopausal women (n = 2381 and n = 248), we examined the association between two polymorphisms, one in the AMH gene and one in the AMH type II receptor (AMHR2) gene, and natural age at menopause. Results: The AMH Ile49Ser polymorphism (rs10407022) was not associated with age at menopause in either cohort. In the Rotterdam cohort, the AMHR2 -482 A > G polymorphism (rs2002555) was associated with age at menopause in interaction with the number of offspring (P = 0.001). Nulliparous women homozygous for the G-allele entered menopause 2.6 years earlier compared with nulliparous women homozygous for the A-allele (P = 0.005). In the LASA cohort, women with the G/G genotype tended to enter menopause 2.8 years earlier compared with the A/A genotype (P = 0.063). Conclusions: The observed association of the AMHR2 -482 A > G polymorphism with natural age at menopause suggests a role for AMH signaling in the usage of the primordial follicle pool in women.

Ghrelin is produced by the gastrointestinal tract, and its systemic concentrations are mainly regulated by nutritional factors. Our aim was to investigate: 1) endogenous portal and systemic acylated and unacylated ghrelin levels (AG and UAG, respectively); 2) whether an iv glucose tolerance test (IVGTT) modifies AG and UAG; and 3) whether the liver passage plays a role in regulating systemic AG and UAG. To elucidate this, we evaluated the effects of IVGTT or saline injection on endogenous portal and systemic concentrations of glucose, insulin, AG, and UAG in anesthetized fasting rats. Hepatic extraction of insulin, AG, and UAG and the ratio of AG to UAG were also measured. IVGTT suppressed both portal (P < 0.03) and peripheral (P < 0.05) UAG, whereas it only blunted prehepatic, but not peripheral, AG. During fasting, hepatic clearance of UAG was 11%, and it was decreased to 8% by IVGTT. AG was cleared by the liver by 38% but unaffected by glucose. The AG to UAG ratio was higher in the portal than the systemic circulation, both in the saline (P < 0.004) and IVGTT (P < 0.0005) rats. In conclusion, this study shows that: 1) the ratio of AG to UAG is very low in the portal vein and decreases further in the systemic circulation; 2) IVGTT in anesthetized fasting rats inhibits UAG, whereas it only blunts prehepatic, but not systemic, AG; and 3) hepatic clearance of AG is much higher than that of UAG. Thus, our results suggest that peripheral AG metabolic regulation and action are mainly confined within the gastrointestinal tract.

Rising serum FSH levels is one of the earliest signs of human female reproductive aging. Whether or not elevated FSH remains a passive reflection of a diminishing ovarian follicle pool or actively contributes to declining female fertility with age has not been established. We therefore investigated female reproduction in mice expressing progressively rising serum levels of transgenic human FSH (Tg-FSH, 2.5–10 IU/liter) independently of follicle depletion. We show that serum LH and estradiol levels and uterine size remained normal in Tg-FSH females, whereas ovarian weight and corpora lutea number were significantly increased up to 1.3- and 5-fold, respectively. Furthermore, the monotrophic FSH rise produced a striking biphasic effect on female fertility. Tg-FSH females less than 22 wk old delivered increased litter sizes, then beyond 23 wk, litter sizes decreased rapidly culminating in premature infertility despite continued ovary follicle development, and increased ovulation and uterine embryo implantation sites as well as normal serum levels of anti-Mullerian hormone, a marker of ovarian follicle reserve. We found that rising circulating Tg-FSH produced premature infertility by increasing embryo-fetal resorption and parturition failure with age. Thus, our Tg-FSH mice present a novel paradigm to investigate selective contributions of elevated FSH to age-related female infertility, which revealed that rising FSH levels, despite no exhaustion of ovarian reserve, actively accelerates female reproductive aging primarily by postimplantation reduction of embryo-fetal survival.

BACKGROUND: Ovarian failure as a complication of uterine artery embolization (UAE) for symptomatic uterine fibroids has raised concerns about this new treatment modality.METHODS: We investigated the occurrence of ovarian reserve reduction in a randomized trial comparing UAE and hysterectomy by measuring follicle stimulating hormone (FSH) and anti-Mullerian hormone (AMH). A total of 177 pre-menopausal women with menorrhagia due to uterine fibroids were included (UAE:n=88; hysterectomy:n=89). FSH and AMH were measured at baseline and at several time-points during the 24 months follow-up period. Follow-up AMH levels were also compared to the expected decrease due to ovarian ageing during the observational period.RESULTS: FSH increased significantly compared to baseline in both groups after 24 months follow-up (within group analysis: UAE:+12.1; P=0.001; hysterectomy:+16.3; P40 IU/l was 14/80 in the UAE group and 17/73 in the hysterectomy group (relative risk=0.75; P=0.37). AMH was measured in 63 patients (UAE: n=30; hysterectomy: n=33). After treatment AMH levels remained significantly decreased during the entire follow-up period only in the UAE group compared to the expected AMH decrease due to ageing. No differences were observed between the groups.CONCLUSIONS: This study shows that both UAE and hysterectomy affect ovarian reserve. This results in older women becoming menopausal after the intervention. Therefore, the application of UAE in women who still wish to conceive should only be considered after appropriate counselling.

ContextDespite evidence for the predictive value of both pre-admission characteristics and past performance at medical school, their relative contribution to predicting medical school performance has not been thoroughly investigated.ObjectivesThis study was designed to determine the relative importance of pre-admission characteristics and past performance in medical school in predicting student performance in pre-clinical and clinical training.MethodsThis longitudinal prospective study followed six cohorts of students admitted to a Dutch, 6-year, undergraduate medical course during 2002-2007 (n=2357). Four prediction models were developed using multivariate logistic regression analysis. Main outcome measures were Year1 course completion within 1year' (models 1a, 1b), Pre-clinical course completion within 4years' (model 2) and Achievement of at least three of five clerkship grades of 8.0' (model 3). Pre-admission characteristics (models 1a, 1b, 2, 3) and past performance at medical school (models 1b, 2, 3) were included as predictor variables.ResultsIn model 1a - including pre-admission characteristics only - the strongest predictor for Year1 course completion was pre-university grade point average (GPA). Success factors were selected by admission testing' and age>21years'; risk factors were Surinamese/Antillean background', foreign pre-university degree', doctor parent' and male gender. In model 1b, number of attempts and GPA at 4months were the strongest predictors for Year1 course completion, and male gender remained a risk factor. Year1 GPA was the strongest predictor for pre-clinical course completion, whereas being male or aged 19-21years were risk factors. Pre-clinical course GPA positively predicted clinical performance, whereas being non-Dutch or a first-generation university student were important risk factors for lower clinical grades. Nagelkerke's R-2 ranged from 0.16 to 0.62.ConclusionsThis study not only confirms the importance of past performance as a predictor of future performance in pre-clinical training, but also reveals the importance of a student's background as a predictor in clinical training. These findings have important practical implications for selection and support during medical school.