Psychosocial dwarfism: Detection, evaluation and management

Our experience with 35 children with psychosocial dwarfism (PSD) over five years Is reviewed. Diagnosis and management are difficult. A multidisciplinary approach to the evaluation allows for maximal observation of family psychodynamics and Intervention. Foster placement remains the Intervention of choice in children over four years of age.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/23737/1/0000709.pd

Increasing plasma glucose before the development of type 1 diabetes-the TRIGR study

Objective: The beta-cell stress hypothesis suggests that increased insulin demand contributes to the development of type 1 diabetes. In the TRIGR trial we set out to assess the profile of plasma glucose and HbA1c before the diagnosis of clinical diabetes compared to nondiabetic children. Research Design and Methods: A cohort of children (N = 2159) with an affected first-degree relative and increased HLA risk were recruited 2002-2007 and followed until 2017. To study the relationship between plasma glucose/HbA1c and the development of autoantibodies or clinical disease Kaplan-Meir curves were developed. Mixed models were constructed for plasma glucose and HbA1c separately. Results: A family history of type 2 diabetes was related to an increase in plasma glucose (p < 0.001). An increase in glucose from the previous sample predicted clinical diabetes (p < 0.001) but not autoantibodies. An increase of HbA1c of 20% or 30% from the previous sample predicted the development of any autoantibody (p < 0.003 resp < 0.001) and the development of diabetes (p < 0.002 resp < 0.001. Participants without autoantibodies had lower HbA1c (mean 5.18%, STD 0.24; mean 33.08 mmol/mol, STD 2.85) than those who progressed to clinical disease (5.31%, 0.42; 34.46 mmol/mol, 4.68; p < 0.001) but higher than those who developed any autoantibody (5.10%, 0.30; 32.21 mmol/mol, 3.49; p < 0.001), or multiple autoantibodies (5.11%, 0.35; 32.26 mmol/mol, 3.92; p < 0.003). Conclusions: A pronounced increase in plasma glucose and HbA1c precedes development of clinical diabetes, while the association between plasma glucose or HbA1c and development of autoantibodies is complex. Increased insulin demand may contribute to development of type 1 diabetes.Peer reviewe

Overcoming burdens in the regulation of clinical research in children. Proceedings of a consensus conference, in historical context

<p>Abstract</p> <p>Background</p> <p>Many investigators are concerned that the modes of implementation and enforcement of the federal regulations designed to protect children are unduly impeding pediatric clinical research.</p> <p>Objective</p> <p>To assess regulatory impediments to clinical research involving children and to develop recommendations to ameliorate them.</p> <p>Participants</p> <p>The Pediatric Endocrine Society and The Endocrine Society convened a consensus conference involving experts and stakeholders in patient-oriented research involving children and adolescents in 2008.</p> <p>Consensus process</p> <p>Following presentations that reviewed problematic issues around key regulations, participants divided into working groups to develop potential solutions that could be adopted at local and federal levels. Presentations to the full assembly were then debated. A writing committee then drafted a summary of the discussions and main conclusions, placing them in historical context, and submitted it to all participants for comment with the aim of developing consensus.</p> <p>Conclusions</p> <p>Recommendations designed to facilitate the ethical conduct of research involving children addressed the interpretation of ambiguous regulatory terms such as "minimal risk" and "condition" and called for the development by professional societies of best practice primers for common research procedures that would be informative to both investigators and institutional review boards. A call was issued for improved guidance from the Office for Human Research Protections and Food and Drug Administration as well as for the development by professional societies of a process to monitor progress in improving human subject research regulation. Finally, a need for systematic research to define the nature and extent of institutional obstacles to pediatric research was recognized.</p

The Effects of Protamine on a Murine Leukemia Virus

This study indicated that: (1) i.p. inoculation of protamine into (Rauscher) leukemic mice increased their X death time, (2) protamine was more toxic for leukemic than normal mice and (3) the in vitro reaction between Rauscher virus and protamine reduced its infectivity for mice

Association between family history, early growth and the risk of beta cell autoimmunity in children at risk for type 1 diabetes

Aims/hypothesis The aim of this work was to examine the relationship between family history of type 1 diabetes, birthweight, growth during the first 2 years and development of multiple beta cell autoantibodies in children with a first-degree relative with type 1 diabetes and HLA-conferred disease susceptibility. Methods In a secondary analysis of the Trial to Reduce IDDM in the Genetically at Risk (TRIGR), clinical characteristics and development of beta cell autoantibodies were compared in relation to family history of type 1 diabetes (mother vs father vs sibling) in 2074 children from families with a single affected family member. Results Multiple autoantibodies (>= 2 of 5 measured) developed in 277 (13%) children: 107 (10%), 114 (16%) and 56 (18%) born with a mother, father or sibling with type 1 diabetes, respectively (p <0.001). The HR for time to multiple autoimmunity was 0.54 (95% CI 0.39, 0.75) in offspring of affected mothers (n = 107/1046,p <0.001) and 0.81 (95% CI 0.59, 1.11) (n = 114/722,p = 0.19) in offspring of affected fathers, compared with participants with a sibling with type 1 diabetes (comparator groupn = 56/306). The time to the first autoantibody present (to insulin, GAD, tyrosine phosphatase-related insulinoma-associated 2 molecules, islet cell or zinc transporter 8) was similar in the three groups. Height velocity (zscore/year) in the first 24 months was independently associated with developing multiple antibodies in the total cohort (HR 1.31 [95% CI 1.01, 1.70],p = 0.04). A higher birthweight in children born to an affected mother vs affected father or an affected sibling was not related to the risk of multiple autoimmunity. Conclusions/interpretation The risk of developing multiple autoantibodies was lower in children with maternal type 1 diabetes. For the whole group, this risk of developing multiple autoantibodies was independent of birthweight but was greater in those with increased height velocity during the first 2 years of life. However, the risk associated with paternal type 1 diabetes was not linked to differences in birthweight or early growth.Peer reviewe

A Developmental Analysis of Juxtavascular Microglia Dynamics and Interactions with the Vasculature

Microglia, a resident CNS macrophage, are dynamic cells, constantly extending and retracting their processes as they contact and functionally regulate neurons and other glial cells. There is far less known about microglia-vascular interactions, particularly under healthy steady-state conditions. Here, we use the male and female mouse cerebral cortex to show that a higher percentage of microglia associate with the vasculature during the first week of postnatal development compared with older ages and that the timing of these associations is dependent on the fractalkine receptor (CX3CR1). Similar developmental microglia-vascular associations were detected in the human brain. Using live imaging in mice, we found that juxtavascular microglia migrated when microglia are actively colonizing the cortex and became stationary by adulthood to occupy the same vascular space for nearly 2 months. Further, juxtavascular microglia at all ages associate with vascular areas void of astrocyte endfeet, and the developmental shift in microglial migratory behavior along vessels corresponded to when astrocyte endfeet more fully ensheath vessels. Together, our data provide a comprehensive assessment of microglia-vascular interactions. They support a mechanism by which microglia use the vasculature to migrate within the developing brain parenchyma. This migration becomes restricted on the arrival of astrocyte endfeet such that juxtavascular microglia become highly stationary and stable in the mature cortex. SIGNIFICANCE STATEMENT We report the first extensive analysis of juxtavascular microglia in the healthy, developing, and adult brain. Live imaging revealed that juxtavascular microglia within the cortex are highly motile and migrate along vessels as they are colonizing cortical regions. Using confocal, expansion, super-resolution, and electron microscopy, we determined that microglia associate with the vasculature at all ages in areas lacking full astrocyte endfoot coverage and motility of juxtavascular microglia ceases as astrocyte endfeet more fully ensheath the vasculature. Our data lay the fundamental groundwork to investigate microglia-astrocyte cross talk and juxtavascular microglial function in the healthy and diseased brain. They further provide a potential mechanism by which vascular interactions facilitate microglial colonization of the brain to later regulate neural circuit development

A developmental analysis of juxtavascular microglia dynamics and interactions with the vasculature [preprint]

Microglia, the resident macrophages of the central nervous system (CNS), are dynamic cells, constantly extending and retracting their processes as they contact and functionally regulate neurons and other glial cells. There is far less known about microglia-vascular interactions, particularly under healthy steady-state conditions. Here, we use the male and female mouse cerebral cortex to show that a higher percentage of microglia associate with the vasculature during the first week of postnatal development compared to older ages and the timing of these associations are dependent on the fractalkine receptor (CX3CR1). Similar developmental microglia-vascular associations were detected in the prenatal human brain. Using live imaging in mice, we found that juxtavascular microglia migrated when microglia are actively colonizing the cortex and became stationary by adulthood to occupy the same vascular space for nearly 2 months. Further, juxtavascular microglia at all ages contact vascular areas void of astrocyte endfeet and the developmental shift in microglial migratory behavior along vessels corresponded to when astrocyte endfeet more fully ensheath vessels. Together, our data provide a comprehensive assessment of microglia-vascular interactions. They support a mechanism by which microglia use the vasculature to migrate within the developing brain parenchyma. This migration becomes restricted upon the arrival of astrocyte endfeet when juxtavascular microglia then establish a long-term, stable contact with the vasculature

Mortality trends in type 1 diabetes

WSTĘP. Celem pracy była długoterminowa ocena śmiertelności oraz jej zmian w czasie wśród 1075 pacjentów chorych na cukrzycę typu 1 (początek choroby < 18 rż., chorzy zdiagnozowani w latach 1965-1979), którzy znajdują się w rejestrze obejmującym populację Allegheny County. Ocenę przeprowadzono dnia 1 stycznia 1999 roku. MATERIAŁ I METODY. W badaniu określano śmiertelność w zależności od płci i rasy na osoborok obserwacji. Obliczono również standaryzowane wskaźniki śmiertelności. Stosowano analizę przeżycia oraz model ryzyka proporcjonalnego Coxa. Trendy czasowe oceniono, dzieląc badaną populację na 3 grupy w zależności od roku, w którym postawiono diagnozę cukrzycy (1965-1969, 1970-1974, 1975-1979). WYNIKI. Oceniano przeżycie w 972 przypadkach do dnia 1 stycznia 1999 roku (stopień potwierdzenia 90,4%). Średni czas trwania cukrzycy wynosił 25,2 &plusmn; 5,8 (SD) roku. W całej grupie badanej zmarło 170 osób. Wskaźnik śmiertelności wynosił 627 na 100 000 osobolat (95% CI: 532-728), a standaryzowany wskaźnik śmiertelności - 519 (440-602). Analiza czasu przeżycia metodą Kaplana-Meiera wykazała następujące kumulacyjne wskaźniki przeżycia: 98% po 10 latach, 92,1% po 20 latach i 79,6% po 30 latach trwania cukrzycy. Stwierdzono istotną poprawę wskaźnika przeżycia (za pomocą testu log-rank) w grupie chorych, u których cukrzycę rozpoznano w latach 1965-1969 w porównaniu z grupą chorych zdiagnozowanych pomiędzy rokiem 1975 a 1979 (p = 0,03). Śmiertelność była wyższa u pacjentów pochodzenia afrykańskiego niż u chorych rasy białej, nie obserwowano natomiast różnic między płciami. Poprawa stwierdzana w ostatnich latach dotyczyła obu grup etnicznych i obu płci. WNIOSKI. Obserwowano poprawę długoterminowego przeżycia w grupie, w której diagnozę postawiono w ostatnich latach. Poprawa ta wiąże się z wprowadzeniem oznaczania HbA1c, domowych pomiarów glikemii oraz z poprawą leczenia nadciśnienia tętniczego w latach 80.OBJECTIVES. To investigate long-term mortality and its temporal trends as of 1 January 1999 among the 1,075 patients with type 1 diabetes (onset age < 18 years, diagnosed between 1965 and 1979) who comprise the Allegheny County population- -based registry. RESEARCH DESIGN AND METHODS. Overall, sex- and race-specific mortality rates per person-year of follow- up were determined. Standardized mortality ratios were also calculated. Survival analyses and Cox proportional hazard model were also used. Temporal trends were examined by dividing the cohort into three groups by year of diagnosis (1965&#150;1969, 1970&#150;1974, and 1975&#150;1979). RESULTS. Living status of 972 cases was ascertained as of January 1, 1999 (ascertainment rate 90.4%). The mean duration of diabetes was 25.2 65.8 (SD) years. Overall, 170 deaths were observed. The crude mortality rate was 627 per 100,000 person- years (95% CI 532&#150;728) and standardized mortality ratio was 519 (440&#150;602). Life-table analyses by the Kaplan-Meier method indicated cumulative survival rates of 98.0% at 10 years, 92.1% at 20 years, and 79.6% at 30 years duration of diabetes. There was a significant improvement in the survival rate between the cohort diagnosed during 1965&#150;1969 and that diagnosed during 1975&#150;1979 by the log-rank test (P = 0.03). Mortality was higher in African-Americans than in Caucasians, but there were no differences seen by sex. The improvement in recent years was seen in both ethnic groups and sexes. CONCLUSIONS. An improvement in long-term survival was observed in the more re-cently diagnosed cohort. This improvement is consistent with the introduction of HbA1 testing, home blood glucose monitoring, and improved blood pressure therapy in the 1980s

Association between family history, early growth and the risk of beta cell autoimmunity in children at risk for type 1 diabetes

Aims/hypothesisThe aim of this work was to examine the relationship between family history of type 1 diabetes, birthweight, growth during the first 2 years and development of multiple beta cell autoantibodies in children with a first-degree relative with type 1 diabetes and HLA-conferred disease susceptibility.MethodsIn a secondary analysis of the Trial to Reduce IDDM in the Genetically at Risk (TRIGR), clinical characteristics and development of beta cell autoantibodies were compared in relation to family history of type 1 diabetes (mother vs father vs sibling) in 2074 children from families with a single affected family member.ResultsMultiple autoantibodies (>= 2 of 5 measured) developed in 277 (13%) children: 107 (10%), 114 (16%) and 56 (18%) born with a mother, father or sibling with type 1 diabetes, respectively (p Conclusions/interpretationThe risk of developing multiple autoantibodies was lower in children with maternal type 1 diabetes. For the whole group, this risk of developing multiple autoantibodies was independent of birthweight but was greater in those with increased height velocity during the first 2 years of life. However, the risk associated with paternal type 1 diabetes was not linked to differences in birthweight or early growth.</div

Excess BMI Accelerates Islet Autoimmunity in Older Children and Adolescents

Objective: Sustained excess BMI increases the risk of type 1 diabetes (T1D) in autoantibody-positive relatives without diabetes of patients. We tested whether elevated BMI also accelerates the progression of islet autoimmunity before T1D diagnosis. Research design and methods: We studied 706 single autoantibody-positive pediatric TrialNet participants (ages 1.6-18.6 years at baseline). Cumulative excess BMI (ceBMI) was calculated for each participant based on longitudinally accumulated BMI ≥85th age- and sex-adjusted percentile. Recursive partitioning analysis and multivariable modeling defined the age cut point differentiating the risk for progression to multiple positive autoantibodies. Results: At baseline, 175 children (25%) had a BMI ≥85th percentile. ceBMI range was -9.2 to 15.6 kg/m2 (median -1.91), with ceBMI ≥0 kg/m2 corresponding to persistently elevated BMI ≥85th percentile. Younger age increased the progression to multiple autoantibodies, with age cutoff of 9 years defined by recursive partitioning analysis. Although ceBMI was not significantly associated with progression from single to multiple autoantibodies overall, there was an interaction with ceBMI ≥0 kg/m2, age, and HLA (P = 0.009). Among children ≥9 years old without HLA DR3-DQ2 and DR4-DQ8, ceBMI ≥0 kg/m2 increased the rate of progression from single to multiple positive autoantibodies (hazard ratio 7.32, P = 0.004) and conferred a risk similar to that in those with T1D-associated HLA haplotypes. In participants <9 years old, the effect of ceBMI on progression to multiple autoantibodies was not significant regardless of HLA type. Conclusions: These data support that elevated BMI may exacerbate islet autoimmunity prior to clinical T1D, particularly in children with lower risk based on age and HLA. Interventions to maintain normal BMI may prevent or delay the progression of islet autoimmunity