Changes in Signal Intensity of the Dentate Nucleus and Globus Pallidus in Pediatric Patients: Impact of Brain Irradiation and Presence of Primary Brain Tumors Independent of Linear Gadolinium-based Contrast Agent Administration.

Purpose To determine whether whole-brain irradiation, chemotherapy, and primary brain pathologic conditions affect magnetic resonance (MR) imaging signal changes in pediatric patients independent of the administration of gadolinium-based contrast agents (GBCAs). Materials and Methods This institutional review board-approved, HIPAA-compliant study included 144 pediatric patients who underwent intravenous GBCA-enhanced MR imaging examinations (55 patients with primary brain tumors and whole-brain irradiation, 19 with primary brain tumors and chemotherapy only, 52 with primary brain tumors without any treatment, and 18 with neuroblastoma without brain metastatic disease). The signal intensities (SIs) in the globus pallidus (GP), thalamus (T), dentate nucleus (DN), and pons (P) were measured on unenhanced T1-weighted images. GP:T and DN:P SI ratios were compared between groups by using the analysis of variance and were analyzed relative to group, total cumulative number of doses of GBCA, age, and sex by using multivariable linear models. Results DN:P ratio for the radiation therapy group was greater than that for the other groups except for the group of brain tumors treated with chemotherapy (P < .05). The number of GBCA doses was correlated with the DN:P ratio for the nontreated brain tumor group (P < .0001). The radiation therapy-treated brain tumor group demonstrated higher DN:P ratios than the nontreated brain tumor group for number of doses less than or equal to 10 (P < .0001), whereas ratios in the nontreated brain tumor group were higher than those in the radiation therapy-treated brain tumor group for doses greater than 20 (P = .05). The GP:T ratios for the brain tumor groups were greater than that for the neuroblastoma group (P = .01). Conclusion Changes in SI of the DN and GP that are independent of the administration of GBCA occur in patients with brain tumors undergoing brain irradiation, as well as in patients with untreated primary brain tumors. © RSNA, 2017.

Cerebral Oxygenation and Acceleration in Pediatric and Neonatal Interfacility Transport.

OBJECTIVE: The purpose of this study is to measure peak acceleration forces during interfacility transport; examine whether drops in cerebral oxygenation occurred; and test the associations between cerebral oxygenation, acceleration, and patient positioning. METHODS: A cerebral oximeter (INVOS-5100C; Somanetics, Minneapolis, MN) monitored regional saturation of oxygen (rSO2 [cerebral oxygenation]) in pediatric and neonatal patients (N = 24) transported between facilities by ground ambulance, helicopter, or fixed wing aircraft. An accelerometer (GP1; SENSR, Georgetown, TX) bolted to the isolette or gurney recorded z-axis (aligned with the spine) accelerations. RESULTS: The z-axis peak accelerations (absolute values of g) by transport type were as follows: ground ambulance takeoff mean = 0.16 and landing mean = 0.08, helicopter takeoff mean = 0.16 and landing mean = 0.05, fixed wing aircraft takeoff mean = 0.14 and landing mean = 0.20. During takeoff, 2 of 7 patients in the head-to-front of vehicle position experienced rSO2 drop. During landing, 4 of 13 patients in the head-to-back of vehicle position experienced rSO2 drop. There were no significant associations of rSO2 drop during takeoff and landing with patient positioning or with z-axis peak acceleration. CONCLUSION: Acceleration forces of pediatric and neonatal interfacility transport are small and comparable in magnitude. The relationship between rSO2 drop and patient positioning was not significant in this pilot study.

Effects of vitamin D repletion on glycemic control and inflammatory cytokines in adolescents with type 1 diabetes.

OBJECTIVE: Little is known about the relationship between vitamin D deficiency and adolescents with type 1 diabetes. On the basis of adult studies showing that vitamin D improves insulin sensitivity and decreases inflammatory cytokines linked to microvascular complications, we hypothesized that treating vitamin D deficiency in adolescents with type 1 diabetes would improve glycemia and reduce inflammatory markers. RESEARCH DESIGN AND METHODS: This was a randomized, prospective, crossover study of 25 adolescents with type 1 diabetes for at least a year (aged: 13-21 yr; 62% female; 62% Hispanic) and vitamin D deficiency (25-OH vitamin D ≤30 ng/mL). Subjects received vitamin D3 (20 000 IU/week) for 6 months, either immediately or after 6 months of observation. RESULTS: At baseline, 63% of subjects screened were vitamin D deficient and randomized. Interleukin-6 (IL-6) was significantly higher in the vitamin D deficient group compared with the sufficient group (medians: 0.36 vs. 0.18) (p = 0.026), whereas neither C-reactive protein (CRP) nor tumor necrosis factor-α (TNF-α) differed. Vitamin D treatment increased serum levels of 25-OH vitamin D from 22 ± 5.3 to 34.3 ± 12.1 ng/mL (p < 0.01). However, treatment did not affect glycated hemoglobin (HbA1c), insulin dosage, CRP, interleukin-6 (IL-6), or TNF-α. CONCLUSIONS: Vitamin D deficiency is prevalent in the adolescent type 1 diabetes population, and could be associated with changes in inflammatory markers. However, vitamin D repletion over 6 months did not affect glycemia or markers of inflammation in our study, highlighting the need for additional research to validate these findings.

Pilot study to evaluate the effects of tetrahydrobiopterin on adult individuals with phenylketonuria with measurable maladaptive behaviors.

OBJECTIVES: To evaluate the effects of tetrahydrobiopterin (BH4) on maladaptive behavior in patients with phenylketonuria (PKU). METHODS: In an effort to determine if BH4 has any effects on the central nervous system, we studied 10 individuals with PKU and measurable maladaptive behaviors for 1 year. Behavioral assessments using the Vineland Adaptive Behavior Scales-Second Edition and a PKU Behavior Checklist were obtained at baseline, 6 months, and at the end of the study. Biochemical measures including plasma amino acids were obtained quarterly, and phenylalanine (Phe) and tyrosine (Tyr) were obtained monthly. RESULTS: Out of the 10 subjects, 2 were responders to BH4, as determined by a blood Phe reduction >30%. While blood Phe in the 8 nonresponders did not change significantly throughout the study, their Tyr levels were significantly higher at 6 months (p=0.012), but not at 12 months (p=0.23). By the end of the study, 8 subjects exhibited fewer maladaptive behaviors on the components of the Vineland Maladaptive Behavior Index, and all 10 had lower total scores on the PKU Behavior Checklist. CONCLUSION: These findings suggest that there may be direct effects of BH4 on the central nervous system, independent of lowering blood Phe.

Percutaneous progesterone delivery via cream or gel application in postmenopausal women: a randomized cross-over study of progesterone levels in serum, whole blood, saliva, and capillary blood.

OBJECTIVE: This study aims to investigate the distribution of progesterone in venous whole blood, venous serum, fingertip capillary blood, and saliva after its topical application in both cream and gel formulations. METHODS: Ten postmenopausal women were randomized to receive 80 mg of progesterone cream or gel applied daily for 14 days, crossing over after a 14-day washout. On the last day of each treatment period, venous blood, fingertip capillary blood, and saliva were sampled frequently for 24 hours after the final application. RESULTS: After progesterone cream or gel application, serum progesterone levels rose gradually, reaching a peak at 9 and 8 hours, respectively; AUC(0-24) h was significantly higher with cream (12.39 vs 8.32 ng h mL(-1), P = 0.0391). Whole venous blood levels followed a pattern similar to that of serum but were considerably lower. Saliva progesterone showed a peak at 1 and 6 hours after cream and gel application, respectively, and C(max) was comparable with cream and gel. Saliva AUC(0-24) h was substantially higher than the corresponding area under the curve for serum or whole blood but did not differ significantly by delivery method (39.02 and 58.37 ng h mL(-1), P = 0.69). In capillary blood, C(max) was reached at the same time (8 h) and was similar with both formulations; AUC(0-24) h was also similar with both formulations (1,056 ng h mL(-1) for cream and 999 ng h mL(-1) for gel) but was dramatically higher than the corresponding areas under the curve for venous serum and whole blood. CONCLUSIONS: After application of topical progesterone, saliva and capillary blood levels are approximately 10-fold and 100-fold greater, respectively, than those seen in serum or whole blood. High capillary blood and saliva levels indicate high absorption and transport of progesterone to tissues. Reliance on serum levels of progesterone for monitoring topical dose could lead to underestimation of tissue levels and consequent overdose.

Effect of finasteride on serum levels of androstenedione, testosterone and their 5α-reduced metabolites in men at risk for prostate cancer.

Studies show that treatment of men with 5α-reductase inhibitors such as finasteride is effective for the primary prevention of prostate cancer. Although it is known that finasteride treatment suppresses serum levels of dihydrotestosterone (DHT) and its distal metabolite, 5α-androstane-3α,17ß-diol glucuronide (3α-diol G), and increases serum testosterone (T) levels, little is known about its effect on other precursors and metabolites of DHT, as well as on the relationship of these androgens to prostate specific antigen (PSA), a marker of prostatic intraepithelial neoplasia. The present study provides new data on the effect of finasteride on precursors and metabolites of DHT. Fifty-three men, ages 57-79 years, with elevated PSA levels (>4ng/ml), were randomized to treatment with finasteride (5mg/day) or observation (controls) for 12 months. Blood samples were obtained at baseline, 1, 3, 6 and 12 months for measurement of PSA, androstenedione (A), T, DHT, 3α-diol G, androsterone glucuronide (ADT G) and DHT sulfate (DHT S) in serum by validated, highly specific radioimmunoassays. Statistical analysis was carried out using mixed model ANOVA and t-tests. In the control group, PSA and androgen levels were unchanged throughout the 12 months of treatment. In the finasteride group, PSA, DHT, DHT S, 3α-diol G and ADT G decreased from baseline to 1 month by 23.2%, 78.7%, 71.0%, 75.7% and 43.0%, respectively. The change in PSA decreased further to 46.1% and 55.1% at 3 and 12 months of treatment, respectively, whereas the decrease in androgens observed at 1 month did not change by more than 6.9% for DHT, DHT S and 3α-diol G in the subsequent months of sampling. However, the decline in ADT G was only 22.2% at month 3, and remained essentially at this level after that time. In contrast, T and A increased significantly from baseline, and the increase in A of approximately 34.5% was about 1.9 times the increase in T (approximately 18.3%). The present data suggest that either 3α-diol G or DHT S may serve as a potential diagnostic marker of intraprostatic 5α-reductase activity during treatment of patients with 5α-reductase inhibitors.

Circulating hematopoietic and endothelial progenitor cells in newborn infants: effects of gestational age, postnatal age and clinical stress in the first 3 weeks of life.

INTRODUCTION: Circulating endothelial progenitor cells (EPC) are bone marrow derived progenitors that can be mobilized by erythropoietin or in response to tissue injury, and participate in vascular repair. EPC are understudied in human neonates. Whether EPC frequency in newborn infants may be influenced by gestational age or postnatal stress is unknown. METHODS: Blood samples were collected on day 1 of life and weekly for 3 weeks from hospitalized neonates for plasma erythropoietin and flow cytometry analysis for CD34+, CD34+CD45-, CD34+VEGFR2+ and CD34+CD45-VEGFR2+ cells (EPC). Associations between CD34+ cell subsets and clinical parameters were studied. RESULTS: Forty five patients were enrolled. An inverse correlation with gestational age was observed for CD34+ and CD34+ VEGFR2+ cell frequencies in whole blood (WB) on day 1 (p<0.05). In preterm infants, CD34+ cell frequency decreased with increased postnatal age (p=0.0001) and CD34+VEGFR2+ cell frequency was higher at week 3 than on day 1 in WB (p=0.0002). On day one, CD34+ and CD34+CD45- cell frequencies in the mononuclear cell fraction (MNC) were higher in preterm than term infants (p=0.035 and p=0.049, respectively) but CD34+CD45-VEGFR2+ cell frequency (median 2.2/million MNC versus 3.8/million MNC) and erythropoietin levels were not significantly different. Transient increases in EPC were observed in five infants with infection. Four preterm infants who developed bronchopulmonary dysplasia had undetectable or low EPC through the first 3 weeks of life. CONCLUSIONS: Gestational age and postnatal age influenced circulating CD34+ and CD34+VEGFR2+ but not CD34+CD45-VEGFR2+ (EPC) cell frequencies. Circulating EPC in neonates may be influenced by clinical stress.

Near fatal asthma: clinical and airway biopsy characteristics.

Background. Inflammation and remodeling are integral parts of asthma pathophysiology. We sought to describe the clinical and pathologic features of near fatal asthma exacerbation (NFE). Methods. Bronchial biopsies were collected prospectively from NFE I subjects. Another NFE II group and a moderate severity exacerbation control group (ME II) were retrospectively identified-no biopsies obtained. Results. All NFE II (n = 9) subjects exhibited remodeling and significant inflammation (eosinophilic, neutrophilic). NFE II group (n = 37) had a significant history of prior intubation and inhaled corticosteroids usage compared to ME II group (n = 41). They also exhibited leukocytosis, eosinophilia, and longer hospitalization days. Conclusions. Remodeling, eosinophilic, and neutrophilic inflammation were observed in NFE. NFE is associated with prior intubation and inhaled corticosteroids usage.

Longitudinal neurodevelopmental evaluation of children with opsoclonus-ataxia.

OBJECTIVE: We previously reported on children with opsoclonus-ataxia and found pervasive neurodevelopmental deficits, years after onset, without a clear relationship to treatment modality or timing of treatment. A significant negative correlation of functional status with age at testing raised a question of whether opsoclonus-ataxia is a progressive encephalopathy. We attempted to answer this question with serial testing. In addition, we examined the relationship between clinical course and developmental outcome. METHODS: Thirteen of 17 children with opsoclonus-ataxia, all with neuroblastoma, who were previously reported were reevaluated a second time 2 to 4 years after the initial assessment. One subject who lived out of state was partially reevaluated and is included. Five new subjects (2 with neuroblastoma and 3 without) were also enrolled. Each was evaluated twice at a minimum interval of 1 year between sessions. Intercurrent medical course was recorded, emphasizing medication and relapse history. Cognitive, adaptive behavior, academic, speech and language, and motor abilities were assessed. RESULTS: For the group as a whole, overall standardized, age-adjusted cognitive scores improved. Generally, younger subjects' cognitive and adaptive behavior scores improved more than older subjects. Although all subjects had gains in speech, language, and motor function, some progressed at a slow pace, and in some instances, standard scores dropped. There was a striking influence of clinical course. Although initial presentation was severe and all subjects required high doses of corticosteroids or corticotropin, 5 had a monophasic course and were able to be weaned from treatment without relapses. Fourteen had multiple relapses over the years, generally with reduction of medication or intercurrent illnesses. Of the 5 children with monophasic course, 4 are currently functioning in the average range with a full-scale IQ of > or =90 and age-appropriate academic and adaptive skills. CONCLUSIONS: The results continue to raise concern that opsoclonus-ataxia is sometimes a progressive encephalopathy. A minority of children with opsoclonus-ataxia have a monophasic course. Despite initial severity of symptoms, these children may have a more benign prognosis. For the majority of children with opsoclonus-ataxia, the course includes multiple relapses and requires prolonged treatment. Developmental sequelae are significant in these children with chronic course.

Long-term efficacy of enzyme replacement therapy for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID).

Adenosine deaminase (ADA)-deficient Severe Combined Immunodeficiency (ADA-deficient SCID) is characterized by impaired lymphocyte development and function resulting from the adenosine metabolism defect. Enzyme replacement therapy with polyethylene glycol-conjugated adenosine deaminase (PEG-ADA) minimizes infectious complications of ADA-deficient patients who have not received bone marrow transplantation. In PEG-ADA therapy, enzymatically active ADA continuously circulates to act as a metabolic sink, detoxifying the adenosine and deoxyadenosine metabolites that accumulate to high levels in the absence of ADA. Studies have shown that upon the initiation of PEG-ADA therapy, the absolute numbers of circulating T and B lymphocytes and NK cells increase and protective immune function develops. However, the long-term efficacy is unknown. This retrospective study was designed to assess the long-term effectiveness of PEG-ADA treatment, based on evaluation of the immune function of nine ADA-deficient SCID patients (age 5-15) treated over the past decade. The results showed that the lymphocyte counts of all of the PEG-ADA treated patients were below the normal range at all times, despite initial improvements. A gradual decline of mitogenic proliferative responses occurred after a few years of treatment and normal antigenic response occurred less than expected. To this date, these low numbers and functions of lymphocytes had been adequate to provide protective immunity. These patients should be followed closely to detect a premature decline in immune function with aging in future decades of PEG-ADA therapy.

Pregnancy experiences in the woman with mild hyperphenylalaninemia.

OBJECTIVE: A major issue in maternal phenylketonuria (MPKU) has been whether maternal non-PKU mild hyperphenylalaninemia (MHP) is teratogenic. Such untreated pregnancies and their outcomes are presented on this report. METHODS: Enrolled pregnancies in which the untreated prepregnancy assigned phenylalanine level (APL) was no more than 600 micro mol/L were included in the Maternal PKU Collaborative Study and were followed according to protocol. RESULTS: Forty-eight enrolled women with non-PKU MHP had mean APL 408 +/- 114 micromol/L. They had a total of 58 pregnancies that resulted in live births. Fifty were untreated. Maternal phenylalanine (Phe) levels in the untreated pregnancies decreased during pregnancy for average Phe exposure of 270 +/- 84 micromol/L, virtually identical to the level of 269 +/- 136 micromol/L in the 8 treated pregnancies. Birth measurements in the 50 offspring from untreated pregnancies were within normal limits with z scores of -0.25 for weight, 0.28 for length, and -0.63 for head circumference, although birth head circumference was negatively correlated with maternal APL (r = -0.30). Only 1 offspring had congenital heart disease. Offspring IQ was 102 +/- 15 compared with 96 +/- 14 in the mothers with untreated pregnancies and with 109 +/- 21 in control offspring. CONCLUSION: Maternal non-PKU MHP no more than 600 micromol/L does not require dietary therapy. The naturally lower Phe level during pregnancy seems to protect against teratogenesis.