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1.
Environ Res ; 232: 116325, 2023 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-37271437

RESUMEN

BACKGROUND: Emerging evidence supports an association between light at night (LAN) exposure with obesity or overweight in adults. However, effects of LAN exposure during childhood have yet to be further investigated. OBJECTIVE: In this study, we aimed to determine whether LAN exposure is associated with body mass in young children. RESEARCH DESIGN AND METHOD: We used data from the Fr1da cohort study which screened children for early-stage islet autoimmunity in Bavaria, Germany from February 2015 to March 2019. A total of 62,212 children aged <11 years with complete residential information was included in the analysis. Self-reported weight and height were used to calculate age- and sex-specific body mass index (BMI) z-scores. LAN exposure was based on remotely sensed images from Visible Infrared Imaging Radiometer Suite and assigned to the children's residencies. We used generalized additive models to estimate the associations between LAN exposure and BMI adjusting for potential confounders. RESULTS: We observed an increase in BMI z-scores of 34.0% (95% confidence interval (CI): 25.4-42.6) per 10 nW/cm2/sr increment in LAN exposure at baseline (2015) and of 32.6% (24.3-41.0) for LAN exposure one year prior to screening, both adjusted for age and sex. Similar associations were observed after adjustment for socioeconomic status and urbanization degree. CONCLUSION: Our findings suggest that outdoor light exposure may be a risk factor for weight gain during childhood.


Asunto(s)
Índice de Masa Corporal , Peso Corporal , Exposición a Riesgos Ambientales , Contaminación Lumínica , Humanos , Niño , Alemania , Factores de Edad , Factores Sexuales , Luz , Preescolar , Contaminación Lumínica/estadística & datos numéricos , Exposición a Riesgos Ambientales/estadística & datos numéricos , Aumento de Peso
2.
Diabetologia ; 65(12): 2121-2131, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36028774

RESUMEN

AIMS/HYPOTHESIS: The aim of this study was to develop strategies that identify children from the general population who have late-stage presymptomatic type 1 diabetes and may, therefore, benefit from immune intervention. METHODS: We tested children from Bavaria, Germany, aged 1.75-10 years, enrolled in the Fr1da public health screening programme for islet autoantibodies (n=154,462). OGTT and HbA1c were assessed in children with multiple islet autoantibodies for diagnosis of presymptomatic stage 1 (normoglycaemia) or stage 2 (dysglycaemia) type 1 diabetes. Cox proportional hazards and penalised logistic regression of autoantibody, genetic, metabolic and demographic information were used to develop a progression likelihood score to identify children with stage 1 type 1 diabetes who progressed to stage 3 (clinical) type 1 diabetes within 2 years. RESULTS: Of 447 children with multiple islet autoantibodies, 364 (81.4%) were staged. Undiagnosed stage 3 type 1 diabetes, presymptomatic stage 2, and stage 1 type 1 diabetes were detected in 41 (0.027% of screened children), 30 (0.019%) and 293 (0.19%) children, respectively. The 2 year risk for progression to stage 3 type 1 diabetes was 48% (95% CI 34, 58) in children with stage 2 type 1 diabetes (annualised risk, 28%). HbA1c, islet antigen-2 autoantibody positivity and titre, and the 90 min OGTT value were predictors of progression in children with stage 1 type 1 diabetes. The derived progression likelihood score identified substages corresponding to ≤90th centile (stage 1a, n=258) and >90th centile (stage 1b, n=29; 0.019%) of stage 1 children with a 4.1% (95% CI 1.4, 6.7) and 46% (95% CI 21, 63) 2 year risk of progressing to stage 3 type 1 diabetes, respectively. CONCLUSIONS/INTERPRETATION: Public health screening for islet autoantibodies found 0.027% of children to have undiagnosed clinical type 1 diabetes and 0.038% to have undiagnosed presymptomatic stage 2 or stage 1b type 1 diabetes, with 50% risk to develop clinical type 1 diabetes within 2 years.


Asunto(s)
Diabetes Mellitus Tipo 1 , Islotes Pancreáticos , Niño , Humanos , Diabetes Mellitus Tipo 1/epidemiología , Islotes Pancreáticos/metabolismo , Salud Pública , Autoanticuerpos , Tamizaje Masivo , Progresión de la Enfermedad
3.
Environ Res ; 212(Pt D): 113503, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35609657

RESUMEN

OBJECTIVE: Incidence of early-onset type 1 diabetes (T1D) has been increasing worldwide. Only few studies examined the relationship between geographical environmental variation and T1D incidence or its presymptomatic stage of islet autoimmunity. Our study aimed to investigate the effect of long-term environmental exposures during pregnancy and early life on childhood islet autoimmunity. RESEARCH DESIGN AND METHODS: We used data from the Fr1da cohort study which screened children aged 1.75-5.99 years for multiple islet autoantibodies in Bavaria, Germany between 2015 and 2019. We included 85,251 children with valid residential information. Daily averages for particulate matter with a diameter <2.5 µm, nitrogen dioxide, ozone, air temperature, and greenness were averaged for each zip-code or directly assigned to the addresses. The exposure windows included pregnancy, the first year and the first two years of life. Generalized additive models adjusting for individual and socioeconomic variables were used to investigate associations between environmental exposures and islet autoimmunity development. RESULTS: Islet autoimmunity was diagnosed in 272 children. Colder air temperature during pregnancy was associated with developing islet autoimmunity at the address (per 2.2 °C decrease, Odds ratio (OR): 1.49; 95% Confidence interval (CI): 1.21-1.83) and zip-code level (per 2.4 °C decrease, OR: 1.31; 95% CI: 1.08-1.59). Using the addresses, significant associations were also observed during the first years of life. CONCLUSION: In this study, children's residential exposure to lower levels of air temperature during pregnancy and early life increased the risk of islet autoimmunity before the age of six.


Asunto(s)
Contaminantes Atmosféricos , Contaminación del Aire , Diabetes Mellitus Tipo 1 , Contaminantes Atmosféricos/análisis , Contaminantes Atmosféricos/toxicidad , Contaminación del Aire/análisis , Autoinmunidad , Niño , Estudios de Cohortes , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/etiología , Exposición a Riesgos Ambientales/análisis , Femenino , Alemania/epidemiología , Humanos , Material Particulado/análisis , Embarazo
4.
JAMA ; 323(4): 339-351, 2020 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-31990315

RESUMEN

IMPORTANCE: Public health screening for type 1 diabetes in its presymptomatic stages may reduce disease severity and burden on a population level. OBJECTIVE: To determine the prevalence of presymptomatic type 1 diabetes in children participating in a public health screening program for islet autoantibodies and the risk for progression to clinical diabetes. DESIGN, SETTING, AND PARTICIPANTS: Screening for islet autoantibodies was offered to children aged 1.75 to 5.99 years in Bavaria, Germany, between 2015 and 2019 by primary care pediatricians during well-baby visits. Families of children with multiple islet autoantibodies (presymptomatic type 1 diabetes) were invited to participate in a program of diabetes education, metabolic staging, assessment of psychological stress associated with diagnosis, and prospective follow-up for progression to clinical diabetes until July 31, 2019. EXPOSURES: Measurement of islet autoantibodies. MAIN OUTCOMES AND MEASURES: The primary outcome was presymptomatic type 1 diabetes, defined by 2 or more islet autoantibodies, with categorization into stages 1 (normoglycemia), 2 (dysglycemia), or 3 (clinical) type 1 diabetes. Secondary outcomes were the frequency of diabetic ketoacidosis and parental psychological stress, assessed by the Patient Health Questionnaire-9 (range, 0-27; higher scores indicate worse depression; ≤4 indicates no to minimal depression; >20 indicates severe depression). RESULTS: Of 90 632 children screened (median [interquartile range {IQR}] age, 3.1 [2.1-4.2] years; 48.5% girls), 280 (0.31%; 95% CI, 0.27-0.35) had presymptomatic type 1 diabetes, including 196 (0.22%) with stage 1, 17 (0.02%) with stage 2, 26 (0.03%) with stage 3, and 41 who were not staged. After a median (IQR) follow-up of 2.4 (1.0-3.2) years, another 36 children developed stage 3 type 1 diabetes. The 3-year cumulative risk for stage 3 type 1 diabetes in the 280 children with presymptomatic type 1 diabetes was 24.9% ([95% CI, 18.5%-30.7%]; 54 cases; annualized rate, 9.0%). Two children had diabetic ketoacidosis. Median (IQR) psychological stress scores were significantly increased at the time of metabolic staging in mothers of children with presymptomatic type 1 diabetes (3 [1-7]) compared with mothers of children without islet autoantibodies (2 [1-4]) (P = .002), but declined after 12 months of follow-up (2 [0-4]) (P < .001). CONCLUSIONS AND RELEVANCE: Among children aged 2 to 5 years in Bavaria, Germany, a program of primary care-based screening showed an islet autoantibody prevalence of 0.31%. These findings may inform considerations of population-based screening of children for islet autoantibodies.


Asunto(s)
Autoanticuerpos/sangre , Diabetes Mellitus Tipo 1/epidemiología , Islotes Pancreáticos/inmunología , Tamizaje Masivo , Enfermedades Asintomáticas/epidemiología , Enfermedades Asintomáticas/psicología , Preescolar , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/psicología , Femenino , Estudios de Seguimiento , Alemania/epidemiología , Humanos , Masculino , Padres , Encuestas y Cuestionarios
5.
Pediatr Diabetes ; 20(6): 720-727, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31192505

RESUMEN

Primary prevention of type 1 diabetes (T1D) requires intervention in genetically at-risk infants. The Global Platform for the Prevention of Autoimmune Diabetes (GPPAD) has established a screening program, GPPAD-02, that identifies infants with a genetic high risk of T1D, enrolls these into primary prevention trials, and follows the children for beta-cell autoantibodies and diabetes. Genetic testing is offered either at delivery, together with the regular newborn testing, or at a newborn health care visits before the age of 5 months in regions of Germany (Bavaria, Saxony, Lower Saxony), UK (Oxford), Poland (Warsaw), Belgium (Leuven), and Sweden (Region Skåne). Seven clinical centers will screen around 330 000 infants. Using a genetic score based on 46 T1D susceptibility single-nucleotide polymorphisms (SNPs) or three SNPS and a first-degree family history for T1D, infants with a high (>10%) genetic risk for developing multiple beta-cell autoantibodies by the age of 6 years are identified. Screening from October 2017 to December 2018 was performed in 50 669 infants. The prevalence of high genetic risk for T1D in these infants was 1.1%. Infants with high genetic risk for T1D are followed up and offered to participate in a randomized controlled trial aiming to prevent beta-cell autoimmunity and T1D by tolerance induction with oral insulin. The GPPAD-02 study provides a unique path to primary prevention of beta-cell autoimmunity in the general population. The eventual benefit to the community, if successful, will be a reduction in the number of children developing beta-cell autoimmunity and T1D.


Asunto(s)
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/prevención & control , Pruebas Genéticas , Selección de Paciente , Prevención Primaria/métodos , Autoanticuerpos/genética , Autoinmunidad/genética , Diabetes Mellitus Tipo 1/diagnóstico , Europa (Continente) , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lactante , Recién Nacido , Islotes Pancreáticos/inmunología , Masculino , Tamizaje Neonatal , Polimorfismo de Nucleótido Simple , Datos Preliminares , Proyectos de Investigación , Factores de Riesgo
7.
Horm Metab Res ; 50(1): 44-49, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29121687

RESUMEN

An increased risk for type 1 diabetes can be identified using genetic and immune markers. The Freder1k study introduces genetic testing for type 1 diabetes risk within the context of the newborn screening in order to identify newborns with a high risk to develop type 1 diabetes for follow-up testing of early stage type 1 diabetes and for primary prevention trials. Consent for research-based genetic testing of type 1 diabetes risk is obtained with newborn screening. Increased risk is assessed using three single nucleotide polymorphisms for HLA DRB1*03 (DR3), HLA DRB1*04 (DR4), HLA DQB1*0302 (DQ8) alleles, and defined as 1. an HLA DR3/DR4-DQ8 or DR4-DQ8/DR4-DQ8 genotype or 2. an HLA DR4-DQ8 haplotype and a first-degree family history of type 1 diabetes. Families of infants with increased risk are asked to participate in follow-up visits at infant age 6 months, 2 years, and 4 years for autoantibody testing and early diagnosis of type 1 diabetes. After 8 months, the screening rate has reached 181 per week, with 63% coverage of newborns within Freder1k-clinics and 24% of all registered births in Saxony. Of 4178 screened, 2.6% were identified to have an increased risk, and around 80% of eligible infants were recruited to follow-up. Psychological assessment of eligible families is ongoing with none of 31 families demonstrating signs of excessive burden associated with knowledge of type 1 diabetes risk. This pilot study has shown that it is feasible to perform genetic risk testing for childhood disease within the context of newborn screening programs.


Asunto(s)
Diabetes Mellitus Tipo 1/diagnóstico , Tamizaje Masivo , Costo de Enfermedad , Humanos , Recién Nacido , Padres/psicología , Proyectos Piloto , Factores de Riesgo
10.
Diabetologia ; 59(10): 2172-80, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27400691

RESUMEN

AIMS/HYPOTHESIS: Progression to type 1 diabetes in children and adolescents is not uniform. Based on individual genetic background and environment, islet autoimmunity may develop at variable age, exhibit different autoantibody profiles and progress to clinical diabetes at variable rates. Here, we aimed to quantify the qualitative dynamics of sequential islet autoantibody profiles in order to identify longitudinal patterns that stratify progression rates to type 1 diabetes in multiple-autoantibody-positive children. METHODS: Qualitative changes in antibody status on follow-up and progression rate to diabetes were analysed in 88 children followed from birth in the prospective BABYDIAB study who developed multiple autoantibodies against insulin (IAA), GAD (GADA), insulinoma-associated antigen-2 (IA-2A) and/or zinc transporter 8 (ZnT8A). An algorithm was developed to define similarities in sequential autoantibody profiles and hierarchical clustering was performed to group children with similar profiles. RESULTS: We defined nine clusters that distinguished children with respect to their sequential profiles of IAA, GADA, IA-2A and ZnT8A. Progression from first autoantibody appearance to clinical diabetes between clusters ranged from 6% (95% CI [0, 16.4]) to 73% (28.4, 89.6) within 5 years. Delayed progression was observed in children who were positive for only two autoantibodies, and for a cluster of 12 children who developed three or four autoantibodies but were IAA-negative in their last samples, nine of whom lost IAA positivity during follow-up. Among all children who first seroconverted to IAA positivity and developed at least two other autoantibodies (n = 57), the 10 year risk of diabetes was 23% (0, 42.9) in those who became IAA-negative during follow-up compared with 76% (58.7, 85.6) in those who remained IAA-positive (p = 0.004). CONCLUSIONS/INTERPRETATION: The novel clustering approach provides a tool for stratification of islet autoantibody-positive individuals that has prognostic relevance, and new opportunities in elucidating disease mechanisms. Our data suggest that losing IAA reactivity is associated with delayed progression to type 1 diabetes in multiple-islet-autoantibody-positive children.


Asunto(s)
Autoanticuerpos/inmunología , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/patología , Algoritmos , Proteínas de Transporte de Catión/metabolismo , Análisis por Conglomerados , Progresión de la Enfermedad , Femenino , Glutamato Descarboxilasa/metabolismo , Humanos , Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Masculino , Estudios Prospectivos , Transportador 8 de Zinc
11.
Public Health Nutr ; 18(1): 50-8, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24476676

RESUMEN

OBJECTIVE: The development of type 1 diabetes (T1D) is potentially influenced by nutrition. The aim of our study was to assess food and nutrient intakes of children at increased risk of T1D. DESIGN: Dietary intake of the last 4 weeks was assessed using a diet history interview. The daily nutrient and food intakes were compared with the German Dietary Reference Intakes, the Optimized Mixed Diet recommendations and those of a representative sample of children from the EsKiMo study. SETTING: Children included in the analysis participated in the prospective TEENDIAB study. SUBJECTS: First-degree relatives of people with T1D (n 268), aged 8-12 years. RESULTS: The TEENDIAB children consumed 52·0 % of their total energy from carbohydrates, 32·6 % from fat and 14·3 % from protein. Compared with the reference values, their intake was lowest for folate at 61·3 % of the reference, for iodine at 58·1 % and for vitamin D at 8·9 %, and exceeded the reference for vitamin K about 5-fold, for Na about 3·5-fold and for protein about 1·5-fold. Their nutrient intakes were similar to those of a control cohort without increased T1D risk. The consumption of non-desirable food groups (meat products, sweets/snacks) was above the recommendations and the consumption of desirable food groups (fruits, vegetables, carbohydrate-rich foods) was below the recommendations. CONCLUSIONS: The TEENDIAB children had intakes considerably below the recommendations for vitamin D, iodine, folate and plant-based foods, and intakes above for vitamin K, Na, protein, meat products and sweets/snacks. They showed similar dietary patterns to non-risk children.


Asunto(s)
Fenómenos Fisiológicos Nutricionales Infantiles , Diabetes Mellitus Tipo 1/etiología , Dieta/efectos adversos , Salud de la Familia , Política Nutricional , Cooperación del Paciente , Adolescente , Fenómenos Fisiológicos Nutricionales de los Adolescentes , Niño , Estudios de Cohortes , Diabetes Mellitus Tipo 1/epidemiología , Femenino , Estudios de Seguimiento , Alemania/epidemiología , Humanos , Masculino , Estudios Prospectivos , Factores de Riesgo , Encuestas y Cuestionarios
12.
Diabetes Metab Res Rev ; 29(8): 631-5, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23861173

RESUMEN

BACKGROUND: Insulin resistance has been postulated to be linked to the frequent onset of type 1 diabetes (T1D) during puberty. Very few studies have investigated the time course of insulin resistance in childhood. To address the question of how insulin resistance develops with age and how this is related to puberty onset, we examined insulin resistance and pubertal development over time in children at increased risk for T1D. METHODS: Homeostasis model assessment of insulin resistance (HOMA-IR) was measured in 1848 fasting samples of 1177 children (aged 5-15 years) in a cross-sectional analysis. All children had a first degree relative with T1D, 120 developed islet autoantibodies. Pubertal development was determined by Tanner staging. RESULTS: Insulin resistance rose continuously from age 5 to 13 years in girls and from age 5 to 14 years in boys with an average increase of 0.09 (95 % confidence interval [CI]: 0.08-0.10) per year for girls and 0.07 (95 % CI: 0.06-0.08) for boys. The rise preceded the onset of puberty (Tanner stage 2), which was reported between 10 and 12 years of age in 80.4 % of the children (mean age: 11.2 ± 0.06 years). No difference was seen between children with or without islet autoantibodies. CONCLUSIONS: There was a constant age-dependent rise of insulin resistance during childhood without observed associations to the onset of puberty or the presence of islet autoimmunity in children at increased risk for T1D. Our data show that insulin resistance emerges well before the initiation of physical changes of puberty.


Asunto(s)
Diabetes Mellitus Tipo 1/fisiopatología , Resistencia a la Insulina/fisiología , Pubertad/fisiología , Adolescente , Niño , Preescolar , Estudios Transversales , Femenino , Homeostasis , Humanos , Masculino
13.
Arch Dis Child ; 108(1): 26-30, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36171064

RESUMEN

OBJECTIVE: INGR1D (INvestigating Genetic Risk for type 1 Diabetes) was a type 1 diabetes (T1D) genetic screening study established to identify participants for a primary prevention trial (POInT, Primary Oral Insulin Trial). METHODS: The majority of participants were recruited by research midwives in antenatal clinics from 18 weeks' gestation. Using the NHS Newborn Bloodspot Screening Programme (NBSP) infrastructure, participants enrolled in INGR1D had an extra sample taken from their day 5 bloodspot card sent for T1D genetic screening. Those at an increased risk of T1D were informed of the result, given education about T1D and the opportunity to take part in POInT. RESULTS: Between April 2018 and November 2020, 66% of women approached about INGR1D chose to participate. 15 660 babies were enrolled into INGR1D and 14 731 blood samples were processed. Of the processed samples, 157 (1%) had confirmed positive results, indicating an increased risk of T1D, of whom a third (n=49) enrolled into POInT (20 families were unable to participate in POInT due to COVID-19 lockdown restrictions). CONCLUSION: The use of prospective consent to perform personalised genetic testing on samples obtained through the routine NBSP represents a novel mechanism for clinical genetic research in the UK and provides a model for further population-based genetic studies in the newborn.


Asunto(s)
COVID-19 , Diabetes Mellitus Tipo 1 , Recién Nacido , Femenino , Humanos , Embarazo , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/genética , Estudios Prospectivos , Control de Enfermedades Transmisibles , Pruebas Genéticas , Consentimiento Informado , Reino Unido
14.
Med ; 2(2): 149-163.e4, 2021 02 12.
Artículo en Inglés | MEDLINE | ID: mdl-33163984

RESUMEN

BACKGROUND: Antibody responses to virus reflect exposure and potential protection. METHODS: We developed a highly specific and sensitive approach to measuring antibodies against SARS-CoV-2 for population-scale immune surveillance. Antibody positivity was defined as a dual-positive response against both the receptor-binding domain and nucleocapsid proteins of SARS-CoV-2. Antibodies were measured by immunoprecipitation assays in capillary blood from 15,771 children aged 1 to 18 years living in Bavaria, Germany, and participating in a public health type 1 diabetes screening program (ClinicalTrials.gov: NCT04039945), in 1,916 dried blood spots from neonates in a Bavarian screening study (ClinicalTrials.gov: NCT03316261), and in 75 SARS-CoV-2-positive individuals. Virus positive incidence was obtained from the Bavarian health authority data. FINDINGS: Dual-antibody positivity was detected in none of the 3,887 children in 2019 (100% specificity) and 73 of 75 SARS-CoV-2-positive individuals (97.3% sensitivity). Antibody surveillance in children during 2020 resulted in frequencies of 0.08% in January to March, 0.61% in April, 0.74% in May, 1.13% in June, and 0.91% in July. Antibody prevalence from April 2020 was 6-fold higher than the incidence of authority-reported cases (156 per 100,000 children), showed marked variation between the seven Bavarian regions (p < 0.0001), and was not associated with age or sex. Transmission in children with virus-positive family members was 35%. 47% of positive children were asymptomatic. No association with type 1 diabetes autoimmunity was observed. Antibody frequency in newborns was 0.47%. CONCLUSIONS: We demonstrate the value of population-based screening programs for pandemic monitoring. FUNDING: The work was supported by funding from the BMBF (FKZ01KX1818).


Asunto(s)
COVID-19 , Diabetes Mellitus Tipo 1 , Anticuerpos Antivirales , COVID-19/diagnóstico , Niño , Diabetes Mellitus Tipo 1/diagnóstico , Humanos , Recién Nacido , Salud Pública , SARS-CoV-2
15.
Phys Rev Lett ; 104(16): 160503, 2010 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-20482035

RESUMEN

We propose an interface between the spin of a photon and the spin of an electron confined in a quantum dot embedded in a microcavity operating in the weak-coupling regime. This interface, based on spin selective photon reflection from the cavity, can be used to construct a CNOT gate, a multiphoton entangler and a photonic Bell-state analyzer. Finally, we analyze experimental feasibility, concluding that the schemes can be implemented with current technology.

16.
Nat Commun ; 7: 10991, 2016 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-26975663

RESUMEN

Immune tolerance is executed partly by Foxp3(+)regulatory T (Treg) cells, which suppress autoreactive T cells. In autoimmune type 1 diabetes (T1D) impaired tolerance promotes destruction of insulin-producing ß-cells. The development of autoantigen-specific vaccination strategies for Foxp3(+)Treg-induction and prevention of islet autoimmunity in patients is still in its infancy. Here, using human haematopoietic stem cell-engrafted NSG-HLA-DQ8 transgenic mice, we provide direct evidence for human autoantigen-specific Foxp3(+)Treg-induction in vivo. We identify HLA-DQ8-restricted insulin-specific CD4(+)T cells and demonstrate efficient human insulin-specific Foxp3(+)Treg-induction upon subimmunogenic vaccination with strong agonistic insulin mimetopes in vivo. Induced human Tregs are stable, show increased expression of Treg signature genes such as Foxp3, CTLA4, IL-2Rα and TIGIT and can efficiently suppress effector T cells. Such Foxp3(+)Treg-induction does not trigger any effector T cells. These T1D vaccine candidates could therefore represent an expedient improvement in the challenge to induce human Foxp3(+)Tregs and to develop novel precision medicines for prevention of islet autoimmunity in children at risk of T1D.


Asunto(s)
Diabetes Mellitus Tipo 1/inmunología , Factores de Transcripción Forkhead/inmunología , Regulación de la Expresión Génica/inmunología , Insulina/inmunología , Activación de Linfocitos/inmunología , Autotolerancia/inmunología , Linfocitos T Reguladores/inmunología , Vacunas/inmunología , Adolescente , Adulto , Animales , Autoantígenos/inmunología , Autoinmunidad/inmunología , Antígeno CTLA-4/genética , Antígeno CTLA-4/inmunología , Niño , Preescolar , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Femenino , Factores de Transcripción Forkhead/genética , Antígenos HLA-DQ/genética , Trasplante de Células Madre Hematopoyéticas , Humanos , Tolerancia Inmunológica/inmunología , Subunidad alfa del Receptor de Interleucina-2/genética , Subunidad alfa del Receptor de Interleucina-2/inmunología , Masculino , Ratones , Ratones Transgénicos , Receptores Inmunológicos/genética , Receptores Inmunológicos/inmunología , Adulto Joven
17.
BMJ Open ; 6(5): e011144, 2016 05 18.
Artículo en Inglés | MEDLINE | ID: mdl-27194320

RESUMEN

INTRODUCTION: Type 1 diabetes can be diagnosed at an early presymptomatic stage by the detection of islet autoantibodies. The Fr1da study aims to assess whether early staging of type 1 diabetes (1) is feasible at a population-based level, (2) prevents severe metabolic decompensation observed at the clinical manifestation of type 1 diabetes and (3) reduces psychological distress through preventive teaching and care. METHODS AND ANALYSIS: Children aged 2-5 years in Bavaria, Germany, will be tested for the presence of multiple islet autoantibodies. Between February 2015 and December 2016, 100 000 children will be screened by primary care paediatricians. Islet autoantibodies are measured in capillary blood samples using a multiplex three-screen ELISA. Samples with ELISA results >97.5th centile are retested using reference radiobinding assays. A venous blood sample is also obtained to confirm the autoantibody status of children with at least two autoantibodies. Children with confirmed multiple islet autoantibodies are diagnosed with pre-type 1 diabetes. These children and their parents are invited to participate in an education and counselling programme at a local diabetes centre. Depression and anxiety, and burden of early diagnosis are also assessed. RESULTS: Of the 1027 Bavarian paediatricians, 39.3% are participating in the study. Overall, 26 760 children have been screened between February 2015 and November 2015. Capillary blood collection was sufficient in volume for islet autoantibody detection in 99.46% of the children. The remaining 0.54% had insufficient blood volume collected. Of the 26 760 capillary samples tested, 0.39% were positive for at least two islet autoantibodies. DISCUSSION: Staging for early type 1 diabetes within a public health setting appears to be feasible. The study may set new standards for the early diagnosis of type 1 diabetes and education. ETHICS DISSEMINATION: The study was approved by the ethics committee of Technische Universität München (Nr. 70/14).


Asunto(s)
Autoanticuerpos/sangre , Diabetes Mellitus Tipo 1/sangre , Islotes Pancreáticos/inmunología , Tamizaje Masivo/métodos , Estado Prediabético/sangre , Estado Prediabético/diagnóstico , Recolección de Muestras de Sangre , Capilares , Cuidadores/educación , Preescolar , Consejo Dirigido , Diagnóstico Precoz , Femenino , Glutamato Descarboxilasa/inmunología , Humanos , Masculino , Educación del Paciente como Asunto , Estado Prediabético/psicología , Datos Preliminares , Proteínas Tirosina Fosfatasas Clase 8 Similares a Receptores/inmunología , Proyectos de Investigación , Estrés Psicológico/sangre , Estrés Psicológico/etiología , Transportador 8 de Zinc/inmunología
18.
Diabetes Technol Ther ; 18(11): 687-693, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27552135

RESUMEN

BACKGROUND: Testing for beta cell autoantibodies is used for wide-scale identification of early stages of type 1 diabetes. This requires suitable screening assays. We aimed to establish screening that utilized a first step assay (3 Screen) able to detect autoantibodies to the target antigens glutamic acid decarboxylase-65 (GAD), insulinoma-associated antigen 2 (IA-2), and zinc transporter 8 (ZnT8) to identify children positive for multiple beta cell autoantibodies. METHODS: An ELISA format was used where plates were coated with a mixture of recombinant GAD, IA-2, and ZnT8325W/R-dimer molecules. The performance was determined in venous blood from 686 first-degree relatives of patients with type 1 diabetes, and 200 patients at onset of type 1 diabetes, and applied as a screening assay in capillary blood from 33,639 general population children. RESULTS: The 3 Screen assay sensitivity for detecting autoantibody-positive patients at onset of type 1 diabetes was similar to that achieved by separate radiobinding assays (RBAs) for antibodies to GAD, IA-2, and ZnT8. Results in venous and capillary serum were correlated (R = 0.987). At a threshold corresponding to the 98th centile (29.1 U/mL) of all 33,639 capillary samples, the 3 Screen was positive in 123 samples with two or more RBA-positive antibodies to insulin, GAD, IA-2, or ZnT8, 146 with one antibody, and 479 that were RBA negative for beta cell autoantibodies. CONCLUSION: A 3 Screen ELISA was developed that was suitable for first step screening of multiple beta cell autoantibodies in capillary blood.


Asunto(s)
Autoanticuerpos/sangre , Capilares , Diabetes Mellitus Tipo 1/inmunología , Ensayo de Inmunoadsorción Enzimática/métodos , Células Secretoras de Insulina/inmunología , Adolescente , Proteínas de Transporte de Catión/inmunología , Niño , Femenino , Glutamato Descarboxilasa/inmunología , Humanos , Masculino , Proteínas Tirosina Fosfatasas Clase 8 Similares a Receptores/inmunología , Sensibilidad y Especificidad , Transportador 8 de Zinc
19.
Science ; 346(6207): 332-5, 2014 Oct 17.
Artículo en Inglés | MEDLINE | ID: mdl-25278508

RESUMEN

Light-matter interaction has played a central role in understanding as well as engineering new states of matter. Reversible coupling of excitons and photons enabled groundbreaking results in condensation and superfluidity of nonequilibrium quasiparticles with a photonic component. We investigated such cavity-polaritons in the presence of a high-mobility two-dimensional electron gas, exhibiting strongly correlated phases. When the cavity was on resonance with the Fermi level, we observed previously unknown many-body physics associated with a dynamical hole-scattering potential. In finite magnetic fields, polaritons show distinct signatures of integer and fractional quantum Hall ground states. Our results lay the groundwork for probing nonequilibrium dynamics of quantum Hall states and exploiting the electron density dependence of polariton splitting so as to obtain ultrastrong optical nonlinearities.

20.
J Phycol ; 49(5): 838-47, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27007310

RESUMEN

Currently, very few studies address the relationship between diversity and biomass/lipid production in primary producer communities for biofuel production. Basic studies on the growth of microalgal communities, however, provide evidence of a positive relationship between diversity and biomass production. Recent studies have also shown that positive diversity-productivity relationships are related to an increase in the efficiency of light use by diverse microalgal communities. Here, we hypothesize that there is a relationship between diversity, light use, and microalgal lipid production in phytoplankton communities. Microalgae from all major freshwater algal groups were cultivated in treatments that differed in species richness and functional group richness. Polycultures with high functional group richness showed more efficient light use and higher algal lipid content with increasing species richness. There was a clear correlation between light use and lipid production in functionally diverse communities. Hence, a powerful and cost-effective way to improve biofuel production might be accomplished by incorporating diversity related, resource-use-dynamics into algal biomass production.

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