Essential fatty acids and phospholipase A2 in autistic spectrum disorders

A health questionnaire based on parental observations of clinical signs of fatty acid deficiency (FAD) showed that patients with autism and Asperger's syndrome (ASP) had significantly higher FAD scores (6.34+/-4.37 and 7.64+/-6.20, respectively) compared to controls (1.78+/-1.68). Patients with regressive autism had significantly higher percentages of 18:0,18:2n-6 and total saturates in their RBC membranes compared to controls, while 24:0, 22:5n-6, 24:1 and the 20:4n-6/20:5n-3 ratio were significantly higher in both regressive autism and ASP groups compared to controls. By comparison, the 18:1n-9 and 20:4n-6 values were significantly lower in patients with regressive autism compared to controls while 22:5n-3, total n-3 and total dimethyl acetals were significantly lower in both regressive autism and ASP groups compared to controls. Storage of RBC at -20 degrees C for 6 weeks resulted in significant reductions in highly unsaturated fatty acid levels in polar lipids of patients with regressive autism, compared to patients with classical autism or ASP, or controls. Patients diagnosed with both autism and ASP showed significantly increased levels of EPA ( approximately 200%) and DHA ( approximately 40%), and significantly reduced levels of ARA ( approximately 20%), 20:3n-6 and ARA/EPA ratio in their RBC polar lipids, when supplemented with EPA-rich fish oils, compared to controls and non-supplemented patients with autism. Patients with both regressive autism and classical autism/Asperger's syndrome had significantly higher concentrations of RBC type IV phospholipase A2 compared to controls. However, patients with autism/ASP, who had taken EPA supplements, had significantly reduced PLA2 concentrations compared to unsupplemented patients with classical autism or ASP.     

Genetic studies in children with intellectual disability and autistic spectrum of disorders

Autism is one of the five disorders that falls under the umbrella of Pervasive Developmental Disorders (PDD) or Autism Spectrum Disorder (ASD), a category of neurological disorders characterized by "severe and pervasive impairment in several areas of development." ASD is characterized by varying degrees of impairment in communication skills, social interaction and restricted, repetitive stereotyped patterns of behavior. The five disorders under PDD are autistic disorder, Asperger's disorder, childhood disintegrative disorder, Rett's disorder and PDD-not otherwise specified. ASD can often be reliably detected by the age of 3 years and, in some cases, as early as 18 months. The appearance of any warning signs of ASD is reason to have the child evaluated by a professional specializing in these disorders.     

A clinical and laboratory evaluation of methionine cycle-transsulfuration and androgen pathway markers in children with autistic disorders

BACKGROUND/AIMS: The prevalence of autism spectrum disorders (ASDs) is 1 in 300 children in the US. ASDs are characterized by impairments in social relatedness and communication, repetitive behaviors, abnormal movement patterns, and sensory dysfunction. Pre-pubertal age children with ASDs were assessed for metabolites in the methionine cycle-transsulfuration and androgen pathways, and for present physical development/behaviors indicative of hyperandrogenicity. METHODS: The Institutional Review Board of the Institute for Chronic Illnesses (Office for Human Research Protections, US Department of Health and Human Services IRB number: IRB00005375) approved the present study. Sixteen consecutive pre-pubertal age children (相似文献   

Rare de novo and transmitted copy-number variation in autistic spectrum disorders

To explore the genetic contribution to autistic spectrum disorders (ASDs), we have studied genomic copy-number variation in a large cohort of families with a single affected child and at least one unaffected sibling. We confirm a major contribution from de novo deletions and duplications but also find evidence of a role for inherited "ultrarare" duplications. Our results show that, relative to males, females have greater resistance to autism from genetic causes, which raises the question of the fate of female carriers. By analysis of the proportion and number of recurrent loci, we set a lower bound for distinct target loci at several hundred. We find many new candidate regions, adding substantially to the list of potential gene targets, and confirm several loci previously observed. The functions of the genes in the regions of de novo variation point to a great diversity of genetic causes but also suggest functional convergence.     

A prospective study of androgen levels, hormone-related genes and risk of rheumatoid arthritis

Introduction

Since current treatment options for patients suffering from active rheumatoid arthritis (RA) remain inadequate, especially for those unresponsive to disease-modifying antirheumatic drugs (DMARDs), new and improved medication is needed. This study evaluates the safety and efficacy of masitinib (AB1010), a potent and selective protein tyrosine kinase inhibitor of c-KIT, in the monotherapy treatment of DMARD-refractory RA.

Methods

This was a multicentre, uncontrolled, open-label, randomised, dose-ranging, phase 2a trial. Masitinib was administered orally to 43 patients who had inadequate response to DMARDs, at initial randomised dosing levels of 3 and 6 mg/kg per day over a 12-week period. Dose adjustment was permitted based upon tolerability and response criteria. Efficacy was assessed via American College of Rheumatology 20%/50%/70% improvement criteria (ACR20/50/70) responses, disease activity score using 28 joint counts (DAS28), index of improvement in RA (ACRn) and C-reactive protein (CRP) improvement, relative to baseline at week 12.

Results

Improvement was observed in all efficacy endpoints, including ACR20/50/70 scores of 54%, 26% and 8%, respectively, and a reduction in CRP level by greater than 50% for approximately half the population. This improvement was sustainable throughout an extension phase (> 84 weeks) and was also independent of initial DMARD resistance (anti-tumour necrosis factor-alpha and/or methotrexate). A relatively high patient withdrawal rate (37%) required the use of last observation carried forward (LOCF) data imputation. Incidence of adverse events was high (95%), although the majority were of mild or moderate severity with a considerable decline in frequency observed after 12 weeks of treatment. Two nonfatal serious adverse events were reported. Dose-response analyses tentatively indicate that an initial dosing level of 6.0 mg/kg per day administered orally in two daily intakes is the most appropriate, based upon potency and tolerability trends.

Conclusions

Treatment with masitinib improved DMARD-refractory active RA. Following an initial high incidence of mostly mild to moderate side effects during the first 12 weeks of treatment, masitinib appears to be generally well tolerated. This, together with evidence of a sustainable efficacy response, suggests that masitinib is suitable for long-term treatment regimens. Since this was the first study of masitinib in a nononcologic pathology, the relatively high patient withdrawal rate observed can be partly attributed to a highly cautious response to adverse events. There is sufficient compelling evidence to warrant further placebo-controlled investigation.

Trial registration

ClinicalTrials.gov NCT00831922.     

Clinical diagnosis, biochemical findings and MRI spectrum of peroxisomal disorders

Peroxisomal disorders are an important group of neurometabolic diseases. The clinical presentation is varied in terms of age of onset, severity, and different neurological symptoms. The clinical course spans from death in infancy, rapid functional decline, slow decline on long-term followup, to apparent stable course. Leukoencephalopathy and developmental anomalies are characteristic findings on cerebral MR imaging. From a diagnostic point of view the disorders can be clinically subdivided into four broad categories: (1) the Zellweger spectrum disorders and the peroxisomal ?-oxidation disorders, (2) the rhizomelic chondrodysplasia punctata spectrum disorders, (3) the X-linked adrenoleukodystrophy/adrenomyeloneuropathy complex and (4) the remaining disorders. This article discusses the role of MRI findings in the clinical approach of peroxisomal disorders with neurological disease. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of peroxisomes in Health and Disease.     

Mutation screening of melatonin-related genes in patients with autism spectrum disorders

Background

One consistent finding in autism spectrum disorders (ASD) is a decreased level of the pineal gland hormone melatonin and it has recently been demonstrated that this decrease to a large extent is due to low activity of the acetylserotonin O-methyltransferase (ASMT), the last enzyme in the melatonin synthesis pathway. Moreover, mutations in the ASMT gene have been identified, including a splice site mutation, that were associated with low ASMT activity and melatonin secretion, suggesting that the low ASMT activity observed in autism is, at least partly, due to variation within the ASMT gene.

Methods

In the present study, we have investigated all the genes involved in the melatonin pathway by mutation screening of AA-NAT (arylalkylamine N-acetyltransferase), ASMT, MTNR1A, MTNR1B (melatonin receptor 1A and 1B) and GPR50 (G protein-coupled receptor 50), encoding both synthesis enzymes and the three main receptors of melatonin, in 109 patients with autism spectrum disorders (ASD). A cohort of 188 subjects from the general population was used as a comparison group and was genotyped for the variants identified in the patient sample.

Results

Several rare variants were identified in patients with ASD, including the previously reported splice site mutation in ASMT (IVS5+2T>C). Of the variants affecting protein sequence, only the V124I in the MTNR1B gene was absent in our comparison group. However, mutations were found in upstream regulatory regions in three of the genes investigated, ASMT, MTNR1A, and MTNR1B.

Conclusions

Our report of another ASD patient carrying the splice site mutation IVS5+2T>C, in ASMT further supports an involvement of this gene in autism. Moreover, our results also suggest that other melatonin related genes might be interesting candidates for further investigation in the search for genes involved in autism spectrum disorders and related neurobehavioral phenotypes. However, further studies of the novel variants identified in this study are warranted to shed light on their potential role in the pathophysiology of these disorders.     

Subtelomeric region of chromosome 2 in patients with autism spectrum disorders

Autism spectrum disorders are severe psychiatric diseases commonly identified in the population. They are diagnosed during childhood and the etiology has been much debated due to their variations and complexity. Onset is early and characterized as communication and social interaction disorders and as repetitive and stereotyped behavior. Autistic disorders may occur together with various genetic and chromosomal diseases. Several chromosomal regions and genes are implicated in the predisposition for these diseases, in particular those with products expressed in the central nervous system. There are reports of autistic and mentally handicapped patients with submicroscopic subtelomeric alterations at the distal end of the long arm of chromosome 2. Additionally, there is evidence that alterations at 2q37 cause brain malformations that result in the autistic phenotype. These alterations are very small and not identified by routine cytogenetics to which patients are normally submitted, which may result in an underestimation of the diagnosis. This study aimed at evaluating the 2q37 region in patients with autistic disorders. Twenty patients were studied utilizing the fluorescence in situ hybridization technique with a specific probe for 2q37. All of them were also studied by the GTC banding technique to identify possible chromosomal diseases. No alterations were observed in the 2q37 region of the individuals studied, and no patient presented chromosomal diseases. This result may be due to the small sample size analyzed. The introduction of routine analysis of the 2q37 region for patients with autistic disorders depends on further studies.     

Serum levels of glial fibrillary acidic protein and Nogo-A in children with autism spectrum disorders

Context: Improved biomarkers would facilitate the diagnosis and treatment of autism spectrum disorders (ASD).

Objective: Our objective was to examine the levels of Nogo-A and glial fibrillary acidic protein (GFAP) in children with ASD.

Materials and methods: Serum concentrations of GFAP and Nogo-A were determined by enzyme-linked immunosorbent assay.

Results: In this preliminary study, we found that serum Nogo-A was not found significantly different between groups, while serum levels of GFAP were significantly lower in ASD than controls.

Discussion and conclusions: It will be of great interest to determine other potential causes of elevated serum levels of GFAP, and whether this elevation has any phenotypic effect.     

Oxytocin plasma concentrations in children and adolescents with autism spectrum disorder: correlation with autistic symptomatology

Findings from research in animal models and humans have shown a clear role for the neuropeptide oxytocin (OT) on complex social behaviors. This is also true in the context of autism spectrum disorder (ASD). Previous studies on peripheral OT concentrations in children and young adults have reported conflicting results with the initial studies presenting mainly decreased OT plasma levels in ASD compared to healthy controls. Our study therefore aimed to further investigate changes in peripheral OT concentrations as a potential surrogate for the effects observed in the central nervous system (CNS) in ASD. OT plasma concentrations were assessed in 19 male children and adolescents with ASD, all with an IQ > 70 (age 10.7 ± 3.8 years), 17 healthy male children (age 13.6 ± 2.1 years) and 19 young male patients with attention deficit hyperactivity disorder (ADHD) as a clinical control group (age 10.4 ± 1.9 years) using a validated radioimmunoassay. Analysis of covariance revealed significant group differences in OT plasma concentrations (F(2, 48) = 9.574, p < 0.001, η ² = 0.285; plasma concentrations ASD 19.61 ± 7.12 pg/ml, ADHD 8.05 ± 5.49 pg/ml, healthy controls 14.43 ± 9.64 pg/ml). Post hoc analyses showed significantly higher concentrations in children with ASD compared to ADHD (p < 0.001). After Bonferroni correction, there was no significant difference in ASD in comparison with healthy controls (p = 0.132). A significant strong correlation between plasma OT and autistic symptomatology, assessed by the Autism Diagnostic Observation Schedule, was observed in the ASD group (p = 0.013, r = 0.603). Patients with ADHD differed from healthy control children by significantly decreased OT concentrations (p = 0.014). No significant influences of the covariates age, IQ, medication and comorbidity could be seen. Our preliminary results point to a correlation of OT plasma concentrations with autistic symptom load in children with ASD and a modulation of the OT system also in the etiologically and phenotypically overlapping disorder ADHD. Further studies in humans and animal models are warranted to clarify the complex association of the OT system with social impairments as well as stress-related and depressive behavior and whether peripheral findings reflect primary changes of OT synthesis and/or release in relevant areas of the CNS.     

Correlation of serum trace elements and melatonin levels to radiological, biochemical, and histological assessment of degeneration in patients with intervertebral disc herniation

The aim of our study was to assess the blood concentrations of some trace elements and melatonin (MLT) in patients with intervertebral disc herniation (IDH) and to investigate the interaction of histological and biochemical degeneration findings with aging. The present study was carried out on 13 subjects (8 women and 5 men) diagnosed with IDH. They were divided into three groups according to their ages. Nighttime serum MLT, zinc (Zn), and magnesium (Mg) levels were determined in all patients. In addition, computed tomography (CT) scan of the brain and magnetic resonance imaging examination of the lumbar spine were obtained in this study. The Zn level and Zn/Mg ratio showed a decline in patients with IDH with aging, whereas the serum Mg level and tissue hydroxyproline content increased. A positive correlation between serum Zn and MLT concentrations was found (r=0.104, p=0.734). In addition, there was a positive correlation between serum Zn level and Zn/Mg ratio (r=0.835 and p<0.01), and a negative correlation between serum Mg level and Zn/Mg ratio (r=−0.571, p<0.05). On CT study, both volume percentage of calcified pineal gland and density of calcification were found to increase progressively with advancing age. The results of semiquantitative evaluation of disc tissues of patients with IDH for histological degeneration findings showed that 66.7% of discs treated had slight degeneration in younger age group, but 75.0% and 100% of discs had moderate or marked degeneration in older age groups. Our data indicated that there is a close relationship between MLT and Zn or Mg levels in the serum samples of patients with IDH, and the levels of these elements might be affected by the presence of degeneration process and serum MLT level, or vice versa.     

Postural stability in subjects with temporomandibular disorders and healthy controls: A comparative assessment

Purpose of the studyThe influence of the stomatognathic apparatus on body posture is a continuously discussed topic with contrasting results. The aim of this study is to analyze differences in postural stability between subjects with and without myogenous TMD.Methods25 subjects affected by myogenous TMD according with DC/TMD (6 males, 19 females; mean age 31.75 ± 6.68 years) and a healthy control group of 19 subjects (4 Males, 15 Females; mean age 27.26 ± 3.85 years) were enrolled in the study.Both groups underwent a posturo-stabilometric force platform exam under different mandibular and visual conditions. Sway area and sway velocity of the COP (Center Of foot Pressure) posturo-stabilometric parameters were evaluated and compared applying Mann-U-Whitney statistical test.ResultsThe sway area and sway velocity parameters resulted statistically significantly higher in the TMD group (sway area p < 0.01; sway velocity p < 0.05) in mandibular maximum intercuspation and rest positions with eyes open.ConclusionsThis study demonstrates a significant difference in body postural stability between subjects with myogenous TMD and healthy controls. In particular, sway area and sway velocity postural parameters are increased in these subjects.     

Elevated immunoreactive-adrenomedullin levels in the aqueous humor of patients with uveitis and vitreoretinal disorders

To clarify possible involvement of adrenomedullin in the pathophysiology of inflammation of eyes, we measured immunoreactive-adrenomedullin concentrations in the aqueous humor and plasma obtained from 14 control subjects and 56 patients with uveitis or vitreoretinal disorders. Immunoreactive-adrenomedullin levels in the aqueous humor were significantly elevated in patients with active uveitis, proliferative vitreoretinopathy and proliferative diabetic retinopathy, as compared with control subjects. The plasma immunoreactive-adrenomedullin levels were not significantly correlated with the aqueous humor levels. These findings suggest that adrenomedullin produced locally in the eyes is involved in the pathophysiology of uveitis and some proliferative vitreoretinal disorders.     

A comparison of estrogen and androgen receptor levels in human prostatic tissue from patients with non-metastatic and metastatic carcinoma and benign prostatic hyperplasia

Estrogen receptors (ER, N = 72) and androgen receptors (AR, N = 33) were determined by high pressure liquid chromatography (HPLC) in 72 human prostatic tissues obtained at prostatectomy, and exploratory statistical analyses of the resulting data were performed. To facilitate use of these data as well as other pertinent information from the patient charts, a program for a comparatively large data base was implemented on a Wang minicomputer. The median values of cytosolic AR in the four cancer stages examined were statistically different from each other (P = 0.01), with AR increasing from stages A through D. Even though ER differences between the four stages were not significant (P = 0.13), there was a trend, in the data examined, for median ER values to decrease with stages B through D. On the other hand, median BPH values for both ER and AR were found to lie mid-scale compared with the respective cancer stages, leading to the conclusion that receptor measurements probably cannot distinguish between CA and BPH in human prostatic tissue, at least as measured by competitive binding techniques.