Intranasal epidermal growth factor treatment rescues neonatal brain injury.

There are no clinically relevant treatments available that improve function in the growing population of very preterm infants (less than 32 weeks' gestation) with neonatal brain injury. Diffuse white matter injury (DWMI) is a common finding in these children and results in chronic neurodevelopmental impairments. As shown recently, failure in oligodendrocyte progenitor cell maturation contributes to DWMI. We demonstrated previously that the epidermal growth factor receptor (EGFR) has an important role in oligodendrocyte development. Here we examine whether enhanced EGFR signalling stimulates the endogenous response of EGFR-expressing progenitor cells during a critical period after brain injury, and promotes cellular and behavioural recovery in the developing brain. Using an established mouse model of very preterm brain injury, we demonstrate that selective overexpression of human EGFR in oligodendrocyte lineage cells or the administration of intranasal heparin-binding EGF immediately after injury decreases oligodendroglia death, enhances generation of new oligodendrocytes from progenitor cells and promotes functional recovery. Furthermore, these interventions diminish ultrastructural abnormalities and alleviate behavioural deficits on white-matter-specific paradigms. Inhibition of EGFR signalling with a molecularly targeted agent used for cancer therapy demonstrates that EGFR activation is an important contributor to oligodendrocyte regeneration and functional recovery after DWMI. Thus, our study provides direct evidence that targeting EGFR in oligodendrocyte progenitor cells at a specific time after injury is clinically feasible and potentially applicable to the treatment of premature children with white matter injury.

Native T1 values identify myocardial changes and stratify disease severity in patients with Duchenne muscular dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked, inherited disorder causing dilated cardiomyopathy with variable onset and progression. Currently we lack objective markers of the effect of therapies targeted towards preventing progression of subclinical cardiac disease. Thus, our aim was to compare the ability of native T1 and extracellular volume (ECV) measurements to differentiate risk of myocardial disease in DMD and controls. METHODS: Twenty boys with DMD and 16 age/gender-matched controls without history predisposing to cardiac fibrosis, but with a clinical indication for cardiovascular magnetic resonance (CMR) evaluation, underwent CMR with contrast. Data points collected include left ventricular ejection fraction (LVEF), left ventricular mass, and presence of late gadolinium enhancement (LGE). Native T1, and ECV regional mapping were obtained using both a modified Look-Locker (MOLLI) and saturation recovery single shot sequence (SASHA) on a 1.5T scanner. Using ordinal logistic regression models, controlling for age and LVEF, LGE-free septal we evaluated the ability native T1 and ECV assessments to differentiate levels of cardiomyopathy. RESULTS: Twenty DMD subjects aged 14.4 ± 4 years had an LVEF of 56.3 ± 7.4 %; 12/20 had LGE, all confined to the lateral wall. Sixteen controls aged 16.1 ± 2.2 years had an LVEF 60.4 ± 5.1 % and no LGE. Native T1 and ECV values were significantly higher in the DMD group (p < 0.05) with both MOLLI and SASHA imaging techniques. Native T1 demonstrated a 50 % increase in the ability to predict disease state (control, DMD without fibrosis, DMD with fibrosis). ECV demonstrated only the ability to predict presence of LGE, but could not distinguish between controls and DMD without fibrosis. CONCLUSIONS: LGE-spared regions of boys with DMD have significantly different native T1 and ECV values compared to controls. Native T1 measurements can identify early changes in DMD patients without the presence of LGE and help predict disease severity more effectively than ECV. Native T1 may be a novel outcome measure for early cardiac therapies in DMD and other cardiomyopathies.

Are asymptomatic carriers of OTC deficiency always asymptomatic? A multicentric retrospective study of risk using the UCDC longitudinal study database.

BACKGROUND: Ornithine transcarbamylase deficiency (OTCD) due to an X-linked OTC mutation, is responsible for moderate to severe hyperammonemia (HA) with substantial morbidity and mortality. About 80% of females with OTCD remain apparently "asymptomatic" with limited studies of their clinical characteristics and long-term health vulnerabilities. Multimodal neuroimaging studies and executive function testing have shown that asymptomatic females exhibit limitations when stressed to perform at higher cognitive load and had reduced activation of the prefrontal cortex. This retrospective study aims to improve understanding of factors that might predict development of defined complications and serious illness in apparent asymptomatic females. A proband and her daughter are presented to highlight the utility of multimodal neuroimaging studies and to underscore that asymptomatic females with OTCD are not always asymptomatic. METHODS: We review data from 302 heterozygote females with OTCD enrolled in the Urea Cycle Disorders Consortium (UCDC) longitudinal natural history database. We apply multiple neuroimaging modalities in the workup of a proband and her daughter. RESULTS: Among the females in the database, 143 were noted as symptomatic at baseline (Sym). We focused on females who were asymptomatic (Asx, n = 111) and those who were asymptomatic initially upon enrollment in study but who later became symptomatic sometime during follow-up (Asx/Sym, n = 22). The majority of Asx (86%) and Asx/Sym (75%) subjects did not restrict protein at baseline, and ~38% of Asx and 33% of Asx/Sym subjects suffered from mild to severe neuropsychiatric conditions such as mood disorder and sleep problems. The risk of mild to severe HA sometime later in life for the Asx and Asx/Sym subjects as a combined group was ~4% (5/133), with ammonia ranging from 77 to 470 µM and at least half (2/4) of subjects requiring hospital admission and nitrogen scavenger therapy. For this combined group, the median age of first HA crisis was 50 years, whereas the median age of first symptom which included neuropsychiatric and/or behavioral symptoms was 17 years. The multimodal neuroimaging studies in female heterozygotes with OTCD also underscore that asymptomatic female heterozygotes with OTCD (e.g., proband) are not always asymptomatic. CONCLUSIONS: Analysis of Asx and Asx/Sym females with OTCD in this study suggests that future evidence-based management guidelines and/or a clinical risk score calculator for this cohort could be useful management tools to reduce morbidity and improve long-term quality of life.

The use of near-infrared spectroscopy during an extubation readiness trial as a predictor of extubation outcome.

OBJECTIVES: To determine whether the measurement of cerebral and somatic regional oxygen saturation during an extubation readiness trial predicts extubation failure in postoperative cardiac patients. DESIGN: Prospective observational study. SETTING: Tertiary care center cardiac ICU. PATIENTS: Pediatric patients 1 day to 21 years old following cardiac surgery for congenital heart disease. Patients were included if they were intubated for greater than 12 hours and were undergoing an extubation readiness trial. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data collection included patient demographic, procedural, laboratory, and physiologic variables. Regional oxygen saturation values were recorded using near-infrared spectroscopy at baseline, during a 2-hour extubation readiness trial, and in the first 2 hours postextubation. Ninety-nine extubation readiness trials were conducted in 79 patients. Adjusting for baseline somatic regional oxygen saturation, logistic regression analysis demonstrated that patients with a decline in their minimum somatic regional oxygen saturation of at least 10% during an extubation readiness trial had a 6-time increased odds of extubation failure (p = 0.02; 95% CI, 1.26-29.8). Receiver-operating characteristic curve analysis demonstrated that a 12% decline in the minimum regional oxygen saturation best predicted extubation failure with 54% sensitivity and 82% specificity. CONCLUSIONS: A 12% decline in somatic regional oxygen saturation during an extubation readiness trial is associated with an increased risk of extubation failure following a successful extubation readiness trial. The addition of somatic regional oxygen saturation measurements to an extubation readiness trial may improve our ability to predict extubation outcome.

Analysis of pediatric autologous PBSC apheresis and transplant: age is a major factor affecting post-transplant toxicity.

BACKGROUND: High-dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT) is used in many therapeutic protocols for pediatric intra- and extra-cranial solid tumors. HCT can be curative, but is associated with significant toxicity. PROCEDURE: Between January 2001 and June 2009, 92 solid tumor patients (age 6 months to 27 years) underwent 94 autologous apheresis procedures at Children's National Medical Center. Out of that group, 71 patients, who underwent 162 autologous HCT, were analyzed for transplant outcomes. Multiple variable modeling was used to identify independent variables related to transplant toxicity outcome measures, such as bacteremia, intensive care admission, and death. Other outcome measures (time to pre-apheresis peripheral blood CD34+ count, product yield, and time to engraftment) were also analyzed. Independent variables included patient-specific variables (age, weight, tumor type, chemotherapy administered, and primary vs. relapsed disease) and harvest or transplant-related variables (total white blood cell and CD34+ cell counts prior to transplant, and quantity of total nucleated cells and CD34+ cells infused during transplant). RESULTS: Transplant toxicity was significantly greater in younger patients (P = 0.001) and in neuroblastoma patients (P = 0.003). The time to neutrophil engraftment, controlling for weight, age, and chemotherapy, was positively related to absolute CD34+ cells/kg infused (P = 0.01). The time to CD34+ recovery pre-apheresis was affected by patient diagnosis (P = 0.05). CONCLUSIONS: Younger patients had increased transplant toxicity, with infants <1 year of age at highest risk for fever, bacteremia, admission to intensive care, and death. Infants would likely benefit from hospitalization after autologous HCT until neutrophil recovery.

Inverse zonation of hepatocyte transduction with AAV vectors between mice and non-human primates.

Gene transfer vectors based on adeno-associated virus 8 (AAV8) are highly efficient in liver transduction and can be easily administered by intravenous injection. In mice, AAV8 transduces predominantly hepatocytes near central veins and yields lower transduction levels in hepatocytes in periportal regions. This transduction bias has important implications for gene therapy that aims to correct metabolic liver enzymes because metabolic zonation along the porto-central axis requires the expression of therapeutic proteins within the zone where they are normally localized. In the present study we compared the expression pattern of AAV8 expressing green fluorescent protein (GFP) in liver between mice, dogs, and non-human primates. We confirmed the pericentral dominance in transgene expression in mice with AAV8 when the liver-specific thyroid hormone-binding globulin (TBG) promoter was used but also observed the same expression pattern with the ubiquitous chicken ß-actin (CB) and cytomegalovirus (CMV) promoters, suggesting that transduction zonation is not caused by promoter specificity. Predominantly pericentral expression was also found in dogs injected with AAV8. In contrast, in cynomolgus and rhesus macaques the expression pattern from AAV vectors was reversed, i.e. transgene expression was most intense around portal areas and less intense or absent around central veins. Infant rhesus macaques as well as newborn mice injected with AAV8 however showed a random distribution of transgene expression with neither portal nor central transduction bias. Based on the data in monkeys, adult humans treated with AAV vectors are predicted to also express transgenes predominantly in periportal regions whereas infants are likely to show a uniform transduction pattern in liver.

Systematic evaluation of AAV vectors for liver directed gene transfer in murine models.

Vectors based on adeno-associated viruses (AAVs) are being evaluated for use in liver-directed gene therapy. Candidates have been preselected on the basis of capsid structure that plays an important role in determining performance profiles. We describe a comprehensive and statistically powered set of mouse studies designed to compare the performance of vectors based on seven novel AAV capsids. The key criteria used to select candidates for successful gene therapy are high level and stable transgene expression in the absence of toxicity. Based on these criteria, the best performing vectors, AAV8, AAVhu.37, and AAVrh.8, will be further evaluated in nonhuman primates (NHPs).

High-dose dexmedetomidine increases the opioid-free interval and decreases opioid requirement after tonsillectomy in children.

PURPOSE: Dexmedetomidine, a selective α(2) adrenoreceptor agonist, has analgesic and sedative properties, minimal impact on respiratory parameters, and reportedly decreases analgesic requirements after surgery. Given its pharmacodynamic profile, dexmedetomidine might have a role for postoperative pain control in children undergoing tonsillectomy. In this study, we hypothesized that dexmedetomidine would delay and decrease opioid requirements after tonsillectomy. METHODS: In a double-blind controlled trial, participants undergoing tonsillectomy were randomized to receive one intravenous dose of fentanyl (1 µg·kg(-1) or 2 µg·kg(-1)) or dexmedetomidine (2 µg·kg(-1) or 4 µg·kg(-1)) immediately after endotracheal intubation. Primary outcomes included requirement for rescue morphine in the initial postoperative period. RESULTS: One hundred and one children were enrolled. During the postoperative period, dexmedetomidine (2 and 4 µg·kg(-1) groups combined) significantly prolonged the opioid-free interval of children who underwent tonsillectomy compared with fentanyl (1 and 2 µg·kg(-1) groups combined) (P < 0.001). Children treated with dexmedetomidine 2 µg·kg(-1) vs dexmedetomidine 4 µg·kg(-1) had similar cumulative incidence curves for time to morphine rescue, whereas there was a small difference in time to first morphine rescue administration when comparing fentanyl 1 µg·kg(-1) vs fentanyl 2 µg·kg(-1). Furthermore, length of stay in the postanesthesia care unit was significantly longer for children treated with dexmedetomidine vs children treated with fentanyl (P = 0.0016). CONCLUSIONS: High-dose dexmedetomidine decreases opioid requirements, prolongs the opioid-free interval after tonsillectomy, and prolongs length of stay in the postanesthesia care unit. It is conceivable that these early opioid-sparing effects could benefit patients at risk for respiratory complications early in the postoperative course after tonsillectomy (e.g., patients with obstructive sleep apnea). (ClinicalTrials.gov number, NCT00654511).

The effect of dexmedetomidine during myringotomy and pressure-equalizing tube placement in children.

BACKGROUND: Bilateral myringotomy (BMT) is a commonly performed otolaryngologic procedure in children. OBJECTIVES: To examine the effects of intranasal dexmedetomidine, an α(2)-adrenoceptor agonist, on time-averaged pain scores, pain control, need for rescue analgesia, and agitation scores in children undergoing BMT. METHODS: We designed a trial to enroll 160 children randomized to one of four groups: two study groups, dexmedetomidine (1 or 2 µg·kg(-1)), or two control groups representing our institutional standards of practice (intranasal fentanyl-2 µg·kg(-1) or acetaminophen as needed postoperatively). RESULTS: After 101 children were enrolled, patient caregivers observed that some enrollees were excessively sedated and required prolonged postanesthesia care unit (PACU) stay. This observation led to an unplanned interim analysis and early trial termination. After data were collected, severe nonnormality of pain and agitation scores necessitated a switch of the outcome to assess repeated measurements of the proportion of patients with pain, severe pain, and agitation. Demographics, time to emergence, and agitation were similar among all groups. The risk of requiring acetaminophen rescue (P < 0.0001) and proportion of patients having pain (P = 0.016) was significantly higher in one control group (rescue analgesia only) compared with fentanyl or dexmedetomidine groups. Importantly, length of stay in the PACU was significantly longer in dexmedetomidine-2 µg·kg(-1)-treated compared with dexmedetomidine-1 µg·kg(-1)-treated, fentanyl-treated, or the control group, P = 0.0037. CONCLUSIONS: In this trial, we were unable to answer the original question as to the role of dexmedetomidine on time-averaged pain and agitation scores after BMT. However, our findings clearly demonstrate that in children undergoing BMT, at higher doses, dexmedetomidine significantly prolongs length of stay in the PACU.

Does prearrival communication from a poison center to an emergency department decrease time to activated charcoal for pediatric poisoning?

OBJECTIVE: A poison center plays an important role in directing appropriate care, which is critical in reducing morbidity due to poisoning. Activated charcoal (AC) is one intervention for some poisonings. This study examined whether children with a poisoning who were preannounced by a poison center received AC earlier than patients without a referral. METHODS: A retrospective review of AC administration in children aged 0 to 18 years in a pediatric emergency department (ED) from 2000 to 2006 was performed. Abstracted covariates were poison center referral status, age, sex, acuity, disposition, transportation mode, triage time, and time of AC administration. Analysis of variance controlling for covariates tested the equality of mean time intervals between the groups with and without a poison center referral. RESULTS: Three hundred fifty-one cases met the inclusion criteria. One hundred thirty-five (39%) were male. Eighty cases (23%) had a poison center referral. Time from triage to charcoal administration for patients with a poison center referral was a mean of 59 (SD, 34) minutes. Time for the group without a referral was a mean of 71 (SD, 43) minutes (P = 0.0036). CONCLUSIONS: Advanced communication from a poison center was associated with earlier administration of AC in the ED for this population. Nevertheless, the duration to charcoal administration was frequently suboptimal. Triage and prehospital practices should be reexamined to improve timeliness of AC when indicated and consider exclusion of administration if beyond an appropriate time frame. Advanced notification should be the paradigm for all poison centers, and early response protocols for poison center referrals should be used by EDs.

Hemoglobin glycation index: a robust measure of hemoglobin A1c bias in pediatric type 1 diabetes patients.

BACKGROUND: The hemoglobin glycation index (HGI) assesses biological variation in A1c after accounting for the effect of mean blood glucose (MBG). Previous studies minimized analytical variation that could mask biological variation and showed that HGI was consistent within individuals over time and positively associated with risk for microvascular complications. We tested the hypothesis that biological variation in A1c can be assessed by HGI calculated using routine MBG and A1c data obtained from a typical diabetes clinic. METHODS: Self-monitored MBG and A1c were collected from charts of 202 pediatric type 1 diabetes patients attending 1612 clinic visits over 6 yr. Predicted A1c was calculated from the linear regression equation of A1c on MBG in the study population. HGI was calculated by subtracting predicted A1c from observed A1c. Patients were divided into low, moderate, and high HGI tertile groups. RESULTS: Patients used 12 models of glucose meters. Download protocols varied with clinical practice over time. A1c was measured by multiple assays and laboratories. Despite this analytical heterogeneity, HGI was significantly different between individuals and correlated within individuals. MBG (mean ± SD, mg/dL) was similar in the low (186 ± 31), moderate (195 ± 28), and high (199 ± 42) HGI groups. A1c (%) was significantly different (p < 0.0001) in the low (7.6 ± 0.7), moderate (8.4 ± 0.7), and high (9.6 ± 1.1) HGI groups. CONCLUSION: Biological variation in A1c is a robust quantitative trait that can be assessed using HGI calculated from routine clinic data. This suggests that HGI could be used clinically for more personalized assessment of complications risk.

Does emergency medical services transport for pediatric ingestion decrease time to activated charcoal?

OBJECTIVE: Activated charcoal (AC) is a potentially beneficial intervention for some toxic ingestions. When administered within one hour, it can reduce absorption of toxins by up to 75%. This study evaluated whether pediatric emergency department (ED) patients arriving by ambulance receive AC more quickly than patients arriving by alternative modes of transport. METHODS: This was a retrospective review of AC administration in children in a large, urban pediatric ED from January 2000 until January 2006. Patients aged 0-18 years were identified from pharmacy billing codes and the National Capital Poison Center's database. Charts were reviewed for age, gender, triage acuity, disposition, transportation mode, triage time, and time of AC administration; analysis of variance (ANOVA) controlling for these covariates tested the equality of mean time intervals. RESULTS: Pharmacy billing codes identified 394 cases, and poison center records identified 34 cases. Three hundred fifty-one patients met the inclusion criteria. One hundred thirty-eight (39%) were male; 216 (61%) were female. Two-hundred twenty-one (63%) patients were aged 5 years and under; in this subset, 116 were male and 105 were female. Twenty-one (6%) patients were aged 6-12 years; nine were male and 12 were female. One hundred nine (31%) patients were aged 13-18 years; 13 were male and 96 were female. One hundred eighteen (34%) arrived by emergency medical services (EMS). Time from triage to charcoal administration in patients transported via EMS was a mean of 65 minutes (standard deviation [SD] = 44 minutes). Time for the alternative transport group was a mean of 70 minutes (SD = 40 minutes) (p = 0.59). In the subset of patients triaged as most acute and arriving by EMS, time to charcoal administration was a mean of 42 minutes (SD = 22 minutes); time to AC in the alternative transport group was a mean of 67.8 minutes (SD = 42 minutes) (p = 0.013). CONCLUSION: The sickest patients arriving by EMS had a faster time from triage to AC administration. However, when comparing patients of all triage categories, EMS arrival alone did not influence time to AC administration. Furthermore, the interval from triage to charcoal administration was often insufficiently long. This suboptimal timing of charcoal administration demonstrates the need for reevaluation of triage and prehospital practices.

Assessment of relationship between nutrition and growth in pediatric hemodialysis patients.

OBJECTIVE: Nutrition and growth are important outcome indicators in pediatric (Ped) hemodialysis (HD) patients. We hypothesized that there is a discrepancy among traditional measures of nutrition, and that adequate nutrition may not reliably predict growth. METHODS: We assessed longitudinal nutrition and growth parameters in 14 Ped HD patients over 1 year. Their age at the end of the study was 15.9 +/- 0.6 years, SEM. RESULTS: For the entire cohort over 1 year, serum albumin (Alb) was 4.3 +/- 0.0 g/dL, and the normalized protein catabolic rate (nPCR) was 1.0 +/- 0.0 (correlation, 0.33; P < .0001). The relationship between Alb and nPCR was significant in only 4/14 (29%). The mean standard deviation and variance were higher for Alb (0.27 +/- 0.03) compared with nPCR (0.18 +/- 0.02). The body mass index percentile (BMI%) was 35.5 +/- 2.9, the percent ideal body weight (%IBW) was 96.2 +/- 1.5, the height-SDS, or standard deviation score (Ht-SDS) was -1.30 +/- 0.11, and the percent weight change (PWC) was +4.9% +/- 1.9%. The highest incidence of reaching our targets for growth was seen for the BMI% (64% of patients) and PWC (79% of patients). The target for Ht-SDS was attained in only 21%. There was a significant negative relationship between Alb and nPCR with BMI%, %IBW, and Ht-SDS, and a significant positive relationship between Alb and nPCR with PWC. CONCLUSION: We conclude that the relationship between Alb and nPCR is weak in individual patients, and that adequate nutrition does not reliably predict growth in Ped HD patients.

Cross-sectional multicenter study of patients with urea cycle disorders in the United States.

Inherited urea cycle disorders comprise eight disorders (UCD), each caused by a deficiency of one of the proteins that is essential for ureagenesis. We report on a cross-sectional investigation to determine clinical and laboratory characteristics of patients with UCD in the United States. The data used for the analysis was collected at the time of enrollment of individuals with inherited UCD into a longitudinal observation study. The study has been conducted by the Urea Cycle Disorders Consortium within the Rare Diseases Clinical Research Network (RDCRN) funded by the National Institutes of Health. One-hundred eighty-three patients were enrolled into the study. Ornithine transcarbamylase (OTC) deficiency was the most frequent disorder (55%), followed by argininosuccinic aciduria (16%) and citrullinemia (14%). Seventy-nine percent of the participants were white (16% Latinos), and 6% were African American. Intellectual and developmental disabilities were reported in 39% with learning disabilities (35%) and half had abnormal neurological examination. Sixty-three percent were on a protein restricted diet, 37% were on Na-phenylbutyrate and 5% were on Na-benzoate. Forty-five percent of OTC deficient patients were on L-citrulline, while most patients with citrullinemia (58%) and argininosuccinic aciduria (79%) were on L-arginine. Plasma levels of branched-chain amino acids were reduced in patients treated with ammonia scavenger drugs. Plasma glutamine levels were higher in proximal UCD and in neonatal type disease. The RDCRN allows comprehensive analyses of rare inherited UCD, their frequencies and current medical practices.

Lipoprotein profile changes in children after renal transplantation in the modern immunosuppression era.

There are little data on prevalence of dyslipidemia in pediatric kidney TX recipients in the modern IS era. LP profiles of 38 TX recipients receiving triple IS with MMF, prednisone, and tacrolimus were compared with those of 11 children on HD using mixed model multiple linear regression analysis of repeated measures after adjusting for age, sex, ethnicity, duration of ESRD, and BMI. TC and LDL levels were significantly higher in TX compared with HD, whereas there was no difference in the HDL, VLDL, and TG levels. TC and LDL in TX children had no association with age, sex, ethnicity, and duration of ESRD, stage of chronic kidney disease, DM, BMI percentile, and gain in percentage IBW. Five children treated with atrovastatin had a significant reduction in TC, LDL, VLDL, and TG at 3-6 months post-treatment compared with pretreatment levels, whereas there was no difference in HDL or tacrolimus levels after treatment. No side effects of therapy were observed. Although dyslipidemia remains a significant problem in pediatric renal TX recipients in the modern era, the prevalence may have decreased with use of newer IS drugs.

Mean blood glucose and biological variation have greater influence on HbA1c levels than glucose instability: an analysis of data from the Diabetes Control and Complications Trial.

OBJECTIVE: Mean blood glucose (MBG) over 2-3 months is a strong predictor of HbA(1c) (A1C) levels. Glucose instability, the variability of blood glucose levels comprising the MBG, and biological variation in A1C (BV) have also been suggested as predictors of A1C independent of MBG. To assess the relative importance of MBG, BV, and glucose instability on A1C, we analyzed patient data from the Diabetes Control and Complications Trial (DCCT). RESEARCH DESIGN AND METHODS: A glucose profile set and sample for A1C were collected quarterly over the course of the DCCT from each participant (n = 1,441). The glucose profile set consisted of seven samples, one each drawn before and 90 min after breakfast, lunch, and dinner and one before bedtime. MBG and glucose instability (SD of blood glucose [SDBG]) were calculated as the arithmetic mean and SD of glucose profile set samples for each visit, respectively. A statistical model was developed to predict A1C from MBG, SDBG, and BV, adjusted for diabetes duration, sex, treatment group, stratum, and race. RESULTS: Data from 32,977 visits were available. The overall model was highly statistically significant (log likelihood = -41,818.75, likelihood ratio chi2[7] = 7,218.71, P > chi2 = 0.0000). MBG and BV had large influences on A1C based on their standardized coefficients. SDBG had only 1/14 of the impact of MBG and 1/10 of the impact of BV. CONCLUSIONS: MBG and BV have a large influence on A1C, whereas SDBG is relatively unimportant. Consideration of BV as well as MBG in the interpretation of A1C may enhance our ability to monitor diabetes management and predict complications.

Potential outcome factors in subacute combined degeneration: review of observational studies.

BACKGROUND: Subacute combined degeneration is an acquired myelopathy caused by vitamin B12 deficiency. Therapy with B12 leads to improvement in most but to complete recovery in only a few patients. Prognostic indicators in subacute combined degeneration are unknown; therefore, predicting complete recovery of neurologic deficits is challenging. PURPOSE: To identify potential correlates of outcome and to generate hypotheses concerning predictors of complete resolution of neurologic deficits in subacute combined degeneration. DATA SOURCE: We searched EMBASE (1974 to October 2005), MEDLINE (1968 to October 2005), and references from identified reports. REPORTS SELECTION: Reports of patients with subacute combined degeneration containing results of magnetic resonance imaging (MRI) and description of outcome and 1 patient treated by the authors. DATA EXTRACTION, SYNTHESIS: We extracted data from 45 reports and 57 patients (36 males, 21 females; age range: 10 to 81) with a diagnosis of subacute combined degeneration, and estimated the strength of association between clinical, laboratory, and radiological factors and complete resolution of signs and symptoms. RESULTS: Eight patients (14%) achieved clinical resolution and 49 (86%) improved with B12 therapy. The absence of sensory dermatomal deficit, Romberg, and Babinski signs were associated with a higher complete resolution rate. Patients with MRI lesions in < or = 7 segments and age less than 50 also appear to have higher rates of complete resolution. CONCLUSIONS: B12 therapy is reported to stop progression and improve neurologic deficits in most patients with subacute combined degeneration. However, complete resolution only occurs in a small percentage of patients and appears to be associated with factors suggestive of less severe disease at the time of diagnosis.

Morbidities associated with bullying behaviors in adolescents. School based study of American adolescents.

UNLABELLED: To assess the prevalence of bullying behaviors and morbidities, including overweight/obesity and frequent physical and emotional symptoms, and the associations between such morbidities and frequent involvement in bullying behaviors among US adolescents in grades 6 through 10. DESIGN, SETTING, AND PARTICIPANTS: This study was based on an analysis of US data from the 1998 World Health Organization Health Behavior in School-aged Children survey. The survey provides nationally representative, cross-sectional survey information on 15,686 US students in grades 6 through 10. OUTCOME MEASURES: Involvement in bullying as a victim and/or as a bully; body mass index; and self-reported headaches, stomachaches, backaches, dizziness, irritability, "feeling low", "feeling nervous", and sleeping difficulties. RESULTS: Fifteen per cent of the students were involved in bullying others and/or were victims of bullies at least once a week. The bullying activities took place both at school and elsewhere. Students who suffered from at least one or more frequent physical or emotional symtom, occuring several times a week, were at 2.4 to 3.5 times more likely to be involved in frequent bullying incidents, as compared to students, who did not experience frequent symptoms. CONCLUSIONS: The present study confirmed that frequent participation in bullying behaviors, as a bully, a victim, or both, was associated with poor health status. The existence of a morbidity spectrum associated with participation in bullying behaviors is important information for pediatric practice and merits further investigation.

A comparison of the Glycosylation Gap and Hemoglobin Glycation Index in patients with diabetes.

PROBLEM: The Glycosylation Gap (GGAP) based on fructosamine (F) measurement and the Hemoglobin Glycation Index (HGI) based on mean blood glucose (MBG) are two indices of between-individual differences in glycated hemoglobin (HbA1c) adjusted for glycemia. We sought to simultaneously compare GGAP with HGI and other estimates of glycemia. METHODS: HbA1c, F, and MBG level were obtained at a clinic visit from 62 patients with Type 1 diabetes. GGAP and HGI were calculated from the data as previously described. The variables were compared by correlation analysis. The concordance of patient classification by GGAP and HGI was compared by weighted kappa test. RESULTS: The mean HbA1c=11.1+/-2.7%, F=372.0+/-136.6 mol/l, MBG=186.5+/-58.4 mg/dl, HGI=0.0+/-2.0, and GGAP=0.0+/-1.9. MBG, HbA1c, and F were all highly correlated with each other. The HGI and GGAP were highly correlated (r=.73, P<.0001) and similar in both magnitude and direction. There was good agreement between HGI and GGAP classifications of patients into high, moderate, and low glycation groups (P<.0075). CONCLUSIONS: GGAP and MBG give similar information regarding between-patient differences in HbA1c among patients with diabetes. Thus, biological variation in HbA1c is not an artifact of variability in glucose measurements comprising the MBG. Individual patient factors influence the intracellular glycation of HbA1c in addition to the effect of extracellular glycemia, which is manifested as a between-individual biological variation in HbA1c.