Nutritional and Metabolic Biomarkers in Autism Spectrum Disorders: An Exploratory Study.

CONTEXT: Autism spectrum disorder (ASD) is currently on the rise, now affecting approximately 1 in 68 children in the United States according to a 2010 surveillance summary from the Centers for Disease Control and Prevention (CDC). This figure is an estimated increase of 78% from the figure in 2002. The CDC suggests that more investigation is needed to understand this astounding increase in autism in such a short period. OBJECTIVE: The aim of this pilot study was to determine whether a group of children with ASD exhibited similar variations in a broad array of potential correlates, including medical histories, symptoms, genetics, and multiple nutritional and metabolic biomarkers. DESIGN: This study was a retrospective, descriptive chart review. SETTING: The study took place at the University of Kansas Medical Center (KUMC). PARTICIPANTS: Participants were 7 children with ASD who had sought treatment at the Integrative Medicine Clinic at the medical center. RESULTS: A majority of the children exhibited an elevated copper:zinc ratio and abnormal vitamin D levels. Children also demonstrated abnormal levels of the essential fatty acids: (1) α-linolenic acid (ALA)- C13:3W3, and (2) linoleic acid (LA)-C18:2W6; high levels of docosahexaenoic acid (DHA); and an elevated ω-6:ω-3 ratio. Three of 7 children demonstrated abnormal manganese levels. Children did not demonstrate elevated urine pyruvate or lactate but did have abnormal detoxification markers. Three of 7 patients demonstrated abnormalities in citric acid metabolites, bacterial metabolism, and fatty acid oxidation markers. A majority demonstrated elevated serum immunoglobulin G (IgG) antibodies to casein, egg whites, egg yolks, and peanuts. A majority had absent glutathione S-transferase (GSTM) at the 1p13.3 location, and 3 of 7 children were heterozygous for the glutathione S-transferase I105V (GSTP1). A majority also exhibited genetic polymorphism of the mitochondrial gene superoxide dismutase A16V (SOD2). CONCLUSIONS: The findings from this small group of children with ASD points to the existence of nutritional, metabolic, and genetic correlates of ASD. These factors appear to be important potential abnormalities that warrant a case control study to evaluate their reliability and validity as markers of ASD.

Headstrong intervention for pediatric migraine headache: a randomized clinical trial.

BACKGROUND: The purpose of this study was to evaluate the efficacy of a self-guided CD-ROM program ("Headstrong") containing cognitive-behavioral self-management strategies versus an educational CD-ROM program for treating headaches, headache-related disability, and quality of life. METHODS: Participants were 35 children ages 7-12 years with migraine recruited from one university medical center and two children's hospital headache clinics. Participants were randomly assigned to complete the Headstrong or educational control CD-ROM program over a 4-week period. Data on headache frequency, duration, and severity, migraine-related disability, and quality of life (QOL) were obtained at baseline, post-intervention, and 3-months post-intervention. RESULTS: At post-intervention, Headstrong resulted in lower severity (on a 10-point scale) than the control group by child report (5.06 ± 1.50 SD vs. 6.25 ± 1.92 SD, p = 0.03, ES = 0.7). At 3-months post-intervention, parents reported less migraine-related disability (on the PedMIDAS) in the Headstrong group compared to the control group (1.36 ± 2.06 SD vs. 5.18 ± 6.40 SD; p = 0.04, ES = 0.8). There were no other group differences at post treatment or at 3-months post-intervention. CONCLUSIONS: When compared to an educational control, Headstrong resulted in lower pain severity at post-treatment and less migraine-related disability at 3-months post-intervention, by child and parent report respectively. Headache frequency and quality of life did not change more for Headstrong versus control. Additional research is needed on the Headstrong Program to increase its efficacy and to test it with a larger sample recruited from multiple centers simultaneously.

Effects of lactose-containing vs lactose-free infant formula on postprandial superior mesenteric artery flow in term infants.

BACKGROUND: Dietary dextrose and fructose may promote vascular inflammation and endothelial dysfunction. In certain infant populations, altered postprandial mesenteric hyperemia (PPH) may increase risk for feeding intolerance. OBJECTIVE: To compare superior mesenteric artery (SMA) PPH following feeds of lactose-containing (LC) formula vs lactose-free (LF; dextrose + sucrose) formula. METHODS: In a 2 × 2 crossover study with 6 term newborns, 3 received LC first followed by LF 3 hours later. The remaining 3 received the reverse order. Ultrasound measures of pre- and postprandial SMA flow, diameter, and resistance were taken 5 minutes preprandial and 10, 30, and 40 minutes postprandial. RESULTS: Mean ± SD age and weight (n = 6) were 24.1 ± 2.3 hours and 3.1 ± 0.21 kg. Formula intake was similar for LC and LF (22.5 ± 2.8 mL and 25 ± 1.8 mL, respectively; P = .076). Both formulas increased SMA flow at 10 and 30 minutes. However, postprandial flow was greater for LC overall (P = .004) and especially at 30 minutes (LC 103 ml/min, 52% increase vs LF 92.7 ml/min, 31% increase; P = .014). For both formulas, vasodilation was seen at 10 and 30 minutes and was overall significantly greater following LC than following LF (9.1% VS 6.5%; P = .028). Both formulas elicited significant decreases in sma vascular resistance over the 10- to 30-minute period (overall P = .016). However, decreases did not differ across formulas (P = .672). CONCLUSIONS: The LC formula elicited a greater SMA PPH response than did LF. SMA flow for both formulas was within normal limits; thus, differences are likely inconsequential for a term newborn. However, in a vulnerable preterm infant, differences may become significant.

Beyond matching on the mean in developmental disabilities research.

The matching of groups is a traditional way to control for confounding variables in developmental disabilities research. The equivalency of means across groups is routinely checked for these variables, but not the homogeneity of their variances or the shapes of their distributions. In the present paper, it is argued that group matching can go seriously wrong unless it directly confronts the distributional concerns by the use of well-known statistical indices and very simple graphical displays of the distributions. The question of the equivalency of item response profiles is also addressed since two participants or two groups of participants can obtain the same overall score on the matching variable by passing different items. In this case, the matching cannot be considered satisfactory because of poor concordance between the molar (overall score) and molecular (item scores) levels of matching. Angoff's Delta plot method, a statistical approach for detecting differential item functioning across small groups is described. It is promising as a simple way to prove whole test/individual item correspondence and, in addition, a useful tool for making post hoc statistical analyses at the item level on the dependent variables.

Discrepancies between creatinine- and cystatin C-based equations: implications for identification of chronic kidney disease in the general population.

OBJECTIVE: Early detection and treatment of chronic kidney disease (CKD) is important for slowing the progression of the disease and decreasing the associated risk of cardiovascular disease. This study examined how two creatinine-based and two cystatin C-based equations for calculating estimated glomerular filtration rate (eGFR) perform relative to each other in identifying CKD in a large cohort of community-dwelling individuals. MATERIAL AND METHODS: A total of 1630 adults were recruited from the Reykjavik area. Each subject's eGFR was calculated using the Modification of Diet in Renal Disease (MDRD) Study and Cockroft-Gault equations, and two cystatin C-based equations. The prevalence of decreased eGFR obtained by the four equations was compared and the relative performance of the equations examined. RESULTS: The MDRD equation labelled significantly fewer individuals as having CKD (5.3%) relative to the other equations (12.8-19.7%). Agreement between equations was limited, with up to one-third of subjects diagnosed as having CKD by the MDRD equation being classified as normal by other equations. Correlations between creatinine- and cystatin C-based equations varied with age, gender and diuretic use. CONCLUSIONS: The MDRD equation results in lower population-wide estimates of CKD relative to the other equations tested. An understanding of the performance of these equations is critical when they are used for estimating the prevalence of CKD in a population-wide setting or for diagnosing the disorder in clinical practice.

Effectiveness of teaching cardiac auscultation to residents during an elective pediatric cardiology rotation.

This study aimed to assess the effectiveness of randomized tracks of prerecorded cardiac sounds as a teaching tool for cardiac auscultation. The study focused on recognizing murmurs when present, distinguishing functional from organic murmurs, and detecting heart disease by auscultation. At both pre- and posttesting, 26 residents listened to 15 randomized tracks of live-recorded cardiac sounds and identified key features. The results indicate that the residents improved at detecting any murmur (66% vs 76%, p = 0.007) and functional murmur (37% vs 54%, p = 0.048), and marginally improved at detecting organic murmur (75% vs 84%, p = 0.129). Detection of absence of murmur declined slightly (69% vs 62%, p = 0.723). The posttest difference in identifying organic versus functional murmurs was striking (84% vs 54%, p < 0.001). Detection of heart disease (sensitivity) improved significantly (76% to 86%, p = 0.016), but there was scant improvement in detecting no disease (specificity) (55% vs 59%, p = 0.601). The residents increased in their ability to detect heart disease when present. However, the false-positive rate for a diagnosis of heart disease remained quite high. To ensure that appropriate referrals will be made, teaching should specifically target the confident recognition of functional murmurs.

Effect of low-density lipoprotein apheresis on inflammatory and noninflammatory high-density lipoprotein cholesterol.

Low-density lipoprotein (LDL) apheresis, a treatment for familial hypercholesterolemia, significantly decreases LDL cholesterol and inflammatory markers such as C-reactive protein, CD40 ligand, and tissue factor. LDL apheresis also decreases high-density lipoprotein (HDL) cholesterol, which might be considered therapeutically counterproductive because HDL is known to be anti-inflammatory. However, recent studies have shown that HDL also possesses proinflammatory properties, as seen in its ability to alter LDL-induced monocyte chemotactic activity. We examined the acute effects of LDL apheresis on inflammatory HDL activity in 13 patients with familial hypercholesterolemia and cardiovascular disease who had been receiving bi-weekly LDL apheresis treatments. Immediately before and immediately after treatment, each patient's plasma was collected for analysis of inflammatory HDL and full lipid profile. LDL apheresis reduced LDL by 52% (from 208 +/- 89 to 99 +/- 48 mg/dl, p <0.002), and HDL decreased by 16% (49 +/- 15 to 41 +/- 13 mg/dl, p <0.003). At the same time, inflammatory HDL activity (in migrated monocytes per high-power field) decreased from 22 +/- 4 to 14 +/- 2, a 37% acute reduction (p <0.003). Moreover, inflammatory HDL before HDL apheresis was highly correlated with its acute reduction (r(s) = 0.85, p <0.001). In conclusion, our findings indicate that, in addition to decreasing LDL, LDL apheresis also decreases inflammatory HDL. The clinical significance of reducing inflammatory HDL is currently unknown, and further research is needed to examine its potential benefit for cardiovascular disease.

The epidemiology of pediatric environmental exposures.

Currently, the only national databases that are available to aid in a search to assess the effect of environmental exposures on children's health are those provided by the Pediatric Environmental Health Specialty Units and poison control centers. Both have limitations and are largely deficient in accurate, helpful numbers. Both, however, offer insight into factors that are important to the public and health care professionals and provide some outcome data to measure morbidity and mortality. This article presents an analysis of the information in these databases about children's exposure to toxic environmental substances.

Electronically monitored adherence to medications by newly diagnosed patients with juvenile rheumatoid arthritis.

OBJECTIVE: To describe patterns of adherence to nonsteroidal antiinflammatory drugs (NSAIDs) in newly diagnosed patients with juvenile rheumatoid arthritis (JRA), and to examine demographic and disease-related variables as potential predictors of adherence. METHODS: Adherence to NSAIDs was monitored in 48 children with JRA (mean age 8.6 years) over 28 consecutive days using an electronic monitoring device. Measures of disease activity (active joint counts, morning stiffness) and demographics (age, sex, ethnicity, socioeconomic status) were also obtained. RESULTS: Using an 80% adherence cut point, 25 (52%) patients were classified as adherent and 23 (48%) as nonadherent. There was considerable variability across patients, with full adherence (taking all doses on time) ranging from 0 to 100% of the monitored days. Logistic regression showed that active joint count and socioeconomic status were the only significant predictors. Both were positively related to adherence. The model correctly classified 70.5% of patients as either adherent or nonadherent (Cox and Snell R(2) = 0.295, P = 0.0005). CONCLUSION: Children newly diagnosed with JRA are more likely to adhere to an NSAID regimen if they have a greater number of active joints or their families have higher socioeconomic status. The former finding suggests that children's adherence is symptom-driven, while the latter suggests that families of lower socioeconomic status deserve special attention to address adherence issues.

Pyridoxamine lowers oxalate excretion and kidney crystals in experimental hyperoxaluria: a potential therapy for primary hyperoxaluria.

In order to prevent kidney stones and nephrolithiasis in hyperoxaluria, a new treatment that specifically reduces oxalate production and therefore urinary oxalate excretion would be extremely valuable. Pyridoxamine(PM) could react with the carbonyl intermediates of oxalate biosynthesis, glycolaldehyde and glyoxylate, and prevent their metabolism to oxalate. In PM treated rats, endogenous urinary oxalate levels were consistently lower and became statistically different from controls after 12 days of experiment. In ethylene glycol-induced hyperoxaluria, PM treatment resulted in significantly lower (by ~50%) levels of urinary glycolate and oxalate excretion compared to untreated hyperoxaluric animals, as well as in a significant reduction in calcium oxalate crystal formation in papillary and medullary areas of the kidney. These results, coupled with favorable toxicity profiles of PM in humans, show promise for the therapeutic use of PM in primary hyperoxaluria and other kidney stone diseases.

Functional characteristics of disruptive behavior in developmentally disabled children with and without autism.

Expanding on Reese et al. [2003], functional behavioral assessment interviews [O'Neill et al., 1997] concerning disruptive behavior were conducted with parents of 23 children with autism (6 females, 17 males, chronological ages [CA] 24-60 months) and 23 controls without autism pair-matched for CA, developmental age and sex. All children exhibited frequent disruptive behavior. The interviews suggested that matched control children's disruptive behavior typically functioned to gain attention or items, or to escape demands in general. This was also true for girls with autism. For boys with autism, disruptive behavior more often functioned to (a) escape demands that interfere with repetitive behavior, (b) retain access to an item used in repetitive routines, or (c) avoid idiosyncratically aversive sensory stimuli (e.g., ordinary household noises). These results emphasize the importance of considering behavioral characteristics that are associated with sex and specific disorders or syndromes when conducting functional behavioral assessments.

Pyridoxamine lowers kidney crystals in experimental hyperoxaluria: a potential therapy for primary hyperoxaluria.

BACKGROUND: Primary hyperoxaluria is a rare genetic disorder of glyoxylate metabolism that results in overproduction of oxalate. The disease is characterized by severe calcium oxalate nephrolithiasis and nephrocalcinosis, resulting in end-stage renal disease (ESRD) early in life. Most patients eventually require dialysis and kidney transplantation, usually in combination with the replacement of the liver. Reduction of urinary oxalate levels can efficiently decrease calcium oxalate depositions; yet, no treatment is available that targets oxalate biosynthesis. In previous in vitro studies, we demonstrated that pyridoxamine can trap reactive carbonyl compounds, including intermediates of oxalate biosynthesis. METHODS: The effect of PM on urinary oxalate excretion and kidney crystal formation was determined using the ethylene glycol rat model of hyperoxaluria. Animals were given 0.75% to 0.8% ethylene glycol in drinking water to establish and maintain hyperoxaluria. After 2 weeks, pyridoxamine treatment (180 mg/day/kg body weight) started and continued for an additional 2 weeks. Urinary creatinine, glycolate, oxalate, and calcium were measured along with the microscopic analysis of kidney tissues for the presence of calcium oxalate crystals. RESULTS: Pyridoxamine treatment resulted in significantly lower (by approximately 50%) levels of urinary glycolate and oxalate excretion compared to untreated hyperoxaluric animals. This was accompanied by a significant reduction in calcium oxalate crystal formation in papillary and medullary areas of the kidney. CONCLUSION: These results, coupled with favorable toxicity profiles of pyridoxamine in humans, show promise for therapeutic use of pyridoxamine in primary hyperoxaluria and other kidney stone diseases.

Accuracy of analog telephonic stethoscopy for pediatric telecardiology.

OBJECTIVE: Wide-bandwidth electronic stethoscopy is reliable and accurate for pediatric telecardiology. We tested a much less expensive and more convenient system for the same purpose, a narrow-bandwidth telephonic stethoscope (TS). METHODS: Seventy-six consecutive patients (mean age: 10.0; standard deviation: 6.5 years) in a pediatric cardiology outpatient clinic were studied. One pediatric cardiologist examined the patients with his acoustic stethoscope (AS); a second examined them within a few minutes using a remote TS. A nurse placed the TS chest piece as directed by the remote examiner via intercom, but neither video examination nor conversation with the parent/patient were permitted. Examiners independently recorded the stethoscope findings for all heart sounds, all murmurs, and heart disease (present/absent). TS accuracy was indexed using the kappa statistic for TS/AS agreement and for TS agreement with auscultatory findings predicted from echocardiographic (echo) studies (N = 49). RESULTS: TS/AS agreement was satisfactory for presence/absence of heart disease (kappa = 0.63) and for organic, functional, vibratory, diastolic aortic, and diastolic pulmonic murmurs (kappa range: 0.65-0.75). For other specific murmurs and all heart sounds, TS/AS agreement was either unsatisfactory (kappa < or = 0.60) or indeterminate because prevalence was 0. TS-AS agreement improved when the TS was used by the more-experienced TS examiner and with patients at least 5 years of age. When the older children were examined by the more TS-experienced examiner, the TS-echo comparison yielded kappa = 0.90, raw agreement = 0.96, sensitivity = 0.94, and specificity = 1.00. CONCLUSIONS: In pediatric patients, a narrow-bandwidth telephonic stethoscope can accurately distinguish between functional and organic murmurs and thus can detect heart disease. Accuracy is greatest when the instrument is used by an experienced examiner with patients at least 5 years of age.

Predictors of prosthesis survival, growth, and functional status following mechanical mitral valve replacement in children aged <5 years, a multi-institutional study.

BACKGROUND: Prosthesis survival, growth, and functional status after initial mechanical mitral valve replacement (MVR) in children <5 years of age are poorly defined. METHODS AND RESULTS: The experience of the Pediatric Cardiac Care Consortium (45 centers, 1982 to 1999), which included 102 survivors after initial MVR, was analyzed. Median follow-up: 6.0 years (interquartile range: 3.0 to 10.6 years; 96% complete). Twenty-nine survivors had undergone a second MVR at an interval of 4.8+/-3.8 years after initial MVR. Reasons for second MVR were prosthetic valve stenosis 24 (83%), thrombosis 4 (14%), and endocarditis 1 (3%). For those who had second MVR, prosthesis sizes were: first MVR 19+/-2 mm and second MVR 22+/-3 mm, and their body weight increased from 7.4+/-2.8 kg to 16.8+/-10.5 kg. To identify risk factors for having a second MVR, the 29 second MVR survivors were compared with the 73 who did not have a second MVR on first-MVR demographic and perioperative variables. By univariate analysis, patients with shorter prosthesis survival were younger, weighed less, had smaller prostheses, greater ratio of prosthesis size:body weight, were less likely to have a St. Jude prosthesis and more likely to have Shone's syndrome. By multivariate analysis prosthesis survival was predicted only by first MVR age: odds ratio (OR) 7.7 (95% confidence interval [CI] 2.6-22.7) and prosthesis size: OR 6.8 (95% CI 2.6-18.2). High risk patients (age <2 years and prosthesis <20 mm at first MVR) had an OR=46.3 compared with low-risk patients (age >or=2 years and prosthesis >or=20 mm at first MVR) over similar follow-up intervals. Using first-MVR weight-matched controls, body weight increased similarly for patients <2 years old who had a second MVR versus those who did not. Prosthesis size, however, differed significantly, with second MVR patients having smaller prostheses at first MVR (18.7+/-0.8 mm versus 22.4+/-3.6 mm, P=0.017). An estimate of current New York Heart Association (NYHA) functional status was class 1 in 76%, class 2 in 22%, and classes 3 or 4 in 2%. CONCLUSIONS: Prosthesis survival can be predicted based on first MVR age and prosthesis size. Somatic growth is comparable regardless of the need for second MVR. There is an increment in prosthesis size at second MVR, suggesting continued annular growth. Significant limitation of function after MVR is uncommon. MVR may be an appropriate strategy for children <5 years old despite the risk of second MVR in the youngest patients in whom the smallest prostheses are used.