Carlo L. Acerini
University of Cambridge
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Featured researches published by Carlo L. Acerini.
Nature Genetics | 2008
Deborah J.G. Mackay; Jonathan L. A. Callaway; Sophie Marks; Helen E. White; Carlo L. Acerini; Susanne E Boonen; Pinar Dayanikli; Helen V. Firth; Judith A. Goodship; Andreas P. Haemers; Johanne M D Hahnemann; Olga Kordonouri; Ahmed F Masoud; Elsebet Oestergaard; John Storr; Sian Ellard; Andrew T. Hattersley; David O. Robinson; I. Karen Temple
We have previously described individuals presenting with transient neonatal diabetes and showing a variable pattern of DNA hypomethylation at imprinted loci throughout the genome. We now report mutations in ZFP57, which encodes a zinc-finger transcription factor expressed in early development, in seven pedigrees with a shared pattern of mosaic hypomethylation and a conserved range of clinical features. This is the first description of a heritable global imprinting disorder that is compatible with life.
The New England Journal of Medicine | 2015
Hood Thabit; Martin Tauschmann; Janet Macdonald Allen; Lalantha Leelarathna; Sara Hartnell; Malgorzata E Wilinska; Carlo L. Acerini; Sibylle Dellweg; Carsten Benesch; Lutz Heinemann; Julia K. Mader; Manuel Holzer; Harald Kojzar; Jane Exall; James Yong; Jennifer Pichierri; Katharine Barnard; Craig Kollman; Peiyao Cheng; Peter C. Hindmarsh; Fiona Campbell; Sabine Arnolds; Thomas R. Pieber; Mark L. Evans; David B. Dunger; Roman Hovorka
BACKGROUND The feasibility, safety, and efficacy of prolonged use of an artificial beta cell (closed-loop insulin-delivery system) in the home setting have not been established. METHODS In two multicenter, crossover, randomized, controlled studies conducted under free-living home conditions, we compared closed-loop insulin delivery with sensor-augmented pump therapy in 58 patients with type 1 diabetes. The closed-loop system was used day and night by 33 adults and overnight by 25 children and adolescents. Participants used the closed-loop system for a 12-week period and sensor-augmented pump therapy (control) for a similar period. The primary end point was the proportion of time that the glucose level was between 70 mg and 180 mg per deciliter for adults and between 70 mg and 145 mg per deciliter for children and adolescents. RESULTS Among adults, the proportion of time that the glucose level was in the target range was 11.0 percentage points (95% confidence interval [CI], 8.1 to 13.8) greater with the use of the closed-loop system day and night than with control therapy (P<0.001). The mean glucose level was lower during the closed-loop phase than during the control phase (difference, -11 mg per deciliter; 95% CI, -17 to -6; P<0.001), as were the area under the curve for the period when the glucose level was less than 63 mg per deciliter (39% lower; 95% CI, 24 to 51; P<0.001) and the mean glycated hemoglobin level (difference, -0.3%; 95% CI, -0.5 to -0.1; P=0.002). Among children and adolescents, the proportion of time with the nighttime glucose level in the target range was higher during the closed-loop phase than during the control phase (by 24.7 percentage points; 95% CI, 20.6 to 28.7; P<0.001), and the mean nighttime glucose level was lower (difference, -29 mg per deciliter; 95% CI, -39 to -20; P<0.001). The area under the curve for the period in which the day-and-night glucose levels were less than 63 mg per deciliter was lower by 42% (95% CI, 4 to 65; P=0.03). Three severe hypoglycemic episodes occurred during the closed-loop phase when the closed-loop system was not in use. CONCLUSIONS Among patients with type 1 diabetes, 12-week use of a closed-loop system, as compared with sensor-augmented pump therapy, improved glucose control, reduced hypoglycemia, and, in adults, resulted in a lower glycated hemoglobin level. (Funded by the JDRF and others; AP@home04 and APCam08 ClinicalTrials.gov numbers, NCT01961622 and NCT01778348.).
Pediatric Diabetes | 2014
Marian Rewers; Kubendran Pillay; de Beaufort C; Maria E. Craig; Ragnar Hanas; Carlo L. Acerini; David M. Maahs; Adolescent Diabetes
Marian J Rewersa, Kuben Pillayb, Carine de Beaufortc, Maria E Craigd, Ragnar Hanase, Carlo L Acerinif and David M Maahsa aBarbara Davis Center, University of Colorado Denver, Aurora, CO, USA; bWestville Hospital, Durban, South Africa; cDECCP, Clinique Pediatrique/CHL, Luxembourg, Luxembourg; dInstitute of Endocrinology and Diabetes, Westmead, Australia; eDepartment of Pediatrics, Uddevalla Hospital, Uddevalla, Sweden and fDepartment of Pediatrics, University of Cambridge, Cambridge, UK
Diabetes Care | 2014
Roman Hovorka; Daniela Elleri; Hood Thabit; Janet Macdonald Allen; Lalantha Leelarathna; Ranna El-Khairi; Kavita Kumareswaran; Karen Caldwell; Peter Calhoun; Craig Kollman; Helen R. Murphy; Carlo L. Acerini; Malgorzata E Wilinska; Marianna Nodale; David B. Dunger
OBJECTIVE To evaluate feasibility, safety, and efficacy of overnight closed-loop insulin delivery in free-living youth with type 1 diabetes. RESEARCH DESIGN AND METHODS Overnight closed loop was evaluated at home by 16 pump-treated adolescents with type 1 diabetes aged 12–18 years. Over a 3-week period, overnight insulin delivery was directed by a closed-loop system, and on another 3-week period sensor-augmented therapy was applied. The order of interventions was random. The primary end point was time when adjusted sensor glucose was between 3.9 and 8.0 mmol/L from 2300 to 0700 h. RESULTS Closed loop was constantly applied over at least 4 h on 269 nights (80%); sensor data were collected over at least 4 h on 282 control nights (84%). Closed loop increased time spent with glucose in target by a median 15% (interquartile range −9 to 43; P < 0.001). Mean overnight glucose was reduced by a mean 14 (SD 58) mg/dL (P < 0.001). Time when glucose was <70 mg/dL was low in both groups, but nights with glucose <63 mg/dL for at least 20 min were less frequent during closed loop (10 vs. 17%; P = 0.01). Despite lower total daily insulin doses by a median 2.3 (interquartile range −4.7 to 9.3) units (P = 0.009), overall 24-h glucose was reduced by a mean 9 (SD 41) mg/dL (P = 0.006) during closed loop. CONCLUSIONS Unsupervised home use of overnight closed loop in adolescents with type 1 diabetes is safe and feasible. Glucose control was improved during the day and night with fewer episodes of nocturnal hypoglycemia.
Journal of diabetes science and technology | 2010
Malgorzata E. Wilinska; Ludovic J. Chassin; Carlo L. Acerini; Janet M. Allen; David B. Dunger; Roman Hovorka
Background: Closed-loop insulin delivery systems linking subcutaneous insulin infusion to real-time continuous glucose monitoring need to be evaluated in humans, but progress can be accelerated with the use of in silico testing. We present a simulation environment designed to support the development and testing of closed-loop insulin delivery systems in type 1 diabetes mellitus (T1DM). Methods: The principal components of the simulation environment include a mathematical model of glucose regulation representing a virtual population with T1DM, the glucose measurement model, and the insulin delivery model. The simulation environment is highly flexible. The user can specify an experimental protocol, define a population of virtual subjects, choose glucose measurement and insulin delivery models, and specify outcome measures. The environment provides graphical as well as numerical outputs to enable a comprehensive analysis of in silico study results. The simulation environment is validated by comparing its predictions against a clinical study evaluating overnight closed-loop insulin delivery in young people with T1DM using a model predictive controller. Results: The simulation model of glucose regulation is described, and population values of 18 synthetic subjects are provided. The validation study demonstrated that the simulation environment was able to reproduce the population results of the clinical study conducted in young people with T1DM. Conclusions: Closed-loop trials in humans should be preceded and concurrently guided by highly efficient and resource-saving computer-based simulations. We demonstrate validity of population-based predictions obtained with our simulation environment.
Archives of Disease in Childhood | 2009
Carlo L. Acerini; Harriet Miles; David B. Dunger; Kenneth Ong; Ieuan A. Hughes
Introduction: Recent studies in other European countries suggest that the prevalence of congenital cryptorchidism continues to increase. This study aimed to explore the prevalence and natural history of congenital cryptorchidism in a UK centre. Methods: Between October 2001 and July 2008, 784 male infants were born in the prospective Cambridge Baby Growth Study. 742 infants were examined by trained research nurses at birth; testicular position was assessed using standard techniques. Follow-up assessments were completed at ages 3, 12, 18 and 24 months in 615, 462, 393 and 326 infants, respectively. Results: The prevalence of cryptorchidism at birth was 5.9% (95% CI 4.4% to 7.9%). Congenital cryptorchidism was associated with earlier gestational age (p<0.001), lower birth weight (p<0.001), birth length (p<0.001) and shorter penile length at birth (p<0.0001) compared with other infants, but normal size after age 3 months. The prevalence of cryptorchidism declined to 2.4% at 3 months, but unexpectedly rose again to 6.7% at 12 months as a result of new cases. The cumulative incidence of “acquired cryptorchidism” by age 24 months was 7.0% and these cases had shorter penile length during infancy than other infants (p = 0.003). Conclusions: The prevalence of congenital cryptorchidism was higher than earlier estimates in UK populations. Furthermore, this study for the first time describes acquired cryptorchidism or “ascending testis” as a common entity in male infants, which is possibly associated with reduced early postnatal androgen activity.
Diabetes Care | 2013
Daniela Elleri; Janet M. Allen; Kavita Kumareswaran; Lalantha Leelarathna; Marianna Nodale; Karen Caldwell; Peiyao Cheng; Craig Kollman; Ahmad Haidar; Helen R. Murphy; Malgorzata E. Wilinska; Carlo L. Acerini; David B. Dunger; Roman Hovorka
OBJECTIVE We evaluated the safety and efficacy of closed-loop basal insulin delivery during sleep and after regular meals and unannounced periods of exercise. RESEARCH DESIGN AND METHODS Twelve adolescents with type 1 diabetes (five males; mean age 15.0 [SD 1.4] years; HbA1c 7.9 [0.7]%; BMI 21.4 [2.6] kg/m2) were studied at a clinical research facility on two occasions and received, in random order, either closed-loop basal insulin delivery or conventional pump therapy for 36 h. During closed-loop insulin delivery, pump basal rates were adjusted every 15 min according to a model predictive control algorithm informed by subcutaneous sensor glucose levels. During control visits, subjects’ standard infusion rates were applied. Prandial insulin boluses were given before main meals (50–80 g carbohydrates) but not before snacks (15–30 g carbohydrates). Subjects undertook moderate-intensity exercise, not announced to the algorithm, on a stationary bicycle at a 140 bpm heart rate in the morning (40 min) and afternoon (20 min). Primary outcome was time when plasma glucose was in the target range (71–180 mg/dL). RESULTS Closed-loop basal insulin delivery increased percentage time when glucose was in the target range (median 84% [interquartile range 78–88%] vs. 49% [26–79%], P = 0.02) and reduced mean plasma glucose levels (128 [19] vs. 165 [55] mg/dL, P = 0.02). Plasma glucose levels were in the target range 100% of the time on 17 of 24 nights during closed-loop insulin delivery. Hypoglycemia occurred on 10 occasions during control visits and 9 occasions during closed-loop delivery (5 episodes were exercise related, and 4 occurred within 2.5 h of prandial bolus). CONCLUSIONS Day-and-night closed-loop basal insulin delivery can improve glucose control in adolescents. However, unannounced moderate-intensity exercise and excessive prandial boluses pose challenges to hypoglycemia-free closed-loop basal insulin delivery.
European Journal of Endocrinology | 2008
Ieuan A. Hughes; Carlo L. Acerini
Descent of the testis from an intra-abdominal site in foetal life to an extracorporeal location after birth is a mandatory developmental process to ensure that the mature testis promotes normal spermatogenesis. The two phases of transabdominal and inguinoscrotal descent occur approximately during the first and last thirds of gestation respectively. Key anatomical events to release the testis from its urogenital ridge location and to guide the free gonad into the scrotum are the degeneration of the cranio-suspensory ligament and a thickening of the gubernaculum. Androgens play a role in both these processes, particularly with respect to enabling the testis to traverse the inguinal canal in the final phase of descent. Experiments in animals suggest that androgens mediate this effect via the release of calcitonin gene-related peptide by the genitofemoral nerve, but direct evidence for such a mechanism is lacking in humans. The transabdominal phase of descent is under the control of insulin-like 3 (INSL3), a product of the Leydig cells. Definitive evidence of its role in rodent testis descent is illustrated by the phenotype of bilateral cryptorchidism in Insl3-/- null mice. Circulating levels of INSL3 are higher in boys at puberty, are undetectable in girls and are lower in boys with undescended testes. A minority also have a mutation either in the INSL3 gene or affecting its receptor gene, relaxin/insulin-like family peptide receptor 2 (LGRF8). Other factors that may play a role in testis descent include the anti-Mullerian hormone and members of the HOX gene family. Evidence that the prevalence of undescended testis may be increasing provides a phenotypic readout for the effects of postulated chemicals in the environment interfering in some way with the action of factors that control testis descent. Epidemiological studies point to profound geographical variations in prevalence in countries such as Denmark and Finland. Associations have been found with levels of chemicals labelled as endocrine disruptors being higher in breast milk samples from mothers with cryptorchid boys when compared with controls. The adverse effects of these compounds (e.g. bisphenol A) can be replicated in the offspring of dams exposed during pregnancy. A sensitive marker of an anti-androgen effect of a compound is a reduction in the anogenital distance, an anthropometric measurement that is significantly greater in males compared with females. The observation of an association between the anogenital distance in infant boys and the level of pesticides in the urine of their mothers in late gestation indicates that this has the potential to be a useful surrogate marker of the effects of environmental chemicals on testis descent in human population studies. The rightful place for the testis at birth is in the scrotum in order to provide the temperature differential essential for normal spermatogenesis. Appropriate screening programmes and early surgical intervention are the prerequisites to ensure optimal fertility in adulthood and a considerably lessened risk of testis cancer.
Environmental Health Perspectives | 2009
Ajay Thankamony; Ken K. Ong; David B. Dunger; Carlo L. Acerini; Ieuan A. Hughes
Background Anogenital distance (AGD) is sexually dimorphic in rodents and humans, being 2- to 2.5-fold greater in males. It is a reliable marker of androgen and antiandrogen effects in rodent reproductive toxicologic studies. Data on AGD in humans are sparse, with no longitudinal data collected during infancy. Objective This study was designed to determine AGD from birth to 2 years in males and females and relate this to other anthropometric measures. Materials and Methods Infants were recruited from the Cambridge Baby Growth Study. AGD was measured from the center of the anus to the base of the scrotum in males and to the posterior fourchette in females. Measurements were performed at birth and at 3, 12, 18, and 24 months of age. Results Data included 2,168 longitudinal AGD measurements from 463 male and 426 female full-term infants (median = 2 measurements per infant). Mean AGD (± SD) at birth was 19.8 ± 6.1 mm in males and 9.1 ± 2.8 mm in females (p < 0.0001). AGD increased up to 12 months in both sexes and in a sex-dimorphic pattern. AGD was positively correlated with penile length at birth (r = 0.18, p = 0.003) and the increase in AGD from birth to 3 months was correlated with penile growth (r= 0.20, p = 0.001). Conclusion We report novel, longitudinal data for AGD during infancy in a large U.K. birth cohort. AGD was sex dimorphic at all ages studied. The availability of normative data provides a means of utilizing this biological marker of androgen action in population studies of the effects of environmental chemicals on genital development.
Archives of Disease in Childhood | 2008
Ritika R. Kapoor; Susan Burke; Susan Sparrow; Ieuan A. Hughes; David B. Dunger; Ken K. Ong; Carlo L. Acerini
Concordance with growth hormone (GH) therapy in 75 children was objectively assessed using data on GP prescriptions over 12 months. 23% missed >2 injections/week. Lower concordance was associated with longer duration on GH therapy (p<0.005), lack of choice of delivery device (p<0.005) and short prescription durations (p<0.005), and predicted lower height velocities (p<0.05).