Context:
GLIS3 (GLI-similar 3) is a member of the GLI-similar zinc finger protein family encoding for a nuclear protein with 5 C2H2-type zinc finger domains. The protein is expressed early in ...embryogenesis and plays a critical role as both a repressor and activator of transcription. Human GLIS3 mutations are extremely rare.
Objective:
The purpose of this article was determine the phenotypic presentation of 12 patients with a variety of GLIS3 mutations.
Methods:
GLIS3 gene mutations were sought by PCR amplification and sequence analysis of exons 1 to 11. Clinical information was provided by the referring clinicians and subsequently using a questionnaire circulated to gain further information.
Results:
We report the first case of a patient with a compound heterozygous mutation in GLIS3 who did not present with congenital hypothyroidism. All patients presented with neonatal diabetes with a range of insulin sensitivities. Thyroid disease varied among patients. Hepatic and renal disease was common with liver dysfunction ranging from hepatitis to cirrhosis; cystic dysplasia was the most common renal manifestation. We describe new presenting features in patients with GLIS3 mutations, including craniosynostosis, hiatus hernia, atrial septal defect, splenic cyst, and choanal atresia and confirm further cases with sensorineural deafness and exocrine pancreatic insufficiency.
Conclusion:
We report new findings within the GLIS3 phenotype, further extending the spectrum of abnormalities associated with GLIS3 mutations and providing novel insights into the role of GLIS3 in human physiological development. All but 2 of the patients within our cohort are still alive, and we describe the first patient to live to adulthood with a GLIS3 mutation, suggesting that even patients with a severe GLIS3 phenotype may have a longer life expectancy than originally described.
Aim
To assess the effect of a 5–day structured education course (Kids in Control of Food; KICk–OFF) on biomedical and psychological outcomes in young people with Type 1 diabetes.
Methods
This was a ...cluster‐randomized trial involving 31 UK paediatric centres. Participants were recruited prior to stratified centre randomization. Intervention centres delivered KICk–OFF courses, whereas control centres delivered usual care. Participants were 11–16 years of age and had Type 1 diabetes for at least one year. The KICk–OFF course was delivered by trained educators to eight participants per course. Glycaemic control and quality of life were measured at baseline, 6, 12 and 24 months. Secondary outcomes were hypoglycaemia, ketoacidosis, fear of hypoglycaemia and diabetes self‐efficacy.
Results
Three hundred and ninety‐six participants provided baseline data (199 intervention and 197 control). At 6 and 12 months the intervention group showed significantly improved total generic quality of life scores compared with controls (baseline: 80 vs. 82; 6 months: 82 vs. 82; P = 0.04). Across the whole intervention group mean HbA1c levels were not significantly different from controls; baseline HbA1c mean (95% confidence interval), 78 mmol/mol (75–81) vs. 76 mmol/mol (74–79) 9.3% (9–9.6%) vs. 9.1% (8.9–9.4%); 24 months: 77 mmol/mol (74–79) vs. 78 mmol/mol (75–81) (9.2% (8.9–9.4%) vs. 9.3% (9–9.6%), adjusted mean difference, –2.0 mmol/mol (6.5–2.5) 2.3% (–2.7% to 2.4%), P = 0.38.
Conclusions
Attending a KICk–OFF course was associated with significantly improved total quality of life scores within 6 months. Glycaemic control, as measured by HbA1c, was no different at 24 months. (Clinical Trial Registry No: ISRCTN3704268)
What's new?
KICk–OFF is based on the Dose Adjustment For Normal Eating (DAFNE) programme which is widely available to adults in the NHS. There are no validated courses for children and young people.
The KICk–OFF study is the first randomized controlled trial of intensive structured education in adolescents with Type 1 diabetes. Although recruitment to the study was a challenge, retention within the 5–day course was very good suggesting that it is possible to engage this age group in intensive group education.
National audits have shown that there is a large UK cohort of young people who would potentially benefit from participation in a KICk–OFF course.
We conducted a proof-of-concept, randomized, controlled trial to investigate the effects of a supervised exercise therapy intervention on psychopathologic outcomes in obese adolescents.
The ...participant sample consisted of 81 adolescents (age: 11-16 years) who had been referred to a children's hospital for evaluation of obesity or who responded to a community advertisement. Participants were assigned randomly to exercise therapy, an equal-contact exercise placebo intervention, or usual care. Intervention participants attended 3 one-on-one sessions per week for 8 weeks and then completed a home program for another 6 weeks. Outcomes included self-perceptions (self-esteem), depression, affect, physical activity, aerobic fitness, and BMI.
A total of 18 of 81 participants were categorized as morbidly obese (BMI SD score: > 3.5; adult equivalent BMI: > or = 40). At baseline, 30.3% of participants had a Children's Depression Inventory score of > or = 13, and 27% reported recent suicidal ideation. Repeated-measures mixed analysis of covariance (controlling for baseline scores) revealed significant changes in physical self-worth, associated measures of self-esteem, and physical activity over time, consistently favoring exercise therapy. There were no significant changes in BMI.
Findings confirmed psychopathologic conditions as a serious health concern in obese and morbidly obese adolescents. Our study is the first randomized, controlled trial to demonstrate that a brief supervised exercise therapy intervention has the potential to improve psychopathologic outcomes significantly and to increase physical activity in obese adolescents, relative to usual care.
This note establishes, first of all, the monotonic increase with
N
of the average
K
-body energy of classical
N
-body ground state configurations with
N
≥
K
monomers that interact solely through a ...permutation-symmetric
K
-body potential, for any fixed integer
K
≥
2
. For the special case
K
=
2
this result had previously been proved, and used successfully as a test criterion for optimality of computer-generated lists of putative ground states of
N
-body clusters for various types of pairwise interactions. Second, related monotonicity results are established for
N
-monomer ground state configurations whose monomers interact through additive mixtures of certain types of
k
-meric potentials,
k
∈
{
1
,
…
,
K
}
, with
K
≥
2
fixed and
N
≥
K
. All the monotonicity results furnish simple necessary conditions for optimality that any pertinent list of computer-generated putative global minimum energies for
N
-monomer clusters has to satisfy. As an application, databases of
N
-body cluster energies computed with an additive mix of the dimeric Lennard–Jones and trimeric Axilrod–Teller interactions are inspected. We also address how many local minima satisfy the upper bound inferred from the monotonicity conditions, both from a theoretical and from an empirical perspective.
We have assessed the impact of α-synuclein overexpression on the differentiation potential and phenotypic signatures of two neural-committed induced pluripotent stem cell lines derived from a ...Parkinson's disease patient with a triplication of the human SNCA genomic locus. In parallel, comparative studies were performed on two control lines derived from healthy individuals and lines generated from the patient iPS-derived neuroprogenitor lines infected with a lentivirus incorporating a small hairpin RNA to knock down the SNCA mRNA. The SNCA triplication lines exhibited a reduced capacity to differentiate into dopaminergic or GABAergic neurons and decreased neurite outgrowth and lower neuronal activity compared with control cultures. This delayed maturation phenotype was confirmed by gene expression profiling, which revealed a significant reduction in mRNA for genes implicated in neuronal differentiation such as delta-like homolog 1 (DLK1), gamma-aminobutyric acid type B receptor subunit 2 (GABABR2), nuclear receptor related 1 protein (NURR1), G-protein-regulated inward-rectifier potassium channel 2 (GIRK-2) and tyrosine hydroxylase (TH). The differentiated patient cells also demonstrated increased autophagic flux when stressed with chloroquine. We conclude that a two-fold overexpression of α-synuclein caused by a triplication of the SNCA gene is sufficient to impair the differentiation of neuronal progenitor cells, a finding with implications for adult neurogenesis and Parkinson's disease progression, particularly in the context of bioenergetic dysfunction.
Patients with permanent neonatal diabetes usually present within the first three months of life and require insulin treatment. In most, the cause is unknown. Because ATP-sensitive potassium (K(ATP)) ...channels mediate glucose-stimulated insulin secretion from the pancreatic beta cells, we hypothesized that activating mutations in the gene encoding the Kir6.2 subunit of this channel (KCNJ11) cause neonatal diabetes.
We sequenced the KCNJ11 gene in 29 patients with permanent neonatal diabetes. The insulin secretory response to intravenous glucagon, glucose, and the sulfonylurea tolbutamide was assessed in patients who had mutations in the gene.
Six novel, heterozygous missense mutations were identified in 10 of the 29 patients. In two patients the diabetes was familial, and in eight it arose from a spontaneous mutation. Their neonatal diabetes was characterized by ketoacidosis or marked hyperglycemia and was treated with insulin. Patients did not secrete insulin in response to glucose or glucagon but did secrete insulin in response to tolbutamide. Four of the patients also had severe developmental delay and muscle weakness; three of them also had epilepsy and mild dysmorphic features. When the most common mutation in Kir6.2 was coexpressed with sulfonylurea receptor 1 in Xenopus laevis oocytes, the ability of ATP to block mutant K(ATP) channels was greatly reduced.
Heterozygous activating mutations in the gene encoding Kir6.2 cause permanent neonatal diabetes and may also be associated with developmental delay, muscle weakness, and epilepsy. Identification of the genetic cause of permanent neonatal diabetes may facilitate the treatment of this disease with sulfonylureas.
Summary
Context Increasing numbers of very low birth weight (VLBW) infants are surviving into adulthood because of improvements in neonatal intensive care. Adverse events in early life can have ...long‐term effects through reprogramming of metabolic systems.
Objective To determine whether young adult VLBW survivors have abnormalities of skeletal development or endocrine function.
Design Cross‐sectional, observational, case‐control study.
Participants Thirty‐seven VLBW subjects and 27 healthy controls at peak bone mass (mean age 23).
Measurements Differences between cases and controls in body size, body composition, bone mass and bone geometry assessed by dual‐energy X‐ray absorptiometry (DXA), hip structure analysis and peripheral quantitative computed tomography (pQCT), bone turnover urine N‐terminal telopeptide of type I collagen (NTX), serum C‐terminal telopeptide of type I collagen (CTX), aminoterminal propeptide of type I procollagen (PINP) and bone alkaline phosphatase), hormones (sex steroids, IGF‐1, PTH and 25‐OH vitamin D) and insulin sensitivity (HOMA‐IR and oral glucose tolerance testing).
Results VLBW subjects had lower bone density at the lumbar spine (5.7%) and femoral neck (8.6%), which persisted after correction for bone size by the estimation of volumetric density (bone mineral apparent density). Urine NTX was higher in VLBW subjects than in controls, but there were no significant differences in other bone turnover markers. VLBW survivors had lower insulin sensitivity (mean INS‐30 controls = 57.0, VLBW subjects = 94.3, P < 0.01), but there were no differences in whole body fat mass or truncal fat mass between VLBW subjects and controls.
Conclusions Young adult VLBW survivors have reduced bone density for their bone size and reduced insulin sensitivity, which may have significant implications for their risk of fracture and diabetes in later life.
Context
Measuring testicular volume (TV) by orchidometer is the standard method of male pubertal staging. A paucity of evidence exists as to its inter‐ and intra‐observer reliability and the impact ...of clinicians’ gender, training and experience on accuracy.
Objective
Prosthetic testicular models were engineered to investigate accuracy and reliability of TV estimation.
Design
Simulation study.
Setting
Conducted over three‐day 2015 British Society for Paediatric Endocrinology and Diabetes (BSPED) meeting.
Participants
Two hundred fifteen meeting delegates (161F, 54M): 50% consultants, 30% trainees, 9% clinical nurse specialists, 11% other professionals.
Intervention
Three child‐sized mannequins displayed latex scrotum containing prosthetic testicles of 3, 4, 5, 10 and 20 mL. Demographic data, paediatric endocrinology experience, TV examination training, examination technique and TV estimations were collected. Delegates were asked to repeat their measurements later during the meeting. Scrotum order was changed daily.
Main outcome measures
Accuracy by variance from the simulated TV. Inter‐ and intra‐observer variability.
Results
One thousand two hundred eighty four individual estimations were obtained. Eighty‐five participants repeated measurements. Delegates measured TV accurately on 33.4% (±2.6) of occasions: overestimations 37% (±2.3), underestimations 28% (±1.8) (Fleiss’ Kappa score 0.04). The accuracy of assessing a 4 mL testis was 36%‐39%. Observers underestimated the volume when paired with a 3 mL testis and overestimated when paired with a 5 mL testis demonstrating a tendency impose biological symmetry. Intra‐observer reliability was lacking; individuals giving different estimations for the same size testicle on 61% (±4.2) of occasions, 20% (±3.5) of estimations were more than 1 size outside the previous measurement. On only 39% (±4.2) of occasions did individuals agree with their previous estimation (irrespective of whether or not it was initially accurate). Training did not impact on results but experience did improve accuracy.
Conclusions
Overall TV estimation accuracy was poor. Considerable variation exists between and within subjects. Seniority slightly improved measurement estimation.
Free energy basin-hopping Sutherland-Cash, K.H.; Wales, D.J.; Chakrabarti, D.
Chemical physics letters,
04/2015, Letnik:
625
Journal Article
Recenzirano
Odprti dostop
Display omitted
•A global optimisation scheme is presented based upon approximate local free energies.•The implementation employs basin-hopping with a modified acceptance condition.•Example ...applications are presented for atomic clusters and peptides.•Low-lying free energy minima are efficiently identified.
A global optimisation scheme is presented using basin-hopping with the acceptance criterion based on approximate free energy for the corresponding local minima of the potential energy. The method is illustrated for atomic and colloidal clusters and peptides to examine how the predicted global free energy minimum changes with temperature. Using estimates for the local free energies based on harmonic vibrational densities of states provides a computationally effective framework for predicting trends in structure at finite temperature. The resulting scheme represents a powerful tool for exploration of energy landscapes throughout molecular science.
During early mouse development the homeobox gene Hesx1 is expressed in prospective forebrain tissue, but later becomes restricted to Rathke's pouch, the primordium of the anterior pituitary gland. ...Mice lacking Hesx1 exhibit variable anterior CNS defects and pituitary dysplasia. Mutants have a reduced prosencephalon, anopthalmia or micropthalmia, defective olfactory development and bifurcations in Rathke's pouch. Neonates exhibit abnormalities in the corpus callosum, the anterior and hippocampal commissures, and the septum pellucidum. A comparable and equally variable phenotype in humans is septo-optic dysplasia (SOD). We have cloned human HESX1 and screened for mutations in affected individuals. Two siblings with SOD were homozygous for an Arg53Cys missense mutation within the HESX1 homeodomain which destroyed its ability to bind target DNA. These data suggest an important role for Hesx1/HESX1 in forebrain, midline and pituitary development in mouse and human.
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