Pancreatic endocrine and exocrine function in children following near-total pancreatectomy for diffuse congenital hyperinsulinism.

Published onlineJournal ArticleCONTEXT: Congenital hyperinsulinism (CHI), the commonest cause of persistent hypoglycaemia, has two main histological subtypes: diffuse and focal. Diffuse CHI, if medically unresponsive, is managed with near-total pancreatectomy. Post-pancreatectomy, in addition to persistent hypoglycaemia, there is a very high risk of diabetes mellitus and pancreatic exocrine insufficiency. SETTING: International referral centre for the management of CHI. PATIENTS: Medically unresponsive diffuse CHI patients managed with near-total pancreatectomy between 1994 and 2012. INTERVENTION: Near-total pancreatectomy. MAIN OUTCOME MEASURES: Persistent hypoglycaemia post near-total pancreatectomy, insulin-dependent diabetes mellitus, clinical and biochemical (faecal elastase 1) pancreatic exocrine insufficiency. RESULTS: Of more than 300 patients with CHI managed during this time period, 45 children had medically unresponsive diffuse disease and were managed with near-total pancreatectomy. After near-total pancreatectomy, 60% of children had persistent hypoglycaemia requiring medical interventions. The incidence of insulin dependent diabetes mellitus was 96% at 11 years after surgery. Thirty-two patients (72%) had biochemical evidence of severe pancreatic exocrine insufficiency (Faecal elastase 1<100 µg/g). Clinical exocrine insufficiency was observed in 22 (49%) patients. No statistically significant difference in weight and height standard deviation score (SDS) was found between untreated subclinical pancreatic exocrine insufficiency patients and treated clinical pancreatic exocrine insufficiency patients. CONCLUSIONS: The outcome of diffuse CHI patients after near-total pancreatectomy is very unsatisfactory. The incidence of persistent hypoglycaemia and insulin-dependent diabetes mellitus is very high. The presence of clinical rather than biochemical pancreatic exocrine insufficiency should inform decisions about pancreatic enzyme supplementation

Clinical characteristics and molecular genetic analysis of 22 patients with neonatal diabetes from the South-Eastern region of Turkey: predominance of non-KATP channel mutations.

PublishedJournal ArticleResearch Support, Non-U.S. Gov'tThis is an open access article available at http://www.eje-online.org/content/172/6/697.BACKGROUND: Neonatal diabetes mellitus (NDM) is a rare form of monogenic diabetes and usually presents in the first 6 months of life. We aimed to describe the clinical characteristics and molecular genetics of a large Turkish cohort of NDM patients from a single centre and estimate an annual incidence rate of NDM in South-Eastern Anatolian region of Turkey. DESIGN AND METHODS: NDM patients presenting to Diyarbakir Children State Hospital between 2010 and 2013, and patients under follow-up with presumed type 1 diabetes mellitus, with onset before 6 months of age were recruited. Molecular genetic analysis was performed. RESULTS: Twenty-two patients (59% males) were diagnosed with NDM (TNDM-5; PNDM-17). Molecular genetic analysis identified a mutation in 20 (95%) patients who had undergone a mutation analysis. In transient neonatal diabetes (TNDM) patients, the genetic cause included chromosome 6q24 abnormalities (n=3), ABCC8 (n=1) and homozygous INS (n=1). In permanent neonatal diabetes (PNDM) patients, homozygous GCK (n=6), EIF2AK3 (n=3), PTF1A (n=3), and INS (n=1) and heterozygous KCNJ11 (n=2) mutations were identified. Pancreatic exocrine dysfunction was observed in patients with mutations in the distal PTF1A enhancer. Both patients with a KCNJ11 mutation responded to oral sulphonylurea. A variable phenotype was associated with the homozygous c.-331C>A INS mutation, which was identified in both a PNDM and TNDM patient. The annual incidence of PNDM in South-East Anatolian region of Turkey was one in 48 000 live births. CONCLUSIONS: Homozygous mutations in GCK, EIF2AK3 and the distal enhancer region of PTF1A were the commonest causes of NDM in our cohort. The high rate of detection of a mutation likely reflects the contribution of new genetic techniques (targeted next-generation sequencing) and increased consanguinity within our cohort.The genetic testing was funded by the Wellcome Trust (Senior Investigator Award to Profs S Ellard and A T Hattersley), and by Diabetes UK (Project funding to Dr D J Mackay). H Demirbilek was funded by European Society for Paediatric Endocrinology (ESPE) and The Scientific and Technological Research Council of Turkey (TUBITAK) for his 1 year clinical fellowship at University College London (UCL), Institute of Child Health, Great Ormond Street Hospital for Children, NHS Trust, Department of Paediatric Endocrinology

Turner syndrome and associated problems in turkish children: A multicenter study

Objective: Turner syndrome (TS) is a chromosomal disorder caused by complete or partial X chromosome monosomy that manifests various clinical features depending on the karyotype and on the genetic background of affected girls. This study aimed to systematically investigate the key clinical features of TS in relationship to karyotype in a large pediatric Turkish patient population. Methods: Our retrospective study included 842 karyotype-proven TS patients aged 0-18 years who were evaluated in 35 different centers in Turkey in the years 2013-2014. Results: The most common karyotype was 45,X (50.7%), followed by 45,X/46,XX (10.8%), 46,X,i(Xq) (10.1%) and 45,X/46,X,i(Xq) (9.5%). Mean age at diagnosis was 10.2±4.4 years. The most common presenting complaints were short stature and delayed puberty. Among patients diagnosed before age one year, the ratio of karyotype 45,X was significantly higher than that of other karyotype groups. Cardiac defects (bicuspid aortic valve, coarctation of the aorta and aortic stenosi) were the most common congenital anomalies, occurring in 25% of the TS cases. This was followed by urinary system anomalies (horseshoe kidney, double collector duct system and renal rotation) detected in 16.3%. Hashimoto’s thyroiditis was found in 11.1% of patients, gastrointestinal abnormalities in 8.9%, ear nose and throat problems in 22.6%, dermatologic problems in 21.8% and osteoporosis in 15.3%. Learning difficulties and/or psychosocial problems were encountered in 39.1%. Insulin resistance and impaired fasting glucose were detected in 3.4% and 2.2%, respectively. Dyslipidemia prevalence was 11.4%. Conclusion: This comprehensive study systematically evaluated the largest group of karyotype-proven TS girls to date. The karyotype distribution, congenital anomaly and comorbidity profile closely parallel that from other countries and support the need for close medical surveillance of these complex patients throughout their lifespan. © Journal of Clinical Research in Pediatric Endocrinology

Excitons and rare-earth ions in CsCdBr3

CsCdBr3 has a quasi-linear crystal structure. It consists of covalently bound [CdBr]6 4- chains separated by chains of Cs+ ions. The trivalent rare-earth (RE) ions substitute for divalent Cd ions forming predominantly pair centers of the type RE3+-(Cd vacancy)-RE3+. A minority of RE ions forms "single-ion" centers with more distant charge compensation. The electronic structure around the band gap is determined by the [CdBr]6 4- octahedra. The lowest excitonic states of the lattice are charge-transfer states of these octahedra. At low temperatures they form self-trapped excitons which become mobile around 80 K. In addition we find defect-localized excitons at the RE pairs and single ions with slightly modified spectra. There is a strong energy transfer between the RE ions and the defect-localized excitons in both directions with transition times below 10-8s. For the cooperative fluorescence transition 1D2 × 1G 4 → 3H4 × 3H4 in Pr3+: CsCdBr3 a frequency-modulated vibronic sideband spectrum was found with up to four repetitions of the frequency of the localized optical phonon mode at the ion pair. © 2004 Elsevier B.V. All rights reserved

Spectra and relaxation of electronic excitations in CsCdBr3:Yb3+ and CsCdBr3:Nd3+ monocrystals

Experimental and theoretical studies of the optical and EPR spectra, and the spin-lattice relaxation in CsCdBr3 crystals containing 0.1, 0.3 and 1.0 mol.% of impurity Yb3+ ions have been fulfilled. In the optical excitation spectrum, a broad charge transfer band has been detected in the wave-number range of 25000-35000 cm-1. The hybridization of the excited electron configuration corresponding to the charge transfer from the ligand (Br-) 4p closed shells on the ground 4f13 configuration of the ytterbium ion is considered to interpret the anomalously large crystal field splitting of the 2F5/2 multiplet. The EPR spectra with comparable intensities of the axial single-ion and symmetric dimer centres in the sample containing 0.3 mol.% of impurity Yb3+ ions were observed. Spin-lattice relaxation rates and linewidths in the EPR spectra of the single-ion and dimer centres were measured in the temperature range of 1.5 - 35 K at the frequency of 9.5 GHz at different directions of the applied magnetic field relative to the crystal symmetry axis. Experimental results are analyzed in the framework of the microscopic theory of the electron-phonon interaction with taking into account peculiarities of the phonon spectrum of the impurity CsCdBr3 lattice. High-frequency EPR spectra of dimer centres in CsCdBr3 crystals containing 0.2 and 0.5 mol.% of impurity Nd3+ ions were taken in the range of 205-250 GHz at 4.2 K in the magnetic fields up to 0.8 T parallel to the crystal symmetry axis. The crystal field splitting between the first excited and the ground Kramers doublets, and magnetic splitting factors of these doublets were determined. An estimate of the isotropic ferromagnetic exchange constant A = (2.3±0.3) 10-3 cm-1 in symmetric dimer centres formed by impurity Nd3+ ions was obtained from the zero-field splitting of the EPR signals

Global, multi-center, repeat-dose, phase 2 study of RZ358 (ersodetug), an insulin receptor antibody, for congenital hyperinsulinism

Background: Congenital hyperinsulinism (cHI) is a rare, primarily pediatric disease characterized by dysregulated insulin secretion resulting in severe, persistent hypoglycemia, frequently leading to lifelong neurologic impairments. The safety, pharmacokinetics, and glycemic efficacy of ersodetug, a fully human monoclonal antibody that allosterically and reversibly binds the insulin receptor (INSR) and reduces excess insulin action, are being evaluated for the treatment of cHI-related hypoglycemia. Methods: A global, open-label, phase 2b study (ClinicalTrials.gov: NCT04538989) was conducted in 23 patients with cHI with persistent hypoglycemia on standard-of-care (SOC) therapies. Eligible participants (age ≥2 years) received add-on ersodetug at dose levels between 3 and 9 mg/kg intravenously (i.v.) bi-weekly for 8 weeks in 4 sequential dose cohorts. Findings: Enrolled participants (average age = 6.7 years) on SOC (87% medications; 17% previous pancreatectomy) experienced 13 events/week and 23% time in hypoglycemia at baseline. Ersodetug resulted in predictable, dose-proportional pharmacokinetics. No deaths, adverse drug reactions, study withdrawals, or dose-limiting toxicities occurred. Hypoglycemia (&lt;70 mg/dL) events (self-monitored blood glucose) and time (continuous glucose monitoring) improved from baseline by medians of 59% (p &lt; 0.001) and 54% (p &lt; 0.001), respectively, across pooled dose levels and by 48%–84% (events) and 61%–65% (time) at doses of 6 or 9 mg/kg (p &lt; 0.05) with a nearly universal individual patient response rate. Additional hypoglycemia metrics, including overnight hypoglycemia, similarly improved. Conclusion: Ersodetug was generally well tolerated and significantly improved hypoglycemia in participants with cHI. Ersodetug represents a novel INSR-targeted mechanism of action with the potential to be an effective therapy for all forms of cHI, alone or in combination with other therapies. Funding: Rezolute, Inc. (Redwood City, CA), provided funds.</p

What is Good Design in the Eyes of Older Users?

With the population of older consumers increasing and with the recent changes in legislation and attitudes towards this group, there have been corresponding changes in product design practice and a growing attempt to adopt an inclusive design approach. This recognises that people can become excluded from using products, services or environments if the needs and capabilities of all potential users are not taken into account. The inclusive design approach has developed from collaborations between industry, designers and researchers. One major influence in this area is the i~design project, whose definition is simply that “inclusive design is better design” (EDC, 2011). The Inclusive Design Toolkit website, a key output from the i~design project, states that a successful product must be “functional, usable, desirable and ultimately profitable” and that a key to good design is to reduce the demand on the user when capabilities decline with age or disability (EDC, 2011). It is also important to consider more emotional aspects, such as social acceptability and whether the potential user would actually want to use or be seen using the product (Keates and Clarkson, 2003). Other authors also emphasise that whilst inclusive design research and practice to date have focused primarily on the physical accessibility and usability of products, a better understanding is required of people’s emotional needs, such as social acceptability and desirability of products (Coleman et al, 2007; Lee, 2010). Similar views regarding the required shift in design focus are reflected in a number of other sources: the need to consider the less tangible human factors such as identity, emotion, delight and selfexpression (Cassim et al, 2007); simplicity, aesthetics, pleasure, personality, conspicuousness and fashion (Pullin, 2009); the product’s visual appearance (Crilly et al, 2004); creating pleasurable experiences (Demirbilek and Sener, 2003; Jordan, 2000); and the importance of the emotional aspects of design for a successful product (Norman, 2004), as well as needs related to specific cognitive conditions (e.g. Baumers and Heylighen, 2010)

Systematic genetic testing for recessively inherited monogenic diabetes: a cross-sectional study in paediatric diabetes clinics

Data availability: The datasets supporting the current study have not been deposited in a public repository due to institutional ethics restrictions but are available from the corresponding author on request.This is the final version. Available from Springer via the DOI in this record. AIMS/HYPOTHESIS: Current clinical guidelines for childhood-onset monogenic diabetes outside infancy are mainly focused on identifying and testing for dominantly inherited, predominantly MODY genes. There are no systematic studies of the recessively inherited causes of monogenic diabetes that are likely to be more common in populations with high rates of consanguinity. We aimed to determine the contribution of recessive causes of monogenic diabetes in paediatric diabetes clinics and to identify clinical criteria by which to select individuals for recessive monogenic diabetes testing. METHODS: We conducted a cross-sectional study of 1093 children from seven paediatric diabetes clinics across Turkey (a population with high rates of consanguinity). We undertook genetic testing of 50 known dominant and recessive causes of monogenic diabetes for 236 children at low risk of type 1 diabetes. As a comparison, we used monogenic diabetes cases from UK paediatric diabetes clinics (a population with low rates of consanguinity). RESULTS: Thirty-four children in the Turkish cohort had monogenic diabetes, equating to a minimal prevalence of 3.1%, similar to that in the UK cohort (p = 0.40). Forty-one per cent (14/34) had autosomal recessive causes in contrast to 1.6% (2/122) in the UK monogenic diabetes cohort (p 10%) assisted the identification of the dominant (all p ≤ 0.0003) but not recessive cases (all p ≥ 0.2) in Turkey. The presence of certain non-autoimmune extra-pancreatic features greatly assisted the identification of recessive (p < 0.0001, OR 66.9) but not dominant cases. CONCLUSIONS/INTERPRETATION: Recessively inherited mutations are a common cause of monogenic diabetes in populations with high rates of consanguinity. Present MODY-focused genetic testing strategies do not identify affected individuals. To detect all cases of monogenic paediatric diabetes, it is crucial that recessive genes are included in genetic panels and that children are selected for testing if they have certain non-autoimmune extra-pancreatic features in addition to current criteria.Wellcome TrustRoyal SocietyNational Institute for Health Researc