Decreased serum levels of epidermal growth factor in adult subjects with high-functioning autism.

BACKGROUND: The neurobiological basis for autism remains poorly understood. Given the role of growth factors in brain development, we hypothesized that epidermal growth factor (EGF) may play a role in the pathophysiology of autism. In this study, we examined whether serum levels of EGF are altered in adult subjects with high-functioning autism. METHODS: We measured serum levels of EGF in the 17 male subjects with high-functioning autism and 18 age-matched healthy male subjects. RESULTS: The serum levels of EGF in the subjects with high-functioning autism (72.4 +/- 102.8 pg/mL [mean +/- SD]) were significantly lower (Mann-Whitney U = 22.0, p < .001) than those of normal control subjects (322.3 +/- 122.0 pg/mL [mean +/- SD]). However, there were no correlations between serum EGF levels and clinical variables in the subjects with autism. CONCLUSIONS: This study suggests that decreased levels of EGF might be implicated in the pathophysiology of high-functioning autism.     

No changes in serum epidermal growth factor levels in patients with schizophrenia

A recent report demonstrated that serum levels of epidermal growth factor (EGF) were significantly decreased in patients with schizophrenia, suggesting that impaired EGF signaling might be associated with the pathophysiology of schizophrenia. Our goal in the present study was to determine whether serum levels of EGF are altered in patients with schizophrenia. We found that serum levels of EGF in drug-naive (n = 15) or medicated patients (n = 25) with schizophrenia did not differ from those of age- and sex-matched normal controls (n = 40). However, we found a significant correlation between serum EGF levels and BPRS scores in the combined groups of patients. Therefore, our results do not support the claim that EGF plays a role in the pathogenesis of schizophrenia, but they suggest that EGF may serve as a state marker, that is, as an index of symptom-linked deficits.     

Decreased serum levels of hepatocyte growth factor in male adults with high-functioning autism

BACKGROUND: The mechanisms underlying the pathophysiology of autism are currently unknown. Given the role of hepatocyte growth factor (HGF) in brain development, we hypothesized that HGF plays a role in the pathophysiology of autism. In this study, we studied whether serum HGF levels are altered in subjects with high-functioning autism. METHODS: Using an enzyme-linked immunosorbent assay (ELISA), we measured serum levels of HGF in 17 male adults with high-functioning autism and age-matched 18 male healthy subjects. RESULTS: The serum levels (503.5+/-160.5 pg/mL (mean+/-SD)) of HGF in the subjects with high-functioning autism were significantly (Mann-Whitney U=34.0, p<0.001) lower than those (817.6+/-232.4 pg/mL (mean+/-SD)) of control subjects. However, there were no correlations between serum HGF levels and clinical variables in the patients. CONCLUSIONS: This study suggests that reduced HGF levels may play a role in the pathophysiology of high-functioning autism.     

Low serum levels of brain-derived neurotrophic factor and epidermal growth factor in patients with chronic schizophrenia

Neurotrophic factors (NFs) play a pivotal role in the development of the central nervous system. They are thus also suspected of being involved in the etiology of schizophrenia. Previous studies reported a decreased level of serum brain-derived neurotrophic factor (BDNF) in schizophrenia, whereas the association of epidermal growth factor (EGF) with this illness remains controversial. Using a two-site enzyme immunoassay, we conducted the simultaneous measurement of serum BDNF and EGF levels in a group of patients with chronic schizophrenia (N = 74) and a group of normal controls matched in age, body mass index, smoking habit and sex (N = 87). We found that, compared to normal controls, patients with chronic schizophrenia exhibited lower serum levels of both BDNF and EGF across all ages examined (21–59 years). The serum levels of BDNF and EGF were negatively correlated in the controls (r = − 0.387, P = 0.0002) but not in the patients. Clinical parameters such as duration of illness and psychiatric rating scale also showed no robust correlations with the NF levels. Collectively, these results suggest that pervasive, abnormal signaling of NFs underlies the pathophysiology of chronic schizophrenia.     

Urinary epidermal and insulin-like growth factor excretion in autistic children

Growth factors have been implicated in the pathogenesis of autism. We have investigated daily urinary excretion of insulin-like growth factor-1 (IGF-1), epidermal growth factor, and insulin-like growth factor binding protein-3 in autistic children (n=34, age 2-5 years) and age-matched control children (n=29). The mean urinary IGF-1 level was lower in the autism group than the control group (p=0.03). Height was normal. These findings suggest altered IGF-1 metabolism in young autistic children. The cause-effect relationship should be examined by longitudinal studies and insulin-like growth factor provocation tests.     

Developmental changes in neural progenitor cell lineage commitment do not depend on epidermal growth factor receptor signaling

Multipotent neural progenitor cells become progressively more biased towards a glial fate during development coincident with an increase in expression of the epidermal growth factor receptor (EGFR). To determine whether differences in lineage commitment of neural progenitor cells from different stages are causally related to expression of the EGFR and whether generation of glia is EGFR-dependent, we used an EGFR-specific tyrosine kinase inhibitor, PD158780, to block the activation of EGFR in progenitor cells. Treatment of cultured neonatal progenitor cells with PD158780 completely blocked EGF-induced proliferation of the cells but did not affect bFGF-induced proliferation. Nevertheless, treatment with the inhibitor failed to inhibit the generation of astroglia in the presence of either EGF or bFGF. Treatment with bone morphogenetic protein-2 (BMP2) enhanced astroglial differentiation and suppressed oligodendroglial (OL) differentiation. PD158780 treatment had no effect on the BMP2-induced astroglial differentiation or OL suppression. These observations suggest that the generation of astroglia is not dependent on EGFR activation. Because it was still possible that the progenitor cell responses reflected a prior history of EGFR signaling, rat forebrain cells were cultured in the presence of PD158780 from a time (E12.5) preceding expression of the EGFR. After time in culture, the E12.5 cells expressed EGFR by Western analysis both in the presence and in the absence of PD158780, but activation of EGFR kinase (receptor autophosphorylation) was undetectable in the presence of PD158780 and the cells did not proliferate in response to EGF. Nevertheless, astroglial differentiation was normal in PD158780-treated cells both in the absence and in the presence of BMPs or CNTF. Furthermore, the propensity towards glial differentiation increased with time in culture even in the absence of EGFR signaling. This suggests that the increased bias towards glial differentiation during development does not depend on EGFR signaling.     

Developmental dyspraxia is not limited to imitation in children with autism spectrum disorders.

Impaired imitation of skilled gestures is commonly reported in autism. Questions, however, remain as to whether impaired imitation is associated with a more generalized deficit in performance of gestures consistent with a dyspraxia and whether the pattern of errors differs from that observed in typically developing children. To address these questions, praxis in 21 high-functioning children with autism spectrum disorders (ASD) was compared with 24 typically developing controls using a traditional approach in which performance was evaluated through detailed examination of error types. Children with ASD produced significantly fewer correct responses not only during Gesture to Imitation, but also during Gesture to Command and with Tool Use. The pattern of errors in ASD was similar to that of controls with spatial errors being most common in both groups; however, body-part-for-tool errors were more common in children with ASD, suggesting dyspraxia is not entirely attributable to motor deficits. The findings suggest that autism is associated with a generalized praxis deficit, rather than a deficit specific to imitation. In a developmental disorder such as autism, the findings may reflect abnormalities in frontal/parietal-subcortical circuits important for acquisition (i.e., learning) of sensory representations of movement and/or the motor sequence programs necessary to execute them.     

Multiple system atrophy is associated with changes in peripheral insulin‐like growth factor system

Insulin‐like growth factors (IGF‐I and IGF‐II) have been shown to have several neurotrophic actions and IGF system may be impaired in neurodegenerative disorders. The aim of this study was to investigate the IGF system in patients with MSA and to evaluate correlations between this endocrine system and clinical features of the disease. Serum levels of IGF‐I, IGF‐II, insulin, IGF‐binding protein 1 (BP1), and IGF‐binding protein 3 (BP3) were measured in 25 patients with probable MSA and 25 age, sex and BMI‐matched healthy controls. Clinical status of each patient was evaluated with the Unified Multiple System Atrophy Rating Scale (UMSARS) Part II and the Hoehn and Yahr rating scale. IGF‐I levels were significantly higher in MSA (164.1 + 66.2 μg/L) than in healthy controls (111.7 + 60.3 μg/L; p = 0.001). Insulin levels were significantly higher in MSA patients (21.9 ± 14.4 μU/mL) than in healthy controls (13.3 ± 5.1 μU/mL, p = 0.048). No significant difference was found in serum IGF‐II, IGF‐BP1, and IGF‐ BP3 levels between patients with MSA and healthy controls. There was a trend toward significantly higher IGF‐II levels in MSA patients with UMSARS score <26 (1026.3 ± 442.6 μg/L) than MSA patients with UMSARS score >26 (796.1 ± 234 μg/L, p = 0.055). The results of this study demonstrated that IGF system is altered in MSA. The degenerative process in MSA could lead to a compensatory increase in IGF‐I and insulin in an attempt to provide additional support to degenerating neurons. © 2010 Movement Disorder Society.     

Brain metabolic changes associated with symptom factor improvement in major depressive disorder.

BACKGROUND: Symptoms of major depressive disorder (MDD) have been linked to regional brain function through imaging studies of symptom provocation in normal control subjects and baseline studies of subjects with MDD. We examined associations between change in depressive symptom factors and change in regional brain metabolism from before to after treatment of MDD. METHODS: Thirty-nine outpatients with MDD underwent 18F-fluorodeoxyglucose positron emission tomography scanning before and after treatment with either paroxetine or interpersonal psychotherapy. Associations were determined between changes in regional brain metabolism and changes in four Hamilton Depression Rating Scale factors (anxiety/somatization [ANX], psychomotor retardation [PR], cognitive disturbance [COGN], and sleep disturbance) and two corresponding Profile of Mood States subscales (tension [TENS] and fatigue [FATIG]). RESULTS: Improvement in ANX, PR, TENS, and FATIG factors was associated with decreasing ventral frontal lobe metabolism. Improvement in ANX and TENS was also associated with decreasing ventral anterior cingulate gyrus (AC) and anterior insula activity, whereas improvement in PR was associated with increasing dorsal AC activity. COGN improvement was associated with increasing dorsolateral prefrontal cortex metabolism. CONCLUSIONS: Brain regions that show significant relationships with symptom provocation in normal control subjects have similar relationships with MDD symptoms as they improve with treatment.     

Preoperative statin use is not associated with improvement in survival after glioblastoma surgery

Cohort studies have suggested that the use of statins is associated with decreased risk of glioma formation and mortality. Here, a cohort of patients with glioblastoma multiforme (GBM) was analyzed to further investigate associations between preoperative use of statins and recurrence, and progression free and overall survival. Patients who had surgery for GBM (N = 284) were followed up for a median of 18.1 months. Seventy-eight patients were taking statins preoperatively while the rest were not. Cox proportional hazards models adjusted for several covariates of interest were applied before and after propensity score matching. Compared with statin users, those not taking the lipid-lowering drugs had similar progression free survival before (hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.70–1.26; p = 0.68) and after propensity score matching (HR 0.95, 95% CI 0.67–1.35; p = 0.68). Mortality was similar between both groups of patients before (HR 0.94, 95% CI 0.70–1.22; p =  0.73) and after propensity score matching (HR 1.13, 95% CI 0.78–1.64; p = 0.49). Age and dexamethasone use were independent prognostic factors of survival. Contrary to previously published evidence, this study could not find an association between preoperative statin use and longer survival in GBM patients. Due to the small number of patients and retrospective nature of the study, further work is needed to understand the role of perioperative statins in GBM patients.     

Vascular endothelial growth factor (VEGF) is increased in serum, but not in cerebrospinal fluid in HIV associated CNS diseases

Vascular endothelial growth factor (VEGF) is a potent angiogenic and mitogenic peptide, which also induces several mediators that may play a role in HIV induced CNS damage. VEGF levels were determined in cerebrospinal fluid (CSF) and serum samples from patients with (n = 8) and without (n = 19) directly HIV associated CNS disorders and HIV negative control patients (n = 18). VEGF serum but not CSF levels were significantly increased in HIV infected patients with (381.1 (78.9) pg/ml) HIV associated CNS diseases compared with those without (120.8 (13.1) pg/ml) and HIV negative control patients (133.1(14.8) pg/ml). Serum samples from patients with untreated HIV associated encephalopathy (HIVE, n = 3) contained the highest VEGF levels (583.9 (71.5) pg/ml). In two patients VEGF serum levels were reduced during antiretroviral therapy. However, regardless of effective viral suppression, patients with HIVE still had higher levels compared with HIV infected patients without HIVE. A relevant increase of serum VEGF was not observed in patients without HIVE though high HI viral load. We conclude that HIVE is associated with increased serum VEGF levels. Further studies are warranted to elucidate the role of VEGF in HIVE.     

Anxiety,depression, and irritability in children with autism relative to other neuropsychiatric disorders and typical development

Maternal ratings of anxiety, depression, and irritability were analyzed in 1390 children (6–16 years of age), including 233 children with high functioning autism (HFA, IQ ≥ 80), 117 children with low functioning autism (LFA, IQ < 80), 187 typical children, and 853 children with other disorders. As a group, children with HFA were characterized as irritable and anxious, and children with LFA and ADHD-combined type were irritable only. Children with anxiety disorders were anxious only. Children with major depression or dysthymic disorder were depressed and irritable. Elevated levels of irritability, anxiety, or depression were not found in ADHD-inattentive type, mental retardation, brain injury, or typical development. The frequency of parent reported anxiety symptoms was similar for children with an anxiety disorder and HFA, though some symptoms were more severe in children with anxiety disorders. Children with depression had more frequent and more severe depressive symptoms than children with HFA. Mothers of 54% of children with HFA and 42% with LFA reported depressed mood in their children. Percentages were higher for anxiety (79% and 67%) and irritability (88% and 84%). These remarkably high percentages justify routinely assessing all children with autism for depression, anxiety, and irritability.     

Serum levels of platelet-derived growth factor BB homodimers are increased in male children with autism

Background

The neurobiological basis of autism remains poorly understood. To examine the role played by serum cytokines in brain development, we hypothesized that Platelet-Derived Growth Factor (PDGF) and Vascular Endothelial Growth Factor (VEGF) may be associated with pathophysiology of autism. In this study, we screened serum levels of these growth factors in young male subjects with autism.

Methods

We measured serum levels of PDGF subtypes and VEGF in the 31 male children with autism (6–19 years old) and 31 healthy age- and gender-matched subjects.

Results

The serum levels of PDGF-BB in male children with autism (N = 31, 5624.5 ± 1651.8 pg/mL [mean ± SD]) were significantly higher (two-tailed Student's t-test: p = 0.0188) than those of normal control subjects (N = 31, 4758.2 ± 1521.5 pg/mL [mean ± SD]). There was a significant and positive correlation (Pearson's r = 0.5320, p = 0.0010) between the serum levels of PDGF-BB and the Autism Diagnostic Interview-Revised (ADI-R) domain C scores, which represent stereotyped patterns of behavior in the children with autism. However, there were no marked or significant correlations between serum PDGF-BB levels and clinical variables, including the other ADI-R scores and Intellectual Quotient (IQ) scores by WAIS-R. There were no significant change and correlations with clinical variables in serum PDGF-AA, PDGF-AB, and VEGF levels in the children with autism.

Conclusions

Increased levels of serum PDGF-BB homodimers might be implicated in the pathophysiology of autism.     

Odor detection threshold,but not odor identification,is impaired in children with autism

The aim of our study was to examine odor detection thresholds and odor identification in autistic subjects. Thirty-five patients with Asperger’s syndrome and high functioning autism (mean age 10.8 ± 3.6 years; 31 boys) were compared with 35 healthy control subjects (mean age 10.4 ± 2.4 years; 28 boys). There were no significant differences between groups with regard to mean age (p = 0.598) and gender proportion (p = 0.324). Olfactory testing used the Sniffin’ Sticks test (threshold and identification parts only). Participants with Asperger’s syndrome and high functioning autism, in comparison with healthy controls, were significantly impaired relative to odor detection thresholds (6.3 ± 3.1 vs. 7.9 ± 2.0; p = 0.025). Autistic participants were significantly better in correctly identifying the odor of an orange (94 vs. 63%; p < 0.05) and significantly worse at correctly identifying the odor of cloves (40 vs. 74%; p < 0.05). With regard to identification of fourteen other substances, there were no significant differences. There was no significant difference between autistic and control subjects on the total score of olfactory identification (p = 0.799). Odor identification ability (as expressed by this total score) correlated significantly with age in the control group (p = 0.049), but not in the autism group (p = 0.103). We found impaired odor detection and almost normal odor identification in children with autism. Implications for further research are discussed.     

Physiological growth is associated with esophageal morphometric and biomechanical changes in rats

Esophageal geometry and biomechanical changes were studied during physiological growth in rats aged 1-32 weeks. Histological examination was done after the biomechanical study. The esophageal dimensions increased many-fold from 1-32 weeks, e.g. the weight per unit length increased six-fold and the wall cross-sectional area increased eight-fold. The inner and outer circumferential length of the mucosa and muscle, and the thickness and area of the layers increased as function of age. The opening angle was approximately 140 degrees at age 1 and 2 weeks and gradually decreased to approximately 80 degrees after 16 weeks. The circumferential and longitudinal stress-strain curves were exponential. The circumferential stress-strain curves shifted from left to the right up to 4 weeks of age (P < 0.001) where after no further change was observed, i.e. the esophagus became more compliant during the first 4 weeks of life. The longitudinal stress-strain curves shifted from left to the right up to 16 weeks of age (P < 0.001), i.e. the esophagus became more compliant longitudinally during the first 16 weeks of life. Bi-axial stress-strain analysis with determination of mechanical tissue constants showed that the esophagus was stiffer in the longitudinal direction than in the circumferential direction. In conclusion, a pronounced morphometric and biomechanical remodelling was observed in the rat esophagus during physiological growth. The observed changes likely reflect the development of the physiological function of the esophagus since for other tissues the function dictates the form of the tissue, and growth and remodelling depend on the mechanical loading.     

Altered serum levels of vascular endothelial growth factor and glial-derived neurotrophic factor but not fibroblast growth factor-2 in treatment-naive children with attention deficit/hyperactivity disorder

Abstract

Background and aim: Recent evidence suggests that growth factors might be involved in the pathophysiology of attention deficit hyperactivity disorder (ADHD). The aim of this study was to determine whether serum levels of brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3), nerve growth factor (NGF), fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor (VEGF) were altered in children with ADHD.

Methods: Serum levels of BDNF, GDNF, NT-3, NGF, VEGF and FGF-2 were analyzed in 49 treatment- naive children with ADHD and age, gender matched 36 healthy controls using enzyme-linked immunosorbent assay. ADHD symptoms were scored by Du Paul ADHD Rating Scale and Strengths and Difficulties Questionnaire.

Results: We found that serum VEGF levels were significantly lower (p?<?0.001) and GDNF levels were significantly higher in ADHD group compared to control group (p?=?0.003). However, we found no correlations between ADHD symptoms and serum VEGF or GDNF levels. Furthermore, we observed no significant alterations in serum BDNF, NT-3, NGF, FGF-2 levels in children with ADHD.

Conclusion: To our knowledge, the present study is the first to examine serum VEGF and FGF-2 levels in children with ADHD. Our results indicate that VEGF and GDNF might be involved in the etiology of ADHD. Further studies are required to determine the role of growth factors in the etiology and consequently in the treatment of ADHD.