Arkansas Children's Hospital

Methods are described for the extraction and analysis of hydrophilic and lipophilic antioxidants, using modifications of the oxygen radical absorbing capacity (ORAC(FL)) procedure. These methods provide, for the first time, the ability to obtain a measure of "total antioxidant capacity" in the protein free plasma, using the same peroxyl radical generator for both lipophilic and hydrophilic antioxidants. Separation of the lipophilic and hydrophilic antioxidant fractions from plasma was accomplished by extracting with hexane after adding water and ethanol to the plasma (hexane/plasma/ethanol/water, 4:1:2:1, v/v). Lipophilic and hydrophilic antioxidants were efficiently partitioned between hexane and aqueous solvents. Conditions for controlling temperature effects and decreasing assay variability using fluorescein as the fluorescent probe were validated in different laboratories. Incubation (37 degrees C for at least 30 min) of the buffer to which AAPH was dissolved was critical in decreasing assay variability. Lipophilic antioxidants represented 33.1 +/- 1.5 and 38.2 +/- 1.9% of the total antioxidant capacity of the protein free plasma in two independent studies of 6 and 10 subjects, respectively. Methods are described for application of the assay techniques to other types of biological and food samples.

Recent clinical data on vancomycin pharmacokinetics and pharmacodynamics suggest a reevaluation of current dosing and monitoring recommendations. The previous 2009 vancomycin consensus guidelines recommend trough monitoring as a surrogate marker for the target area under the curve over 24 hours to minimum inhibitory concentration (AUC/MIC). However, recent data suggest that trough monitoring is associated with higher nephrotoxicity. This document is an executive summary of the new vancomycin consensus guidelines for vancomycin dosing and monitoring. It was developed by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists vancomycin consensus guidelines committee. These consensus guidelines recommend an AUC/MIC ratio of 400-600 mg*hour/L (assuming a broth microdilution MIC of 1 mg/L) to achieve clinical efficacy and ensure safety for patients being treated for serious methicillin-resistant Staphylococcus aureus infections.

Autism spectrum disorders (ASDs) are common and clinically heterogeneous neurodevelopmental disorders. Gastrointestinal disorders and associated symptoms are commonly reported in individuals with ASDs, but key issues such as the prevalence and best treatment of these conditions are incompletely understood. A central difficulty in recognizing and characterizing gastrointestinal dysfunction with ASDs is the communication difficulties experienced by many affected individuals. A multidisciplinary panel reviewed the medical literature with the aim of generating evidence-based recommendations for diagnostic evaluation and management of gastrointestinal problems in this patient population. The panel concluded that evidence-based recommendations are not yet available. The consensus expert opinion of the panel was that individuals with ASDs deserve the same thoroughness and standard of care in the diagnostic workup and treatment of gastrointestinal concerns as should occur for patients without ASDs. Care providers should be aware that problem behavior in patients with ASDs may be the primary or sole symptom of the underlying medical condition, including some gastrointestinal disorders. For these patients, integration of behavioral and medical care may be most beneficial. Priorities for future research are identified to advance our understanding and management of gastrointestinal disorders in persons with ASDs.

Importance: Refinement of criteria for multisystem inflammatory syndrome in children (MIS-C) may inform efforts to improve health outcomes. Objective: To compare clinical characteristics and outcomes of children and adolescents with MIS-C vs those with severe coronavirus disease 2019 (COVID-19). Setting, Design, and Participants: Case series of 1116 patients aged younger than 21 years hospitalized between March 15 and October 31, 2020, at 66 US hospitals in 31 states. Final date of follow-up was January 5, 2021. Patients with MIS-C had fever, inflammation, multisystem involvement, and positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcriptase-polymerase chain reaction (RT-PCR) or antibody test results or recent exposure with no alternate diagnosis. Patients with COVID-19 had positive RT-PCR test results and severe organ system involvement. Exposure: SARS-CoV-2. Main Outcomes and Measures: Presenting symptoms, organ system complications, laboratory biomarkers, interventions, and clinical outcomes. Multivariable regression was used to compute adjusted risk ratios (aRRs) of factors associated with MIS-C vs COVID-19. Results: Of 1116 patients (median age, 9.7 years; 45% female), 539 (48%) were diagnosed with MIS-C and 577 (52%) with COVID-19. Compared with patients with COVID-19, patients with MIS-C were more likely to be 6 to 12 years old (40.8% vs 19.4%; absolute risk difference [RD], 21.4% [95% CI, 16.1%-26.7%]; aRR, 1.51 [95% CI, 1.33-1.72] vs 0-5 years) and non-Hispanic Black (32.3% vs 21.5%; RD, 10.8% [95% CI, 5.6%-16.0%]; aRR, 1.43 [95% CI, 1.17-1.76] vs White). Compared with patients with COVID-19, patients with MIS-C were more likely to have cardiorespiratory involvement (56.0% vs 8.8%; RD, 47.2% [95% CI, 42.4%-52.0%]; aRR, 2.99 [95% CI, 2.55-3.50] vs respiratory involvement), cardiovascular without respiratory involvement (10.6% vs 2.9%; RD, 7.7% [95% CI, 4.7%-10.6%]; aRR, 2.49 [95% CI, 2.05-3.02] vs respiratory involvement), and mucocutaneous without cardiorespiratory involvement (7.1% vs 2.3%; RD, 4.8% [95% CI, 2.3%-7.3%]; aRR, 2.29 [95% CI, 1.84-2.85] vs respiratory involvement). Patients with MIS-C had higher neutrophil to lymphocyte ratio (median, 6.4 vs 2.7, P < .001), higher C-reactive protein level (median, 152 mg/L vs 33 mg/L; P < .001), and lower platelet count (<150 ×103 cells/μL [212/523 {41%} vs 84/486 {17%}, P < .001]). A total of 398 patients (73.8%) with MIS-C and 253 (43.8%) with COVID-19 were admitted to the intensive care unit, and 10 (1.9%) with MIS-C and 8 (1.4%) with COVID-19 died during hospitalization. Among patients with MIS-C with reduced left ventricular systolic function (172/503, 34.2%) and coronary artery aneurysm (57/424, 13.4%), an estimated 91.0% (95% CI, 86.0%-94.7%) and 79.1% (95% CI, 67.1%-89.1%), respectively, normalized within 30 days. Conclusions and Relevance: This case series of patients with MIS-C and with COVID-19 identified patterns of clinical presentation and organ system involvement. These patterns may help differentiate between MIS-C and COVID-19.

OBJECTIVE: To develop evidence-based guidelines for preventing or treating neonatal pain and its adverse consequences. Compared with older children and adults, neonates are more sensitive to pain and vulnerable to its long-term effects. Despite the clinical importance of neonatal pain, current medical practices continue to expose infants to repetitive, acute, or prolonged pain. DESIGN: Experts representing several different countries, professional disciplines, and practice settings used systematic reviews, data synthesis, and open discussion to develop a consensus on clinical practices that were supported by published evidence or were commonly used, the latter based on extrapolation of evidence from older age groups. A practical format was used to describe the analgesic management for specific invasive procedures and for ongoing pain in neonates. RESULTS: Recognition of the sources of pain and routine assessments of neonatal pain should dictate the avoidance of recurrent painful stimuli and the use of specific environmental, behavioral, and pharmacological interventions. Individualized care plans and analgesic protocols for specific clinical situations, patients, and health care settings can be developed from these guidelines. By clearly outlining areas where evidence is not available, these guidelines may also stimulate further research. To use the recommended therapeutic approaches, clinicians must be familiar with their adverse effects and the potential for drug interactions. CONCLUSION: Management of pain must be considered an important component of the health care provided to all neonates, regardless of their gestational age or severity of illness.

CONTEXT: The mixed results of success among QI initiatives may be due to differences in the context of these initiatives. METHODS: The business and health care literature was systematically reviewed to identify contextual factors that might influence QI success; to categorize, summarize, and synthesize these factors; and to understand the current stage of development of this research field. FINDINGS: Forty-seven articles were included in the final review. Consistent with current theories of implementation and organization change, leadership from top management, organizational culture, data infrastructure and information systems, and years involved in QI were suggested as important to QI success. Other potentially important factors identified in this review included: physician involvement in QI, microsystem motivation to change, resources for QI, and QI team leadership. Key limitations in the existing literature were the lack of a practical conceptual model, the lack of clear definitions of contextual factors, and the lack of well-specified measures. CONCLUSIONS: Several contextual factors were shown to be important to QI success, although the current body of literature lacks adequate definitions and is characterized by considerable variability in how contextual factors are measured across studies. Future research should focus on identifying and developing measures of context tied to a conceptual model that examines context across all levels of the health care system and explores the relationships among various aspects of context.

BACKGROUND: Because of advancements in care, there has been a decline in mortality from congenital heart defects (CHDs) over the past several decades. However, there are no current empirical data documenting the number of people living with CHDs in the United States. Our aim was to estimate the CHD prevalence across all age groups in the United States in the year 2010. METHODS: The age-, sex-, and severity-specific observed prevalence of CHDs in Québec, Canada, in the year 2010 was assumed to equal the CHD prevalence in the non-Hispanic white population in the United States in 2010. A race-ethnicity adjustment factor, reflecting differential survival between racial-ethnic groups through 5 years of age for individuals with a CHD and that in the general US population, was applied to the estimated non-Hispanic white rates to derive CHD prevalence estimates among US non-Hispanic blacks and Hispanics. Confidence intervals for the estimated CHD prevalence rates and case counts were derived from a combination of Taylor series approximations and Monte Carlo simulation. RESULTS: We estimated that ≈2.4 million people (1.4 million adults, 1 million children) were living with CHDs in the United States in 2010. Nearly 300 000 of these individuals had severe CHDs. CONCLUSIONS: Our estimates highlight the need for 2 important efforts: planning for health services delivery to meet the needs of the growing population of adults with CHD and the development of surveillance data across the life span to provide empirical estimates of the prevalence of CHD across all age groups in the United States.

BACKGROUND: Heavy proteinuria and progressive renal injury recur after transplantation in up to 40 percent of patients with renal failure caused by idiopathic focal segmental glomerulosclerosis. A circulating factor may be responsible for this recurrence. METHODS: To determine whether patients with focal segmental glomerulosclerosis have a circulating factor capable of causing glomerular injury, we tested serum samples from 100 patients with the disorder in an in vitro assay of glomerular permeability to albumin. Of the 56 patients who had undergone renal transplantation, 33 had recurrences. Sixty-four patients, many of whom had undergone transplantation, were being treated with dialysis. Thirty-one patients with other renal diseases and nine normal subjects were also studied. RESULTS: The 33 patients with recurrent focal segmental glomerulosclerosis after transplantation had a higher mean (+/-SE) value for permeability to albumin (0.47+/-0.06) than the normal subjects (0.06+/-0.07) or the patients who did not have recurrences (0.14+/-0.06). After plasmapheresis in six patients with recurrences, the permeability was reduced (from 0.79+/-0.06 to 0.10+/-0.05, P = 0.008), and proteinuria was significantly decreased. Patients with corticosteroid-sensitive nephrotic syndrome or with membranous nephropathy after transplantation had low levels of serum activity. The circulating factor bound to protein A and hydrophobic-interaction columns and had an apparent molecular mass of about 50 kd. CONCLUSIONS: A circulating factor found in some patients with focal segmental glomerulosclerosis is associated with recurrent disease after renal transplantation and may be responsible for initiating the renal injury.

BACKGROUND: For egg allergy, dietary avoidance is the only currently approved treatment. We evaluated oral immunotherapy using egg-white powder for the treatment of children with egg allergy. METHODS: In this double-blind, randomized, placebo-controlled study, 55 children, 5 to 11 years of age, with egg allergy received oral immunotherapy (40 children) or placebo (15). Initial dose-escalation, build-up, and maintenance phases were followed by an oral food challenge with egg-white powder at 10 months and at 22 months. Children who successfully passed the challenge at 22 months discontinued oral immunotherapy and avoided all egg consumption for 4 to 6 weeks. At 24 months, these children underwent an oral food challenge with egg-white powder and a cooked egg to test for sustained unresponsiveness. Children who passed this challenge at 24 months were placed on a diet with ad libitum egg consumption and were evaluated for continuation of sustained unresponsiveness at 30 months and 36 months. RESULTS: After 10 months of therapy, none of the children who received placebo and 55% of those who received oral immunotherapy passed the oral food challenge and were considered to be desensitized; after 22 months, 75% of children in the oral-immunotherapy group were desensitized. In the oral-immunotherapy group, 28% (11 of 40 children) passed the oral food challenge at 24 months and were considered to have sustained unresponsiveness. At 30 months and 36 months, all children who had passed the oral food challenge at 24 months were consuming egg. Of the immune markers measured, small wheal diameters on skin-prick testing and increases in egg-specific IgG4 antibody levels were associated with passing the oral food challenge at 24 months. CONCLUSIONS: These results show that oral immunotherapy can desensitize a high proportion of children with egg allergy and induce sustained unresponsiveness in a clinically significant subset. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00461097.).

Self-destructive behavior in current society promotes a search for psychobiological factors underlying this epidemic. Perinatal brain plasticity increases the vulnerability to early adverse experiences, thus leading to abnormal development and behavior. Although several epidemiological investigations have correlated perinatal and neonatal complications with abnormal adult behavior, our understanding of the underlying mechanisms remains rudimentary. Models of early experience, such as repetitive pain, sepsis, or maternal separation in rodents and other species have noted multiple alterations in the adult brain, correlated with specific behavioral phenotypes depending on the timing and nature of the insult. The mechanisms mediating such changes in the neonatal brain have remained largely unexplored. We propose that lack of N-methyl-D-aspartate (NMDA) receptor activity from maternal separation and sensory isolation leads to increased apoptosis in multiple areas of the immature brain. On the other hand, exposure to repetitive pain may cause excessive NMDA/excitatory amino acid activation resulting in excitotoxic damage to developing neurons. These changes promote two distinct behavioral phenotypes characterized by increased anxiety, altered pain sensitivity, stress disorders, hyperactivity/attention deficit disorder, leading to impaired social skills and patterns of self-destructive behavior. The clinical important of these mechanisms lies in the prevention of early insults, effective treatment of neonatal pain and stress, and perhaps the discovery of novel therapeutic approaches that limit neuronal excitotoxicity or apoptosis.

Autism is a behaviorally defined neurodevelopmental disorder usually diagnosed in early childhood that is characterized by impairment in reciprocal communication and speech, repetitive behaviors, and social withdrawal. Although both genetic and environmental factors are thought to be involved, none have been reproducibly identified. The metabolic phenotype of an individual reflects the influence of endogenous and exogenous factors on genotype. As such, it provides a window through which the interactive impact of genes and environment may be viewed and relevant susceptibility factors identified. Although abnormal methionine metabolism has been associated with other neurologic disorders, these pathways and related polymorphisms have not been evaluated in autistic children. Plasma levels of metabolites in methionine transmethylation and transsulfuration pathways were measured in 80 autistic and 73 control children. In addition, common polymorphic variants known to modulate these metabolic pathways were evaluated in 360 autistic children and 205 controls. The metabolic results indicated that plasma methionine and the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH), an indicator of methylation capacity, were significantly decreased in the autistic children relative to age-matched controls. In addition, plasma levels of cysteine, glutathione, and the ratio of reduced to oxidized glutathione, an indication of antioxidant capacity and redox homeostasis, were significantly decreased. Differences in allele frequency and/or significant gene-gene interactions were found for relevant genes encoding the reduced folate carrier (RFC 80G > A), transcobalamin II (TCN2 776G > C), catechol-O-methyltransferase (COMT 472G > A), methylenetetrahydrofolate reductase (MTHFR 677C > T and 1298A > C), and glutathione-S-transferase (GST M1). We propose that an increased vulnerability to oxidative stress (endogenous or environmental) may contribute to the development and clinical manifestations of autism.

In this paper, we define the Association of Standardized Patient Educators (ASPE) Standards of Best Practice (SOBP) for those working with human role players who interact with learners in a wide range of experiential learning and assessment contexts. These human role players are variously described by such terms as standardized/simulated patients or simulated participants (SP or SPs). ASPE is a global organization whose mission is to share advances in SP-based pedagogy, assessment, research, and scholarship as well as support the professional development of its members. The SOBP are intended to be used in conjunction with the International Nursing Association for Clinical Simulation and Learning (INACSL) Standards of Best Practice: Simulation SM , which address broader simulation practices. We begin by providing a rationale for the creation of the ASPE SOBP, noting that with the increasing use of simulation in healthcare training, it is incumbent on ASPE to establish SOBP that ensure the growth, integrity, and safe application of SP-based educational endeavors. We then describe the three and a half year process through which these standards were developed by a consensus of international experts in the field. Key terms used throughout the document are defined. Five underlying values inform the SOBP: safety, quality, professionalism, accountability, and collaboration. Finally, we describe five domains of best practice: safe work environment; case development; SP training for role portrayal, feedback, and completion of assessment instruments; program management; and professional development. Each domain is divided into principles with accompanying key practices that provide clear and practical guidelines for achieving desired outcomes and creating simulations that are safe for all stakeholders. Failure to follow the ASPE SOBP could compromise the safety of participants and the effectiveness of a simulation session. Care has been taken to make these guidelines precise yet flexible enough to address the diversity of varying contexts of SP practice. As a living document, these SOBP will be reviewed and modified periodically under the direction of the ASPE Standards of Practice Committee as SP methodology grows and adapts to evolving simulation practices.

BACKGROUND: Despite an increasing awareness regarding pain management in neonates and the availability of published guidelines for the treatment of procedural pain, preterm neonates experience pain leading to short- and long-term detrimental effects. OBJECTIVE: To assess the frequency of use of analgesics in invasive procedures in neonates and the associated pain burden in this population. METHODS: For 151 neonates, we prospectively recorded all painful procedures, including the number of attempts required, and analgesic therapy used during the first 14 days of neonatal intensive care unit admission. These data were linked to estimates of the pain of each procedure, obtained from the opinions of experienced clinicians. RESULTS: On average, each neonate was subjected to a mean +/- SD of 14 +/- 4 procedures per day. The highest exposure to painful procedures occurred during the first day of admission, and most procedures (63.6%) consisted of suctioning. Many procedures (26 of 31 listed on a questionnaire) were estimated to be painful (pain scores >4 on a 10-point scale). Preemptive analgesic therapy was provided to fewer than 35% of neonates per study day, while 39.7% of the neonates did not receive any analgesic therapy in the neonatal intensive care unit. CONCLUSIONS: Clinicians estimated that most neonatal intensive care unit procedures are painful, but only a third of the neonates received appropriate analgesic therapy. Despite the accumulating evidence that neonatal procedural pain is harmful, analgesic treatment for painful procedures is limited. Systematic approaches are required to reduce the occurrence of pain and to improve the analgesic treatment of repetitive pain in neonates.

The histologically apparent polymorphism of plaques containing beta-amyloid in Alzheimer's disease is thought to represent different stages in plaque evolution. beta-amyloid-immunopositive plaques were classified according to the pattern of beta-amyloid distribution (diffuse vs dense-core) and the presence or absence of dystrophic beta-amyloid precursor protein-immunopositive (beta-APP+) neurites (neuritic vs non-neuritic). The potential contribution of microglia-derived interleukin-1 (IL-1), an immune response cytokine that induces synthesis and processing of beta-APP, to the possible sequential development of these plaque types was examined through determination of the number of IL-1 alpha+ microglia associated with each of four identified plaque types. Diffuse non-neuritic plaques had the least dense and most widely dispersed beta-amyloid, did not exhibit beta-APP+ dystrophic neurites, but most (78%) contained activated IL-1 alpha+ microglia (2 +/- 0.2/plaque; mean +/- SEM). Diffuse neuritic plaques had more dense, but still widely dispersed beta-amyloid, displayed a profusion of beta-APP+ dystrophic neurites, and had the greatest numbers of associated activated IL-1 alpha+ microglia (7 +/- 0.8/plaque). Dense-core neuritic plaques had both compact and diffuse beta-amyloid and had fewer IL-1 alpha+ microglia (4 +/- 0.4/plaque). Dense-core, non-neuritic plaques had compact beta-amyloid, lacked associated diffuse beta-amyloid, and were devoid of both IL-1 alpha+ microglia and beta-APP+ dystrophic neurites. These results suggest an important immunological component in the evolution of amyloid-containing plaques in Alzheimer's disease and further suggest that IL-1-expressing cells are necessary to initiate dystrophic neurite formation in diffuse beta-amyloid deposits.(ABSTRACT TRUNCATED AT 250 WORDS)

Recent studies have implicated physiological and metabolic abnormalities in autism spectrum disorders (ASD) and other psychiatric disorders, particularly immune dysregulation or inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures ('four major areas'). The aim of this study was to determine trends in the literature on these topics with respect to ASD. A comprehensive literature search from 1971 to 2010 was performed in these four major areas in ASD with three objectives. First, publications were divided by several criteria, including whether or not they implicated an association between the physiological abnormality and ASD. A large percentage of publications implicated an association between ASD and immune dysregulation/inflammation (416 out of 437 publications, 95%), oxidative stress (all 115), mitochondrial dysfunction (145 of 153, 95%) and toxicant exposures (170 of 190, 89%). Second, the strength of evidence for publications in each area was computed using a validated scale. The strongest evidence was for immune dysregulation/inflammation and oxidative stress, followed by toxicant exposures and mitochondrial dysfunction. In all areas, at least 45% of the publications were rated as providing strong evidence for an association between the physiological abnormalities and ASD. Third, the time trends in the four major areas were compared with trends in neuroimaging, neuropathology, theory of mind and genetics ('four comparison areas'). The number of publications per 5-year block in all eight areas was calculated in order to identify significant changes in trends. Prior to 1986, only 12 publications were identified in the four major areas and 51 in the four comparison areas (42 for genetics). For each 5-year period, the total number of publications in the eight combined areas increased progressively. Most publications (552 of 895, 62%) in the four major areas were published in the last 5 years (2006-2010). Evaluation of trends between the four major areas and the four comparison areas demonstrated that the largest relative growth was in immune dysregulation/inflammation, oxidative stress, toxicant exposures, genetics and neuroimaging. Research on mitochondrial dysfunction started growing in the last 5 years. Theory of mind and neuropathology research has declined in recent years. Although most publications implicated an association between the four major areas and ASD, publication bias may have led to an overestimation of this association. Further research into these physiological areas may provide insight into general or subset-specific processes that could contribute to the development of ASD and other psychiatric disorders.

To study the patterns of supraspinal pain processing in neonates, we hypothesized that acute pain causes haemodynamic changes associated with activation of the primary somatosensory cortex. Forty preterm neonates at 28-36 weeks of gestation (mean=32.0) and at 25-42 h (mean=30.7) of age were studied following standardized tactile (skin disinfection) and painful (venipuncture) stimuli. Changes in regional cerebral haemodynamics were monitored by near infrared spectroscopy (NIRS) over both somatosensory cortices in 29 newborns, and over the contralateral somatosensory and occipital areas in 11 newborns. Heart rate (HR) and peripheral oxygen saturation (SaO2) were recorded simultaneously with NIRS parameters: oxygenated [HbO2], deoxygenated, and total hemoglobin. Tactile stimulation produced no changes in HR or SaO2. HR increased in the first 20s (p<0.001), while SaO2 decreased during the 40s after venipuncture (p<0.0001). Following tactile or painful stimulation, [HbO2] increased bilaterally regardless of which hand was stimulated (p<0.0001). Pain-induced [HbO2] increases in the contralateral somatosensory cortex (p<0.05) were not mirrored in the occipital cortex (p>0.1). Pain-related [HbO2] increases were more pronounced in male neonates (p<0.05 on left, p<0.001 on right), inversely correlated with gestational age (r=-0.53 on left, p<0.01; r=-0.42 on right, p<0.05) and directly correlated with postnatal age (r=0.75 on left, p<0.0001; r=0.67 on right, p<0.0001). Painful and tactile stimuli elicit specific haemodynamic responses in the somatosensory cortex, implying conscious sensory perception in preterm neonates. Somatosensory cortical activation occurs bilaterally following unilateral stimulation and these changes are more pronounced in male neonates or preterm neonates at lower gestational ages.

Diabetic osteoporosis is increasingly recognized as a significant comorbidity of type 1 diabetes mellitus. In contrast, type 2 diabetes mellitus is more commonly associated with modest increases in bone mineral density for age. Despite this dichotomy, clinical, in vivo, and in vitro data uniformly support the concept that new bone formation as well as bone microarchitectural integrity are altered in the diabetic state, leading to an increased risk for fragility fracture and inadequate bone regeneration following injury. In this review, we examine the contribution that insulin, as a potential anabolic agent in bone, may make to the pathophysiology of diabetic bone disease. Specifically, we have assimilated human and animal data examining the effects of endogenous insulin production, exogenous insulin administration, insulin sensitivity, and insulin signaling on bone. In so doing, we present evidence that insulin, acting as an anabolic agent in bone, can preserve and increase bone density and bone strength, presumably through direct and/or indirect effects on bone formation.

Despite increasing evidence of oxidative stress in the pathophysiology of autism, most studies have not evaluated biomarkers within specific brain regions, and the functional consequences of oxidative stress remain relatively understudied. We examined frozen samples from the cerebellum and temporal cortex (Brodmann area 22 (BA22)) from individuals with autism and unaffected controls (n=15 and n=12 per group, respectively). Biomarkers of oxidative stress, including reduced glutathione (GSH), oxidized glutathione (GSSG) and glutathione redox/antioxidant capacity (GSH/GSSG), were measured. Biomarkers of oxidative protein damage (3-nitrotyrosine; 3-NT) and oxidative DNA damage (8-oxo-deoxyguanosine; 8-oxo-dG) were also assessed. Functional indicators of oxidative stress included relative levels of 3-chlorotyrosine (3-CT), an established biomarker of a chronic inflammatory response, and aconitase activity, a biomarker of mitochondrial superoxide production. Consistent with previous studies on plasma and immune cells, GSH and GSH/GSSG were significantly decreased in both autism cerebellum (P<0.01) and BA22 (P<0.01). There was a significant increase in 3-NT in the autism cerebellum and BA22 (P<0.01). Similarly, 8-oxo-dG was significantly increased in autism cerebellum and BA22 (P<0.01 and P=0.01, respectively), and was inversely correlated with GSH/GSSG in the cerebellum (P<0.01). There was a significant increase in 3-CT levels in both brain regions (P<0.01), whereas aconitase activity was significantly decreased in autism cerebellum (P<0.01), and was negatively correlated with GSH/GSSG (P=0.01). Together, these results indicate that decreased GSH/GSSG redox/antioxidant capacity and increased oxidative stress in the autism brain may have functional consequence in terms of a chronic inflammatory response, increased mitochondrial superoxide production, and oxidative protein and DNA damage.

N-acetylcysteine (NAC) is recognized for its role in acetaminophen overdose and as a mucolytic. Over the past decade, there has been growing evidence for the use of NAC in treating psychiatric and neurological disorders, considering its role in attenuating pathophysiological processes associated with these disorders, including oxidative stress, apoptosis, mitochondrial dysfunction, neuroinflammation and glutamate and dopamine dysregulation. In this systematic review we find favorable evidence for the use of NAC in several psychiatric and neurological disorders, particularly autism, Alzheimer's disease, cocaine and cannabis addiction, bipolar disorder, depression, trichotillomania, nail biting, skin picking, obsessive-compulsive disorder, schizophrenia, drug-induced neuropathy and progressive myoclonic epilepsy. Disorders such as anxiety, attention deficit hyperactivity disorder and mild traumatic brain injury have preliminary evidence and require larger confirmatory studies while current evidence does not support the use of NAC in gambling, methamphetamine and nicotine addictions and amyotrophic lateral sclerosis. Overall, NAC treatment appears to be safe and tolerable. Further well designed, larger controlled trials are needed for specific psychiatric and neurological disorders where the evidence is favorable.

Although the involvement of genetic abnormalities in autism spectrum disorders (ASD) is well-accepted, recent studies point to an equal contribution by environmental factors, particularly environmental toxicants. However, these toxicant-related studies in ASD have not been systematically reviewed to date. Therefore, we compiled publications investigating potential associations between environmental toxicants and ASD and arranged these publications into the following three categories: (a) studies examining estimated toxicant exposures in the environment during the preconceptional, gestational and early childhood periods; (b) studies investigating biomarkers of toxicants; and (c) studies examining potential genetic susceptibilities to toxicants. A literature search of nine electronic scientific databases through November 2013 was performed. In the first category examining ASD risk and estimated toxicant exposures in the environment, the majority of studies (34/37; 92%) reported an association. Most of these studies were retrospective case-control, ecological or prospective cohort studies, although a few had weaker study designs (for example, case reports or series). Toxicants implicated in ASD included pesticides, phthalates, polychlorinated biphenyls (PCBs), solvents, toxic waste sites, air pollutants and heavy metals, with the strongest evidence found for air pollutants and pesticides. Gestational exposure to methylmercury (through fish exposure, one study) and childhood exposure to pollutants in water supplies (two studies) were not found to be associated with ASD risk. In the second category of studies investigating biomarkers of toxicants and ASD, a large number was dedicated to examining heavy metals. Such studies demonstrated mixed findings, with only 19 of 40 (47%) case-control studies reporting higher concentrations of heavy metals in blood, urine, hair, brain or teeth of children with ASD compared with controls. Other biomarker studies reported that solvent, phthalate and pesticide levels were associated with ASD, whereas PCB studies were mixed. Seven studies reported a relationship between autism severity and heavy metal biomarkers, suggesting evidence of a dose-effect relationship. Overall, the evidence linking biomarkers of toxicants with ASD (the second category) was weaker compared with the evidence associating estimated exposures to toxicants in the environment and ASD risk (the first category) because many of the biomarker studies contained small sample sizes and the relationships between biomarkers and ASD were inconsistent across studies. Regarding the third category of studies investigating potential genetic susceptibilities to toxicants, 10 unique studies examined polymorphisms in genes associated with increased susceptibilities to toxicants, with 8 studies reporting that such polymorphisms were more common in ASD individuals (or their mothers, 1 study) compared with controls (one study examined multiple polymorphisms). Genes implicated in these studies included paraoxonase (PON1, three of five studies), glutathione S-transferase (GSTM1 and GSTP1, three of four studies), δ-aminolevulinic acid dehydratase (one study), SLC11A3 (one study) and the metal regulatory transcription factor 1 (one of two studies). Notably, many of the reviewed studies had significant limitations, including lack of replication, limited sample sizes, retrospective design, recall and publication biases, inadequate matching of cases and controls, and the use of nonstandard tools to diagnose ASD. The findings of this review suggest that the etiology of ASD may involve, at least in a subset of children, complex interactions between genetic factors and certain environmental toxicants that may act synergistically or in parallel during critical periods of neurodevelopment, in a manner that increases the likelihood of developing ASD. Because of the limitations of many of the reviewed studies, additional high-quality epidemiological studies concerning environmental toxicants and ASD are warranted to confirm and clarify many of these findings.