91 research outputs found
Gekend Talent
Rede,
in verkorte vorm uitgesproken
ter gelegenheid van het aanvaarden van het ambt
van bijzonder hoogleraar met als leeropdracht
Experimentele endocrinologie en medisch onderwijs
aan het Erasmus MC, faculteit van de
Erasmus Universiteit Rotterdam
op 11 mei 2009
Mutations of gonadotropins and gonadotropin receptors: elucidating the physiology and pathophysiology of pituitary-gonadal function
The recent unraveling of structures of genes for the gonadotropin subunits
and gonadotropin receptors has provided reproductive endocrinologists with
new tools to study normal and pathological functions of the
hypothalamic-pituitary-gonadal axis. Rare inactivating mutations that
produce distinctive phenotypes of isolated LH or FSH deficiency have been
discovered in gonadotropin subunit genes. In addition, there is a common
polymorphism in the LHbeta subunit gene with possible clinical
significance as a contributing factor to pathologies of LH-dependent
gonadal functions. Both activating and inactivating mutations have been
detected in the gonadotropin receptor genes, a larger number in the LH
receptor gene, but so far only a few in the gene for the FSH receptor.
These mutations corroborate and extend our knowledge of clinical
consequences of gonadotropin resistance and inappropriate gonadotropin
action. The information obtained from human mutations has been
complemented by animal models with disrupted or inappropriately activated
gonadotropin ligand or receptor genes. These clinical and experimental
genetic disease models form a powerful tool for exploring the physiology
and pathophysiology of gonadotropin function and provide an excellent
example of the power of molecular biological approaches in the study of
pathogenesis of diseases
Transducing systems in the hormonal regulation of steroidogenesis in rat Leydig cells
The studies described in this thesis have mainly been concerned
with the elucidation of several of the second messenger
systems present in the Leydig cell and the regulation of
steroidogenesis through pathways that involve cAMP and calcium
ions as second messengers. A general, albeit simplified scheme
for transmembrane signalling which result in stimulation of
steroid production is given in figure 1 .1.
To affect Leydig cell function specific stimulators
(dbcAMP, phorbol esters etc.} or inhibitors (P-site agonists,
diltiazem etc.) of the different second messenger systems were
used in addition to physiological stimuli. The effects of these
probes were measured by determining (1) the activity of adenylate
cyclase through measurements of the intracellular levels of
cAMP, {2) the activity of protein kinases by studying electrophoresis
patterns of proteins labelled with 32Po
4
, (3) stimulation
of de novo protein synthesis by studying the electrophoretic
patterns of proteins labelled with 35s-methionine and
(4) the activity of the cholesterol side chain cleavage enzyme
by measuring the production of pregnenolone from endogenous
precursors.
The results of these studies are described in detail in
chapters 3-6 and in the appendix papers 1, 2, 4 and the
appendix chapter. Results of studies on the involvement of cAMP
and calcium as second messengers in LH action are described in
chapter 4. The mechanism of action of LHRH is discussed in
chapter 5 and data on the presence of GTP-binding proteins N s
and Ni in Leydig cells are given in chapter 6. In chapter 7 an
integrated model of the regulation of properties of Leydig cell
function is discussed with special
derived from the results in
summarize
Regulation of gonadotropin receptor gene expression
The receptors for the gonadotropins differ from the other G protein-coupled receptors by having a large extracellular hormone-binding domain, encoded by nine or ten exons. Alternative splicing of the large pre-mRNA of approximately 100 kb can result in mRNA species that encode truncated receptor proteins. In this review we discuss the regulation of gonadotropin receptor mRNA expression and the possible roles of alternative splicing in gonadotropin receptor function
Regulation of ovarian function: the role of anti-Mullerian hormone
Anti-Mullerian hormone (AMH), also known as Mullerian inhibiting
substance, is a member of the transforming growth factor beta superfamily
of growth and differentiation factors. In contrast to other members of the
family, which exert a broad range of functions in multiple tissues, the
principal function of AMH is to induce regression of the Mullerian ducts
during male sex differentiation. However, the patterns of expression of
AMH and its type II receptor in the postnatal ovary indicate that AMH may
play an important role in ovarian folliculogenesis. This review describes
several in vivo and in vitro studies showing that AMH participates in two
critical selection points of follicle development: it inhibits the
recruitment of primordial follicles into the pool of growing follicles and
also decreases the responsiveness of growing follicles to FSH
Ethnic and social disparities in different types of examinations in undergraduate pre-clinical training
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
The relationship between extracurricular activities assessed during selection and during medical school and performance
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
Alternative splicing of follicle-stimulating hormone receptor pre-mRNA: cloning and characterization of two alternatively spliced mRNA transcripts
Glycoprotein hormone receptors contain a large extracellular domain that
is encoded by multiple exons, facilitating the possibility of expressing
alternatively spliced transcripts. We have cloned two new splice variants
of the rat follicle-stimulating hormone (FSH) receptor gene: FSH-R1 and
FSH-R2. The splice variant FSH-R1 differs from the full-length FSH
receptor mRNA by the inclusion of a small extra exon between exons 9 and
10. FSH-R2 lacks the first three base pairs o
Regulation of gene expression in Sertoli cells by follicle-stimulating hormone (FSH): Cloning and characterization of LRPR1, a primary response gene encoding a leucine-rich protein
Searching for hormone-regulated genes in testicular Sertoli cells, we cloned and sequenced a cDNA of 3108 base pairs, named LRPR1 (signifying leucine-rich primary response gene 1). This cDNA sequence has an open reading frame of 2238 base pairs encoding a leucine-rich protein of 746 amino acid residues with a relative molecular mass of 85.6 kDa. As much as 16% of the amino acid residues is leucine. Database analysis revealed significant similarity of LRPR1 to the human brain cDNA sequence EST00443, but not to any other sequences present in databases. The expression of LRPR1 mRNA in Sertoli cells is strongly and rapidly up-regulated by follicle-stimulating hormone (FSH). The level of LRPR1 mRNA was very low in Sertoli cells isolated from 21-day-old rats and cultured for 3 days in the absence of FSH, but LRPR1 mRNA expression was markedly increased within 2 h after addition of FSH to these cultures. A maximal response was reached within 4 h. Dibutyryl-cyclic AMP [(Bu)2cAMP] and forskolin had similar effects compared to FSH, indicating that cAMP acts as a second messenger in the regulation of LRPR1 expression. The up-regulation of LRPR1 mRNA expression by FSH was also observed in the presence of the protein synthesis inhibitor cycloheximide, indicating that FSH regulates LRPR1 mRNA expression through a direct mechanism which does not require de novo protein synthesis. Thus, LRPR1 represents a primary response gene in FSH action on Sertoli cells. The presently available data indicate that LRPR1 mRNA expression is regulated specifically by FSH, since several other hormones and growth factors did not affect LRPR1 mRNA expression in the cultured Sertoli cells. LRPR1 mRNA expression is relatively high in testis, ovary and spleen. A much lower mRNA level was found in brain and lung, and no expression was detected in liver, kidney, heart, muscle, pituitary gland, prostate, epididymis and seminal vesicle. The basal level of testicular LRPR1 expression in intact 21-day-old rats was markedly increased within several hours after a single i.p. injection of FSH, indicating that in vivo LRPR1 mRNA expression may appear to be a useful parameter to evaluate testicular FSH action
Integrity situational judgement test for medical school selection
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
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