Intellectual disabilities moderate sex/gender differences in autism spectrum disorder: a systematic review and meta-analysis.

BACKGROUND: Girls/women with autism spectrum disorder (ASD) are suggested to exhibit different symptom profiles than boys/men with ASD. Accumulating evidence suggests that intellectual disability (ID) may affect sex/gender differences in ASD. However, a systematic review and meta-analysis on this topic is missing. METHODS: Two databases (MEDLINE and PsycINFO) were used to search for studies reporting sex/gender differences (girls/women versus boys/men) in social communication and interaction, restrictive and repetitive behaviour and interests (RRBIs), sensory processing, and linguistic and motor abilities in ASD. The final sample consisted of 79 studies. The meta-analysis was performed with Review Manager using a random-effects model. Participants with ASD without and with ID were analysed as separate subgroups, and the effects in these two subgroups were also compared with each other. RESULTS: Girls/women with ASD without ID displayed fewer RRBIs, more sensory symptoms and less problems in linguistic abilities than their boys/men counterparts. In contrast, girls/women with ASD with ID displayed more social difficulties and RRBIs, poorer linguistic abilities and more motor problems than boys/men with ASD with ID. Comparisons of groups of participants with ASD without ID versus participants with ASD with ID confirmed differences in sex/gender effects on social difficulties, sensory processing, linguistic abilities and motor abilities. CONCLUSIONS: Our results clearly suggest that the female phenotype of ASD is moderated by ID. Among individuals with ASD with ID, girls/women seem to be more severely affected than boys/men, whereas among individuals with ASD without ID, girls/women with ASD may have less symptoms than boys/men. Such phenotypic differences could be a potential cause of underrecognition of girls/women with ASD, and it is also possible that observed phenotypic differences may reflect underdiagnosing of girls/women with ASD.

Atopic asthma after rhinovirus-induced wheezing is associated with DNA methylation change in the SMAD3 gene promoter.

Children with rhinovirus-induced severe early wheezing have an increased risk of developing asthma later in life. The exact molecular mechanisms for this association are still mostly unknown. To identify potential changes in the transcriptional and epigenetic regulation in rhinovirus-associated atopic or nonatopic asthma, we analyzed a cohort of 5-year-old children (n = 45) according to the virus etiology of the first severe wheezing episode at the mean age of 13 months and to 5-year asthma outcome. The development of atopic asthma in children with early rhinovirus-induced wheezing was associated with DNA methylation changes at several genomic sites in chromosomal regions previously linked to asthma. The strongest changes in atopic asthma were detected in the promoter region of SMAD3 gene at chr 15q22.33 and introns of DDO/METTL24 genes at 6q21. These changes were validated to be present also at the average age of 8 years.

Spatiotemporal Dynamics of Attention Networks Revealed by Representational Similarity Analysis of EEG and fMRI.

The fronto-parietal attention networks have been extensively studied with functional magnetic resonance imaging (fMRI), but spatiotemporal dynamics of these networks are not well understood. We measured event-related potentials (ERPs) with electroencephalography (EEG) and collected fMRI data from identical experiments where participants performed visual and auditory discrimination tasks separately or simultaneously and with or without distractors. To overcome the low temporal resolution of fMRI, we used a novel ERP-based application of multivariate representational similarity analysis (RSA) to parse time-averaged fMRI pattern activity into distinct spatial maps that each corresponded, in representational structure, to a short temporal ERP segment. Discriminant analysis of ERP-fMRI correlations revealed 8 cortical networks-2 sensory, 3 attention, and 3 other-segregated by 4 orthogonal, temporally multifaceted and spatially distributed functions. We interpret these functions as 4 spatiotemporal components of attention: modality-dependent and stimulus-driven orienting, top-down control, mode transition, and response preparation, selection and execution.

The brains of high functioning autistic individuals do not synchronize with those of others.

Multifaceted and idiosyncratic aberrancies in social cognition characterize autism spectrum disorders (ASDs). To advance understanding of underlying neural mechanisms, we measured brain hemodynamic activity with functional magnetic resonance imaging (fMRI) in individuals with ASD and matched-pair neurotypical (NT) controls while they were viewing a feature film portraying social interactions. Pearson's correlation coefficient was used as a measure of voxelwise similarity of brain activity (InterSubject Correlations-ISCs). Individuals with ASD showed lower ISC than NT controls in brain regions implicated in processing social information including the insula, posterior and anterior cingulate cortex, caudate nucleus, precuneus, lateral occipital cortex, and supramarginal gyrus. Curiously, also within NT group, autism-quotient scores predicted ISC in overlapping areas, including, e.g., supramarginal gyrus and precuneus. In ASD participants, functional connectivity was decreased between the frontal pole and the superior frontal gyrus, angular gyrus, superior parietal lobule, precentral gyrus, precuneus, and anterior/posterior cingulate gyrus. Taken together these results suggest that ISC and functional connectivity measure distinct features of atypical brain function in high-functioning autistic individuals during free viewing of acted social interactions. Our ISC results suggest that the minds of ASD individuals do not 'tick together' with others while perceiving identical dynamic social interactions.

Hormonal deficiencies during and after Puumala hantavirus infection.

Previous reports have described panhypopituitarism associated with severe cases of hemorrhagic fever with renal syndrome (HFRS), but the prevalence of hormonal deficiencies after nephropathia epidemica (NE), a milder form of HFRS, has not been studied. This study was conducted in order to determine the prevalence of hormonal defects in patients with acute NE and during long-term follow-up. Fifty-four patients with serologically confirmed acute NE were examined by serum hormonal measurements during the acute NE, after 3 months, and after 1 to 10 (median 5) years. Thirty out of 54 (56%) patients had abnormalities of the gonadal and/or thyroid axis during the acute NE. After a median follow-up of 5 years, 9 (17%) patients were diagnosed with a chronic, overt hormonal deficit: hypopituitarism was found in five patients and primary hypothyroidism in five patients. In addition, chronic subclinical testicular failure was found in five men. High creatinine levels and inflammatory markers during NE were associated with the acute central hormone deficiencies, but not with the chronic deficiencies. Hormonal defects are common during acute NE and, surprisingly, many patients develop chronic hormonal deficiencies after NE. The occurrence of long-term hormonal defects cannot be predicted by the severity of acute NE.

Model films from native cellulose nanofibrils. Preparation, swelling, and surface interactions.

Native cellulose model films containing both amorphous and crystalline cellulose I regions were prepared by spin-coating aqueous cellulose nanofibril dispersions onto silica substrates. Nanofibrils from wood pulp with low and high charge density were used to prepare the model films. Because the low charged nanofibrils did not fully cover the silica substrates, an anchoring substance was selected to improve the coverage. The model surfaces were characterized using atomic force microscopy (AFM) and X-ray photoelectron spectroscopy (XPS). The effect of nanofibril charge density, electrolyte concentration, and pH on swelling and surface interactions of the model film was studied by quartz crystal microbalance with dissipation (QCM-D) and AFM force measurements. The results showed that the best coverage for the low charged fibrils was achieved by using 3-aminopropyltrimethoxysilane (APTS) as an anchoring substance and hence it was chosen as the anchor. The AFM and XPS measurements showed that the fibrils are covering the substrates. Charge density of the fibrils affected the morphology of the model surfaces. The low charged fibrils formed a network structure while the highly charged fibrils formed denser film structure. The average thickness of the films corresponded to a monolayer of fibrils, and the average rms roughness of the films was 4 and 2 nm for the low and high charged nanofibril films, respectively. The model surfaces were stable in QCM-D swelling experiments, and the behavior of the nanofibril surfaces at different electrolyte concentrations and pHs correlated with other studies and the theories of Donnan. The AFM force measurements with the model surfaces showed well reproducible results, and the swelling results correlated with the swelling observed by QCM-D. Both steric and electrostatic forces were observed and the influence of steric forces increased as the films were swelling due to changes in pH and electrolyte concentration. These films differ from previous model cellulose films due to their chemical composition (crystalline cellulose I and amorphous regions) and fibrillar structure and hence serve as excellent models for the pulp fiber surface.

Multiple endocrine neoplasia type 1 in Northern Finland; clinical features and genotype phenotype correlation.

OBJECTIVE: The existence of genotype-phenotype correlation in multiple endocrine neoplasia type 1 (MEN1) is controversial. Two founder mutations of the MEN1 gene in Northern Finland gave us an opportunity to compare clinical features among heterozygotes of different mutations. DESIGN AND METHODS: Study cohort included 82 MEN1 heterozygotes who were tested for MEN1 during the years 1982-2001. Medical records were reviewed for manifestations of MEN1, other tumours and cause of death by the end of August 2003. Logistic regression analysis was used in evaluating the impact of age, gender and mutational status of affected heterozygotes on the likelihood of developing manifestations of MEN1. RESULTS: Founder mutations 1466del12 and 1657insC were found in 39 and 29 individuals, and D418N, G156R and R527X mutations in 9, 3 and 2 individuals respectively. Except for pituitary adenoma and nonfunctional pancreatic tumour (NFPT), age was a risk factor for all the disease manifestations. For NFPT, frameshift/nonsense mutations (1657insC, R527X) gave an odds ratio (OR) of 3.26 (95% confidence intervals (CI), 1.27-8.33; P = 0.014) compared with in-frame/missense mutations (1466del12, D418N, G156R); including the founder mutation carriers (n = 68) only, the 1657insC mutation gave an OR of 3.56 (CI, 1.29-9.83; P = 0.015). For gastrinoma, in-frame/missense mutations predicted the risk with an OR of 6.77 (CI, 1.31-35.0; P = 0.022), and in the founder mutations group the 1466del12 mutation gave an OR of 15.09 (CI, 1.73-131.9, P = 0.014). CONCLUSIONS: In this study population, NFPT was more common in the frameshift/nonsense or 1657insC mutation carriers, whereas gastrinoma was more common in the in-frame/missense or 1466del12 mutation carriers.

A search strategy for occupational health intervention studies.

BACKGROUND: As a result of low numbers and diversity in study type, occupational health intervention studies are not easy to locate in electronic literature databases. AIM: To develop a search strategy that facilitates finding occupational health intervention studies in Medline, both for researchers and practitioners. METHODS: A gold standard of articles was created by going through two whole volumes of 19 biomedical journals, both occupational health specialty and non-occupational health journals. Criteria for occupational health intervention studies were: evaluating an intervention with an occupational health outcome and a study design with a control group. Each journal was searched independently by two of the authors. Search terms were developed by asking specialists and counting word frequencies in gold standard articles. RESULTS: Out of 11 022 articles published we found 149 occupational health intervention studies. The most sensitive single terms were work*[tw] (sensitivity 71%, specificity 88%) and effect*[tw] (sensitivity 75%, specificity 63%). The most sensitive string was (effect*[tw] OR control*[tw] OR evaluation*[tw] OR program*[tw]) AND (work*[tw] OR occupation*[tw] OR prevention*[tw] OR protect*[tw]) (sensitivity 89%, specificity 78%). The most specific single terms were "occupational health"[tw] (sensitivity 22%, specificity 98%) and effectiveness[tw] (sensitivity 22%, specificity 98%). The most specific string was (program[tw] OR "prevention and control"[sh]) AND (occupational[tw] OR worker*[tw]) (sensitivity 47%, specificity 98%). CONCLUSION: No single search terms are available that can locate occupational health intervention studies sufficiently. The authors' search strings have acceptable sensitivity and specificity to be used by researchers and practitioners respectively. Redefinition and elaboration of keywords in Medline could greatly facilitate the location of occupational health intervention studies.

Geometrical distortions in two-dimensional gels: applicable correction methods.

Two-dimensional electrophoresis (2-DE) provides a rapid means for separating thousands of proteins from cell and tissue samples in one run. Although this powerful research tool has been enthusiastically applied in many fields of biomedical research, accurate analysis and interpretation of the data have provided many challenges. Several analysis steps are needed to convert the large amount of noisy data obtained with 2-DE into reliable and interpretable biological information. The goals of such analysis steps include accurate protein detection and quantification, as well as the identification of differentially expressed proteins between samples run on different gels. To achieve these goals, systematic errors such as geometric distortions between the gels must be corrected by using computer-assisted methods. A wide range of computer software has been developed, but no general consensus exists as standard for 2-DE data analysis protocol. The choice of analysis approach is an important element depending both on the data and on the goals of the experiment. Therefore, basic understanding of the algorithms behind the software is required for optimal results. This review highlights some of the common themes in 2-DE data analysis, including protein spot detection and geometric image warping using both spot- and pixel-based approaches. Several computational strategies are overviewed and their relative merits and potential pitfalls discussed. Finally, we offer our own personal view of future trends and developments in large-scale proteome research.

Working memory, psychiatric symptoms, and academic performance at school.

Previous studies of the relationship among working memory function, academic performance, and behavior in children have focused mainly on clinical populations. In the present study, the associations of the performance in audio- and visuospatial working memory tasks to teacher reported academic achievement and psychiatric symptoms were evaluated in a sample of fifty-five 6-13-year-old school children. Working memory function was measured by visual and auditory n-back tasks. Information on incorrect responses, reaction times, and multiple and missed responses were collected during the tasks. The children's academic performance and behavioral and emotional status were evaluated by the Teacher Report Form. The results showed that good spatial working memory performance was associated with academic success at school. Children with low working memory performance, especially audiospatial memory, were reported to have more academic and attentional/behavioral difficulties at school than children with good working memory performance. An increased number of multiple and missed responses in the auditory and visual tasks was associated with teacher reported attentional/behavioral problems and in visual tasks with teacher reported anxiety/depressive symptoms. The results suggest that working memory deficits may underlie some learning difficulties and behavioral problems related to impulsivity, difficulties in concentration, and hyperactivity. On the other hand, it is possible that anxiety/depressive symptoms affect working memory function, as well as the ability to concentrate, leading to a lower level of academic performance at school.

Thyroid hormone substitution therapy rapidly enhances left-ventricular diastolic function in hypothyroid patients.

OBJECTIVE: Alterations in thyroid status may lead to changes in both systolic and diastolic function of the heart. Pulsed Doppler echocardiography is a reliable non-invasive means of assessing left-ventricular (LV) diastolic function. The aim of the present study was to evaluate LV diastolic function in patients with primary hypothyroidism receiving thyroxine therapy. METHODS: Twelve patients (all females, mean age 47 +/- 17, range 16-69 years) with primary hypothyroidism were studied by pulsed Doppler echocardiography. The first examination was made before the start of thyroxine substitution and the second at 37-68 (mean 53 +/- 10) days after commencing thyroxine treatment (mean dose 136 +/- 22 microg/day). RESULTS: During thyroxine substitution therapy, the hypothyroid patients became clinically euthyroid and serum T4 increased from 51 +/- 21 to 119 +/- 24 nmol/l; TSH decreased from 50.4 +/- 55.3 to 1.2 +/- 1.5 mU/l. During therapy, heart rate increased from 61 +/- 8 to 68 +/- 10 (p = 0.05). The LV posterior wall (7.8 +/- 1.0 mm) and interventricular septum thickness (8.0 +/- 1.4 mm) were significantly greater in hypothyroid patients than in the control subjects (6.4 +/- 1.0 mm, p = 0.007 and 6.8 +/- 1.0 mm, p = 0.04, respectively). There was no significant change in LV dimensions and wall thickness during follow-up. E/A(max) increased significantly during treatment (from 1.679 +/- 0.432 to 1.947 +/- 0.335, p = 0.006). The isovolumic relaxation time shortened significantly (from 88 +/- 23 ms to 75 +/- 24 ms, p = 0.005). CONCLUSIONS: The present study shows that LV diastolic function as assessed by pulsed Doppler echocardiography in hypothyroid patients is enhanced by thyroxine therapy during a rather short follow-up period.

Allele 2 of interleukin-1 receptor antagonist gene increases the risk of thyroid peroxidase antibodies in subacute thyroiditis.

Subacute granulomatous thyroiditis (SAT) is a self-limiting systemic inflammatory disorder with possible transient expression of thyroid antibodies. Persistent hypothyroidism is uncommon. The interleukin-1 receptor antagonist IL-1ra is an inhibitor of IL-1 activity and allele 2 of the IL-1ra gene is associated with inflammatory diseases and IL-1ra production. Forty-eight subjects with SAT were investigated. Polymorphisms of IL-1ra, IL-1beta-511 and TNFalpha genes were studied with respect to thyroid peroxidase antibodies (TPOab), thyroglobulin antibodies, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Serum IL-1ra levels were measured. An increased allelic frequency (43% vs 22%, p=0.039) and carriage rate (79% vs 41%, p=0.018) for IL-1ra allele 2 were observed with expression of TPOab in 14 (29.2%) subjects compared with those with negative findings. The carriage rate for both IL-1ra allele 2 and IL-1beta-511 allele 2 was also increased with TPOab expression (71% vs 27%, p=0.004, respectively). No difference in allele frequency or carriage rate was found compared with healthy controls. Serum IL-1ra levels correlated with S-CRP (r=0.41, p=0.004) and ESR (r=0.34, p=0.016), but the association with genes or thyroid antibodies was statistically insignificant. S-CRP levels and ESR were lower and negatively correlated with expression of TPOab (r=-0.27, p=0.046 and r=-0.32, p=0.017). This study describes the multiplicity of the mechanisms responsible for the severity of the acute-phase response during the course of SAT. IL-1ra may have a significant anti-inflammatory role in SAT. Presence of IL-1ra allele 2 increases the risk of developing TPOab.

Autoimmune hypopituitarism in patients with coeliac disease: symptoms confusingly similar.

Coeliac disease does not always respond properly to a gluten-free diet, and treatment may be complicated by an underlying autoimmune endocrine disorder. We report three cases of hypopituitarism in patients with coeliac disease who seemed to have incomplete dietary response. The first patient had diabetes and suffered from hypoglygaemic events; the second had muscular atrophy of unknown origin while the third had growth failure. None had a pituitary mass, suggesting that hypopituitarism was of autoimmune origin. Overall condition improved only after replacement therapy for the underlying hormone deficiency; this association should thus be recognized.

Clinical and subclinical autoimmune thyroid disease in adult celiac disease.

Our aim was to investigate the occurrence of clinical and subclinical autoimmune thyroid disease in 79 patients with celiac disease as reflected in thyroid function, antibodies, and ultrasound. Since subclinical thyroid diseases are common in the population, 184 nonceliac controls were also studied. Normal thyroid function combined with positive antibodies and marked hypoechogenicity was considered subclinical disease. Autoimmune thyroid disease was observed in 13.9% of celiac patients and in 2.1% of controls (P = 0.0005); and subclinical disease in 10.1% and 3.3%, respectively (P = 0.048). The mean thyroid gland volume was 8.3 ml in celiac patients and 10.4 ml in controls (P = 0.007). Hypoechogenicity was found in 73% of celiac patients and in 42% of controls (P < 0.0001). Positive thyroid antibodies were associated with hypoechogenicity in celiac patients but not in controls. In conclusion, the occurrence of both clinical and subclinical autoimmune thyroid disease was increased in celiac disease; subclinical thyroid disease indicates regular surveillance.

Left ventricular structure and function in primary hyperparathyroidism before and after parathyroidectomy.

OBJECTIVE: Our aim was to study the effect of primary hyperparathyroidism (PHPT) and parathyroidectomy (PTX) on left ventricular (LV) wall thicknesses and systolic and diastolic function. METHODS: Fifteen patients with untreated PHPT were evaluated by applying Doppler and digitized M-mode echocardiography before and 2-3 months after PTX. Fifteen age- and sex-matched healthy controls were also examined echocardiographically. RESULTS: Prior to PTX, interventricular septal thickness (IVST), LV mass (LVM), aortic root dimension and left atrium dimension were greater and LV fractional shortening was slightly decreased in patients as compared to controls. Significantly increased LV peak late diastolic velocity (A(max)) and isovolumic relaxation time, and a slightly decreased ratio of peak early to peak late diastolic velocities (E/A(max)) in the patients indicated impairment of LV diastolic function in hyperparathyroidism. PTX reduced serum total Ca from 2. 79 +/- 0.13 to 2.39 +/- 0.09 mmol/l (p < 0.001) and tended to reduce IVST [10.6 +/- 2.1 vs. 10.4 +/- 2.0 mm; not significant (n.s.)], LV posterior wall thickness (9.6 +/- 2.0 vs. 9.2 +/- 1.0 mm, n.s.) and LVM (250 +/- 102 vs. 213 +/- 42 g; n.s.). Before PTX, there was a significant correlation between serum total Ca and LVM (r = 0.63, p < 0.05), and the PTX-induced change in serum total calcium correlated with the change in LVM (r = 0.59, p < 0.05). PTX induced no significant changes in LV systolic or diastolic function during the follow-up of 2-3 months. CONCLUSIONS: The present findings indicate that PHPT induces LV hypertrophy, slight impairment of LV systolic function and significant impairment of LV diastolic function, which are not substantially improved after TX and 2-3 months of normocalcemia.

Genome-wide scan of obesity in Finnish sibpairs reveals linkage to chromosome Xq24.

Obesity is a multifactorial trait with evidence of a genetic component. Obesity is very common in all westernized countries, including Finland, where 10% of the adult population has a body mass index of 32 kg/m2 or more. Here we report results from a three-stage genome-wide scan of obesity in 188 affected subjects (body mass index, > or =32 kg/m2) from 87 Finnish families. Initially, 374 markers with an average density of 10 centimorgans were genotyped. The strongest evidence for linkage to obesity was detected on chromosome Xq24, with the marker DXS6804 providing a maximum likelihood score (MLS) 3.14 in a model-free 2-point sibpair analysis. Fine-mapping in an extended sample set of 367 affected subjects from 166 families yielded a multipoint MLS of 3.48 over this X-chromosomal region. The Xq24 region contains a plausible candidate gene, serotonin 2C receptor, variants of which have been shown to predispose to obesity and type II diabetes in mice. Another chromosomal region also provided suggestive evidence of linkage, an area on 18q21, flanking the melanocortin-4 receptor, where a 2-point MLS of 2.42 with marker D18S1155 was obtained with a set of 367 affected subjects. In conclusion, our results in this Finnish study sample suggest that a locus on chromosome Xq24 influences the risk of obesity.

Celiac disease and autoimmune endocrinologic disorders.

Patients with insulin-dependent diabetes mellitus, autoimmune thyroid disease, Addison's disease, and alopecia areata are at increased risk of celiac disease. We investigated whether patients with more than one autoimmune endocrinologic disorder are even more susceptible to celiac disease or have celiac-type mucosal inflammation. All 62 patients found to have such multiple diseases in 1994-1996 were investigated. Small bowel biopsy was performed on all voluntary nonceliac subjects. The villous structure and density of intraepithelial lymphocytes were examined, and HLA-DQ alleles were determined. Seven (11%) patients had celiac disease: six cases were detected earlier and there was one new case; in addition, two had minor villous deterioration and five an increased density of mucosal intraepithelial gammadelta+ T-cells. HLA-DQ2 or DQ8 alleles were found in all subjects with mucosal changes. Patients with multiple autoimmune disorders clearly run an increased risk of developing celiac disease, and some of them have minor mucosal changes compatible with the early signs of the disease.

Osteopenia in patients with clinically silent coeliac disease warrants screening.

Bone-mineral density was measured in 19 clinically silent coeliac patients. The density was low, comparable with that in coeliac cases, and improved by gluten-free diet.