22 research outputs found
An update on the long-term outcomes of prenatal dexamethasone treatment in congenital adrenal hyperplasia
First-trimester prenatal treatment with glucocorticoid (GC) dexamethasone (DEX) in pregnancies at risk for classic congenital adrenal hyperplasia (CAH) is associated with ethical dilemmas. Though effective in reducing virilisation in g irls with CAH, it entails exposure to high doses of GC in fetuses that do not benefit from the treatment. The current paper provides an update on the literature on outcomes of prenatal DEX treatment in CAH cases and unaffected subjects. Long-term follow-up resear ch is still needed to determine treatment safety. In addition, advances in early prenatal diagnostics for CAH and sex-typing as well as studies assessing dosing effects of DE X may avoid unnecessary treatment and improve treatment safety
Incentivizing the Dynamic Workforce: Learning Contracts in the Gig-Economy
In principal-agent models, a principal offers a contract to an agent to
perform a certain task. The agent exerts a level of effort that maximizes her
utility. The principal is oblivious to the agent's chosen level of effort, and
conditions her wage only on possible outcomes. In this work, we consider a
model in which the principal is unaware of the agent's utility and action
space. She sequentially offers contracts to identical agents, and observes the
resulting outcomes. We present an algorithm for learning the optimal contract
under mild assumptions. We bound the number of samples needed for the principal
obtain a contract that is within of her optimal net profit for every
Molecular analysis of mutated P450c21 in congenital adrenal hyperplasia
Defects in cytochrome P450c21 (21-hydroxylase, 210H) are the most common
causes of congenital adrenal hyperplasia (CAH). This recessively
inherited disorder demonstrates a wide spectrum of severity as a
consequence of impaired production of cortisol and aldosterone and
excessive secretion of adrenal androgens. A limited number of mutations
accounts for the majority (95%) of mutated alleles and genetic
diagnostics based on detection of these common mutations is well
established. However, additional rare mutations, usually specific for a
single family or population, are responsible for this disorder in certain
patients. Severe forms of 210H deficiency result in prenatal virilizing
malformations of external genitalia in affected girls. In an attempt to
prevent these malformations and avoid reconstructive surgery, prenatal
treatment with dexamethasone (DEX) has been employed. Because eukaryotic
cytochromes P450 are integral membrane proteins, it has been difficult to
purify and crystallize these proteins in order to determine their three
dimensional structures. Useful predictions regarding structure-function
relationships for P450c21 can be obtained by studying bacterial members
of the cytochrome P450 family, in combination with functional analyses of
different P450c21 mutants affecting structurally and/or functionally
important residues of the protein.
Using the approaches of site-directed mutagenesis and transient
expression in COS-I cells, the functional consequences of eight novel
missense mutations in CYP21 have been characterized. All of these mutant
proteins demonstrated impaired enzyme function and were thus responsible
for the disease in the patients in whom they were identified. The degree
of functional impairment was generally in agreement with the severity of
the symptoms displayed by the patient. By direct sequencing of CYP21,
genetic diagnostics was provided for families who do not segregate the
common mutations.
The P105L and P453S mutations were found on the same allele in two
siblings with late-onset disease. Functional studies of each of these
mutant proteins individually revealed an enzymatic activity which was
60-70% of the wild-type, while these two mutations in combination acted
in a synergistic manner to reduce the enzymatic activity to 10%. The
exact mechanism underlying the functional impairment for these mutant
enzymes is not fully understood, since only the Vmax and not the KM value
was affected. Loss of proline residues might disrupt the
three-dimensional structures of the proteins, resulting in reduced
stability. If only one of these mutations is present in a patient with
CAH, the phenotype will most likely be subtle, not including prenatal
virilization. Two other mutations (R356P and R356Q) were identified at
the same position of P450c21. R356P (0.15% of wild-type activity) was
found in a boy with the most severe form of the disease and R356Q (0.65%
activity) was present in a girl with prenatal virilization but no salt
loss. The region where these mutations are located is likely to be
involved in interaction with the NADPH-cytochrome P450 reductase. With
this addition of R356P and R356Q, there is a clear clustering of missense
mutations in arginine residues in this portion of P450c21, supporting the
concept that the region is involved in interactions with redox partners,
since such interactions apparently involve charged amino acid residues.
Other structurally and/or functionally important portions of P450c21
include the regions where the mutations delE196, G291S and R483P are
located. The delE196 and R483P mutant proteins retained some enzymatic
activity and were found in patients with more moderate disease
manifestations. These mutant proteins were more rapidly degraded in COS-I
cells, as assessed by pulse-chase experiments followed by
immunoprecipitation. Thus, the decreased catalytic capacity may be
explained by altered protein structure and consequently reduced levels of
these mutant forms of P450c21. In the bacterial enzymes P450BM-3 and
P450cam, the residue corresponding to G291 of P450c21 has been proposed
to participate in the electron transfer required for catalysis. Our data
on the function of the G291S mutant suggest that this residue is indeed
essential for maintainance of enzyme activity. One fundamental difference
between prokaryotic and eukaryotic P450s is the membrane localization of
the latter. Membrane-anchoring of P450c21 was determined using cell-free
in vitro transcription-translation in the presence of microsomal
membranes. Our data indicate that P450c21 binds to the endoplasmic
reticulum via only one trans-membrane domain in the most proximal
amino-terminal portion of the protein, in agreement with previous
reports. We have also demonstrated that the polymorphism (-L10) and the
severe P30Q mutation, found in the first and second hydrophobic segments
of P450c21 respectively, do not impair the membrane-binding capacity of
the protein.
Scandinavian experience (44 cases) with prenatal treatment of CAH
indicates that such treatment is effective in preventing virilization in
affected females. The majority of treated children are born normal in
size and they develop and grow normally, compared to untreated controls.
However, several adverse events were observed in treated children, such
as failure to thrive and late psychomotor development. Women receiving
DEX report more side-effects and gain more weight during early pregnancy
when treatment is initiated. Therefore, until more experience is gained
this treatment must still be considered to be experimental and
prospective studies should be designed to exclude possible negative
effects on the mother and child
The Success of a Screening Program Is Largely Dependent on Close Collaboration between the Laboratory and the Clinical Follow-Up of the Patients
Neonatal screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency is now performed in an increasing number of countries all over the world. The main goal of the screening is to achieve early diagnosis and treatment in order to prevent neonatal salt-crisis and death. The screening laboratory can also play an important role in increasing the general awareness of the disease and act as the source of information and education for clinicians to facilitate improved initial care, ensure prompt and correct glucocorticoid dosing to optimize the long-term outcome for the patients. A National CAH Registry and CYP21A2 genotyping provide valuable information both for evaluating the screening program and the clinical outcome. The Swedish experience is described
Young adult Swedish patients with autoimmune Addison's disease report difficulties with executive functions in daily life despite overall good cognitive performance
Objectives: Sub-optimal replacement of glucocorticoids (GC) in autoimmune Addison's disease (AAD) may affect cognitive functioning. The present study therefore sought to investigate cognitive performance and self-reported problems with executive functions in a cohort of young adult patients with AAD. Design and methods: 67 patients with AAD (39 females), mean age 32 yrs. (range 19–41), and 80 control participants (43 females), mean age 29 yrs. (range 19–43), completed neuropsychological tests estimating verbal and non-verbal intellectual ability, learning, memory and executive functioning, in addition to self-report scales assessing problems with executive functions, fatigue and symptoms of anxiety and depression. Results: Patients performed within the average range on all cognitive tests compared to population norms. However, female AAD patients reported more problems than controls with both hot (emotion regulation) and cold (cognitive regulation) executive functions in daily life. Moreover, experienced problems with executive functions in both male and female patients were associated with increased mental fatigue and lower GC replacement doses. Conclusions: Despite average performance in neuropsychological tests by both sexes, young adult female patients with AAD experience problems with executive functions in daily life. Coping with mental fatigue and optimization of pharmacotherapy may be important factors to be addressed in order to provide timely support for patients. Future research is needed to further determine other risk factors for experiencing executive function impairments in AAD