Altered expression of hippocampal dentate granule neuron genes in a mouse model of human 22q11 deletion syndrome

Hemizygous deletion of a 3 Mb region of 22q11.2 is found in 1/4000 humans and produces 22q11 deletion syndrome (22q11DS). Up to 35% of 22q11DS patients develop schizophrenia, making it the second highest risk factor for schizophrenia. A mouse model for 22q11DS, the Df1/+ mouse, carries a hemizygous deletion in a region syntenic with the human deletion. Df1/+ mice are mostly viable but display deficits in prepulse inhibition and learning and memory, two common traits of schizophrenia thought to result, at least in part, from defects in hippocampal neurons. We used oligonucleotide microarrays and QRT-PCR to evaluate gene expression changes in hippocampal dentate granule neurons of Df1/+ mice versus wild-type littermates (n=12/group). The expression of only 287 genes changed with p value significance below 0.05 by microarray, yet 12 of the 21 Df1 region genes represented on the array showed highly significantly reduced expression compared to wild-type controls (33% on average, p values from 10(-3) to 10(-7)). Variants in two of these genes, COMT and PRODH, have been linked with schizophrenia. Overlap of the 287 genes with the reportedly reduced expression of mitochondrial, ubiquitin/proteasome, and synaptic plasticity genes in schizophrenia dentate granule neurons, was not significant. However, modest increases in expression of mitochondrial electron transport genes were observed in the Df1/+ mice. This perhaps indicates a compensation for mitochondrial dysfunction caused by the strongly reduced expression of the Df1 region-encoded mitochondrial enzymes proline dehydrogenase (Prodh) and thioredoxin reductase 2 (Txnrd2).     

Evidence of gray matter reduction and dysfunction in chromosome 22q11.2 deletion syndrome

Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with cognitive deficits and morphometric brain abnormalities in childhood and a markedly elevated risk of schizophrenia in adolescence/early adulthood. Determining the relationship between neurocognition and neuroimaging findings would yield crucial information about childhood neurodevelopment and provide a basis for the study of the trajectory that occurs on the pathway to psychosis. We compared morphometric brain findings between non-psychotic children with 22q11DS (n = 22) and healthy controls (n = 16), and examined the association between neurocognitive functioning and morphometric brain findings. Volumetric regional gray matter differences between the 22q11DS and control subjects were measured, and correlations of the regional gray matter volumes and neurocognition were performed. Children with 22q11DS demonstrated reductions in gray matter in several brain regions, chiefly the frontal cortices, the cingulate gyrus and the cerebellum. The volumetric reductions in these salient areas were associated with poor performance in sustained attention, executive function and verbal memory; however, the relation of brain volume with cognitive performance did not differ between the patient and control groups. Thus, children with 22q11DS demonstrate gray matter reductions in multiple brain regions that are thought to be relevant to schizophrenia. The correlation of these volumetric reductions with poor neurocognition indicates that these brain regions may mediate higher neurocognitive functions implicated in schizophrenia.     

Association of IL-12p70 and IL-6:IL-10 ratio with autism-related behaviors in 22q11.2 deletion syndrome: A preliminary report

22q11.2 deletion syndrome (22q11DS) is a genetic disorder that conveys a significant risk for the development of social behavior disorders, including autism and schizophrenia. Also known as DiGeorge syndrome, 22q11DS is the second most common genetic disorder and is characterized by an elevated risk for immune dysfunction, up to 77% of individuals have an identifiable immune deficiency. We hypothesize that this immune dysfunction could contribute to the elevated risk of impaired social behavior seen in 22q11DS. The current study begins to elucidate these immune deficits and link them with the behavioral alterations associated with the disorder. Serum concentrations of a series of cytokines were examined, using a multiplex immunoassay, in sixteen individuals with 22q11DS and screened for autism-related behavior using the Autism Diagnostic Interview-Revised (ADI-R). This preliminary study examined correlations between specific immune proteins and each of the ADI-R algorithm scores (social, communication, and repetitive behavior). The inflammatory cytokine IL-1β, as well as the ratio between the inflammatory cytokine IL-6 and the anti-inflammatory cytokine IL-10, were correlated with social scores (r = 0.851, p = 0.004; r = 0.580, p = 0.018). In addition, the inflammatory cytokines interferon gamma and IL-12p70 were correlated with repetitive behaviors (r = 0.795, p = 0.033; r = 0.774, p = 0.002). Interestingly, IL-12 has been reported to be increased in autistic children. These data show a positive association between severity of autism-related behaviors and level of serum concentrations of inflammatory cytokines in individuals with 22q11DS, providing a basis for further inquiry.     

Cognitive and behavioral trajectories in 22q11DS from childhood into adolescence: A prospective 6-year follow-up study

Patients with 22q11DS are at risk of behavioral problems and cognitive impairment. Recent studies suggest a possible intellectual decline in 22q11DS children. To date it is unknown if cognitive development is related to the behavioral problems in 22q11DS. We studied 53 children with 22q11DS who underwent cognitive and behavioral assessments at 9.5 years (T1) and 15.3 years (T2). In about one third, IQ data obtained at 7.5 years (T0) were also available. Results showed that internalizing behaviors intensified while externalizing behaviors decreased. Simultaneously, in about a third a significant decline in IQ was found, which, surprisingly, was unrelated to the behavioral changes. It can be concluded that children with 22q11DS follow a unique developmental trajectory. Cognitive deterioration is severe in some but does not appear to predict behavioral problems in early adolescence.     

Gene dosage in the developing and adult brain in a mouse model of 22q11 deletion syndrome

We evaluated the consequences of heterozygous chromosome 22q11 deletion – a significant genetic risk for schizophrenia – for expression levels and patterns of a subset of 22q11 genes implicated in schizophrenia and other phenotypes in mouse models of 22q11 deletion syndrome (22q11DS). In deleted embryos, expression levels of at least nine 22q11 orthologues decline by 40–60% in the frontonasal mass/forebrain and other 22q11DS phenotypic sites (branchial and aortic arches, limb buds); however, coincident expression patterns of 22q11 and Snail genes – diagnostic for neural crest-derived mesenchyme – are unchanged, and Snail1 expression levels do not decline. Subsequently, 22q11 mRNA levels are reduced by 40–60% in the brains of developing, adolescent and adult deleted mice without altered expression patterns, dysmorphology or reduced cell density. Apparently, in deleted individuals, 22q11 gene expression declines across otherwise stable cell populations, perhaps disrupting individual cell function via diminished dosage. Such changes might contribute to schizophrenia vulnerability in 22q11DS.     

The lack of association between catechol-O-methyltransferase (COMT) Val108/158Met and brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms and schizophrenia in a group of Turkish population

IntroductionSchizophrenia is a complex neuropsychiatric disorder with deficits of multiple domains of cognitive functions, volition and emotions. Family and twin studies have provided cumulative evidence for the genetic basis of schizophrenia. The aetiolgy of this disease involves the interplay of multifactiorial inheritance operating on brain maturational processes and polygenic inheritance with some genes showing susceptibility at many genomic locations such as 22q and 11q.The catechol-O-methyltransferase (COMT-22q11) is an extensively studied candidate gene for schizophrenia. COMT acts as an enzymatic detoxicating barrier between the blood and other tissues regulating the amounts of active dopamine and norepinephrine in various parts of the brain and therefore to be associated with schizophrenia.The presence of a common functional single nucleotide polymorphism (SNP) in exon 4 [Guanine (G) Adenine (A); Val108/158Met], alters the enzymatic activity with a trimodal distribution of high-HH, intermediate-HL and low-LL activity alleles which appear to have association with schizophrenia.Brain-derived neurotrophic factor (BDNF-11q13) is a member of the nerve growth factor family working as a molecular regulator of neuronal development and plasticity. Molecules that are critical in the development and survival of neurons such as BDNF play a significant role in the neuropathology of schizophrenia. While upregulation of BDNF increases the neuronal cell size and synaptic plasticity, a functional polymorphism at codon 66 [G→A; Val66Met] down regulates this process and induces schizophrenia.ObjectiveIn the present study, our aim was to investigate the differences in allele frequencies between schizophrenic patients [n = 97 (51 men, 46 women)] and control group [n = 376 (228 men, 148 women)] subjects.ResultsWhen the control and schizophrenia groups were compared for BDNFVal66Met polymorphism, we did not find a significant difference between the study groups either for genotype (χ² = 3.370447, p > 0.05) or Val/Met haplotype analysis (χ² = 2.840264, p > 0.05). When a comparison was revealed for COMT-Val108/158Met polymorphism, no significant difference was detected among schizophrenia and control groups for genotype (χ² = 0.373330, p > 0.05) and Val/Met haplotype analysis (χ² = 0.339073, p > 0.05). When the control and study groups were compared for BDNFVal66Met–COMTVal108/158Met polymorphisms compound genotype and haplotype analyses, there was no significant difference between the two groups (χ² = 11.015; p > 0.05 and χ² = 3.191; p > 0.05), respectively.ConclusionOur results indicate that there is no association between schizophrenia and BDNF–COMT polymorphisms and haplotypes analysis. We also did not find an association between schizophrenia and BDNF–COMT compound genotype and haplotype analyses. Although our study is unique in Turkey as combining BDNF and COMT compound genotype–haplotype analyses, for a generalization of Turkish schizophrenia patient's susceptibility to schizophrenia; we need further studies with an enlarged cohort.     

Selective overexpression of Comt in prefrontal cortex rescues schizophrenia-like phenotypes in a mouse model of 22q11 deletion syndrome

The 22q11.2 microdeletion is one of the highest genetic risk factors for schizophrenia. It is not well understood which interactions of deleted genes in 22q11.2 regions are responsible for the pathogenesis of schizophrenia, but catechol-O-methytransferase (COMT) is among the candidates. Df1/+ mice are 22q11.2 deletion syndrome (22q11DS) model mice with a hemizygous deletion of 18 genes in the 22q11-related region. Df1/+ mice showed enhanced response to the dopamine D1 agonist, {"type":"entrez-protein","attrs":{"text":"SKF38393","term_id":"1157151916","term_text":"SKF38393"}}SKF38393, and the N-methyl-D-aspartate antagonist, MK801, which can be normalized by a GABA_A receptor agonist, bretazenil, or a GABA_A α2/α3 receptor agonist, SL651498. Here, we demonstrated the curing effects of virus-mediated reintroduction of Comt to the prefrontal cortex (PFC) in Df1/+ mice. In contrast, both Comt overexpression and Comt inhibition caused an abnormal responsiveness to Bretazenil, a GABA_A receptor agonist in control mice. Comt overexpression increased MK801-induced interneuronal activation and GABA release in the PFC. The expression levels of GABA-related genes such as Gabrb2 (GABA_Areceptor β2), Gad2 (glutamic acid decarboxylase 65 (Gad65)) and Reln (Reelin) correlate with a Comt expression level in PFC. Our data suggest that Comt-mediated regulation of GABAergic system might be involved in the behavioral pathogenesis of Df1/+ mice.     

Prospective control abilities during visuo-manual tracking in children with 22q11.2 Deletion syndrome compared to age- and IQ-matched controls

To examine whether children with a 22q11.2 Deletion syndrome (22q11.2DS) are able to use prospective control, 21 children with 22q11.2DS (mean age = 9.6 ± 1.9; mean FSIQ = 73.05 ± 10.2) and 21 control children (mean age = 9.6 ± 1.9; mean FSIQ = 73.38 ± 12.0) were asked to perform a visuo-manual tracking task in which they had to track a cursor rhythmically between 2 target zones. Children with 22q11.2DS performed worse than the age- and IQ-matched controls (higher absolute time and distance errors) suggesting that the 22q11.2DS group experiences an additional (syndrome specific) processing deficit that cannot be attributed to their lower intellectual abilities. The 22q11.2DS group neither the control group improved their tracking performance throughout five identical full feedback conditions of the tracking task possibly due to a slow visuo-motor adaptation process, a short span of attention and cognitive flexibility impairments. The results showed that both the 22q11.2DS group and the controls had difficulties anticipating the movement of the target (prospective control) and thus are assumed to rely more on feedback instead of on an internal representation of the movement.     

Kinematic movement strategies in primary school children with 22q11.2 Deletion Syndrome compared to age- and IQ-matched controls during visuo-manual tracking

The present study focused on the mechanism subserving the production of kinematic patterns in 21 children with 22q11.2DS (mean age = 9.6 ± 1.9; mean FSIQ = 73.05 ± 10.2) and 21 age- and IQ-matched control children (mean age = 9.6 ± 1.9; mean FSIQ = 73.38 ± 12.0) when performing a visuo-manual tracking task in which they had to track a cursor rhythmically between 2 target zones. Children with 22q11.2DS moved faster (overall) and reached their maximum velocity sooner when compared to controls. However, the number of corrective submovements to attain the target did not differ. Children with 22q11.2DS seem to adopt a young ballistic movement strategy, with a fast ballistic first movement phase, followed by a second movement phase with very little online corrections to attain the target. Children with 22q11.2DS are not able to process the incoming feedback during the second movement phase to maximize the accuracy of the ongoing movement and use this phase to prepare the following. The fact that the parietal cortex and cerebellum are involved in action prediction and internal representation and are implicated in children with 22q11.2DS provides a possible neurological basis for their problems with prospective control and tracking behavior.     

Allelic variants in the zinc transporter-3 gene,SLC30A3, a candidate gene identified from gene expression studies,show gender-specific association with schizophrenia

Previous microarray analysis of gene expression in frontal cortex showed differential expression of genes associated with synaptic function in schizophrenia compared to matched-controls in two independent cohorts. One of these genes validated in both cohorts, SLC30A3, which encodes the Zinc Transporter 3 (ZNT3), is localised to synaptic vesicles in glutamate synapses and known to be involved in cognitive function. In view of the robust depletion of SLC30A3 mRNA in two independent studies and the importance of this gene in cognitive function, we investigated whether single nucleotide polymorphism (SNP) associations with schizophrenia could be detected in a UK case controlled schizophrenia cohort. Four SNPs were selected across this gene and genotyped in a cohort of cases and controls from East UK. We found significant associations with schizophrenia at the allelic (ORs: 1.51 to 1.57), genotype (ORs: 1.46 to 1.53) and haplotype level (P = 2.15 × 10⁻⁴). These associations proved to be gender-specific with significant effects of allele (ORs: 1.74 to 2.11), genotype (ORs: 1.78 to 2.14) and haplotype (P = 3.51 × 10⁻⁵) observed in female schizophrenia cases but not males, when split by gender. In conclusion, SNPs in SLC30A3 showed a gender-specific association with schizophrenia in this East UK cohort, which merits further investigation in other population samples.     

Variability of cognitive development in children with Down syndrome: Relevance of good reasons for using the cluster procedure

The main goal of this cross-sectional study was to demonstrate that, in addition to a main change during childhood, the cognitive development of children with Down syndrome (DS) is characterized by interindividual variability in their cognitive functioning. Eighty-eight French children with DS took part in this experiment. They were divided into six chronological age groups: 6 years (N = 9), 7 years (N = 19), 8 years (N = 18), 9 years (N = 19), 10 years (N = 14) and 11 years (N = 9). They were assessed by means of the Differential Scales of Intellectual Efficiency. This test, composed of six independent scales, measures verbal abilities and nonverbal reasoning abilities. Initial analyses of the verbal and nonverbal subtest scores indicated a main change in cognitive skills. We then used a clustering approach to identify four cognitive profiles that distinguished the children with DS independently of age and gender. The results confirm that there is a growth in the cognitive skills of DS children. They also suggest that the cognitive functioning of DS children is characterized by different individual profiles. Implications for more fine-tuned research and intervention efforts are discussed.     

A patient with DiGeorge syndrome with spina bifida and sacral myelomeningocele,who developed both hypocalcemia-induced seizure and epilepsy

DiGeorge syndrome – a component of the 22q11 deletion syndrome – causes a disturbance in cervical neural crest migration that results in parathyroid hypoplasia. Patients can develop hypocalcemia-induced seizures. Spina bifida is caused by failure of neurulation, including a disturbance in the adhesion processes at the neurula stage. Spina bifida has been reported as a risk factor for epilepsy.We report, for the first time, the case of a patient with DiGeorge syndrome with spina bifida and sacral myelomeningocele, who developed both hypocalcemia-induced seizures and epilepsy. The patient had spina bifida and sacral myelomeningocele at birth. At the age of 13 years, he experienced a seizure for the first time. At this time, the calcium concentration was normal. An electroencephalogram (EEG) proved that the seizure was due to epilepsy. Antiepileptic medications controlled the seizure. At the age of 29, the patient's calcium concentration began to reduce. At the age of 40, hypocalcemia-induced seizure occurred. At this time, the calcium concentration was 5.5 mg/dL (reference range, 8.7–10.1 mg/dL). The level of intact parathyroid hormone (PTH) was 6 pg/mL (reference range, 10–65 pg/mL). Chromosomal and genetic examinations revealed a deletion of TUP-like enhancer of split gene 1 (tuple1)—the diagnostic marker of DiGeorge syndrome. Many patients with DiGeorge syndrome have cardiac anomalies; however, our patient had none.We propose that the association among DiGeorge syndrome, spina bifida, epilepsy, cardiac anomaly, 22q11, tuple1, and microdeletion inheritance should be clarified for appropriate diagnosis and treatment.     

Motor skill assessment in children with Down Syndrome: Relationship between performance-based and teacher-report measures

Resultsof previous studies show a large interindividual variability with regard to motor skills and motor abilities in children with Down Syndrome (DS). In order to provide detailed information for intervention, adequate assessment methods seem to be necessary to address the child's unique motor profile. Typically, children are either examined using a bottom-up (performance-based assessment of motor skills) or a top-down approach (e.g. client-report measure), but rarely both approaches. The aim of this study was to examine the relationship between standardized performance-based, and teacher-report measures of children's motor performance. The performance- and process-based assessment Test of Gross Motor Development (TGMD-2), and the teacher-based Movement Assessment Battery – Checklist (MABC-C) for young children were used to assess the motor performance of 18 children with DS (11 boys, 7 girls) aged 7–11 years (M = 9.06, SD = 0.96) and an age- and sex-matched sample of typically developing (TD) 18 children (11 boys, 7 girls; M = 8.99, SD = 0.93). TD children achieve consistently better results compared to children with DS, both in the TGMD-2 and MABC-C, which differ significantly in most cases. When gender differences were examined for the TGMD-2 scores, boys with DS were better performers of the run, gallop, leap, and catch, as well as the locomotor and object-control skill sum scores, whereas girls of the TD group were more proficient in these areas. TD children achieve significantly better results in 21 out of 28 items of Section A + B of the MABC-C, compared to the children with DS; whereas there are no significant differences for Section C (non-motor factors). Our results show more significant relationships between TGMD-2 and MABC-C sub- and overall scores for the TD sample compared to the children with DS. The correlations range between r = −.21 and −.65 for TD children and between r = −.15 and −.65 for the children with DS. The correlations between both approaches show that the combination of both methods could be useful in getting a more detailed picture of the child's individual motor profile in order to create tailor-made therapies and interventions, both for children with DS and TD children.     

Relationship among clinical,pathological and bio-molecular features in low-grade epilepsy-associated neuroepithelial tumors

The aim of this study was to evaluate the relationship between molecular markers and clinicopathological features in patients operated on for low-grade epilepsy-associated neuroepithelial tumors. Molecular-genetic signatures are becoming increasingly important in characterizing these lesions, which represent the second most common cause of focal epilepsy in patients undergoing epilepsy surgery. Data from 22 patients operated on for histopathologically confirmed low-grade epilepsy-associated neuroepithelial tumors were retrospectively collected. All specimens were examined for BRAF and IDH mutational status, 1p/19q codeletion and CD34 expression. The relationship between bio-molecular markers and several demographic, clinical and pathological features were analyzed. BRAF mutation was found in 11 (50.0%) patients and CD34 expression in 13 (59.1%). No patients presented IDH mutation or 1p/19q codeletion. Multiple seizure types were present in 5 (45.5%) patients with BRAF mutation and in none of those with BRAF wild type (p = 0.035). Moreover, BRAF mutation was predominant in right-sided lesions (p = 0.004) and CD34 expression was significantly associated with a longer duration of epilepsy (p = 0.027). Several other clinicopathological features, such as association with focal cortical dysplasia and postoperative seizure outcome, showed no significant correlation with molecular markers. Further studies are necessary both to confirm these data in larger cohort of patients and to investigate possible relationships between molecular markers and other clinicopathological features.     

Different distribution patterns of lymphocytes and microglia in the hippocampus of patients with residual versus paranoid schizophrenia: Further evidence for disease course-related immune alterations?

Certain cytokines have been identified in the peripheral blood as trait markers of schizophrenia, while others are considered relapse-related state markers. Furthermore, data from peripheral blood, cerebrospinal fluid (CSF) and nuclear imaging studies suggest that (1) blood–brain barrier (BBB) dysfunction (e.g., immigration of lymphocytes into brain tissue and intrathecal antibody production) correlates with the development of negative symptoms, while (2) the brain’s mononuclear phagocyte system (microglial cells) is activated during acute psychosis.Based on these neuroinflammatory hypotheses, we have quantified the numerical density of immunostained CD3+ T-lymphocytes, CD20+ B-lymphocytes, and HLA-DR+ microglial cells in the posterior hippocampus of 17 schizophrenia patients and 11 matched controls. Disease course-related immune alterations were considered by a separate analysis of residual (prevailing negative symptoms, n = 7) and paranoid (prominent positive symptoms, n = 10) schizophrenia cases.Higher densities of CD3+ and CD20+ lymphocytes were observed in residual versus paranoid schizophrenia (CD 3: left: P = 0.047, right: P = 0.038; CD20: left: P = 0.020, right: P = 0.010) and controls (CD3: left: P = 0.057, right: P = 0.069; CD20: left: P = 0.008, right: P = 0.006). In contrast, HLA-DR+ microglia were increased in paranoid schizophrenia versus residual schizophrenia (left: P = 0.030, right: P = 0.012). A similar trend emerged when this group was compared to controls (left: P = 0.090, right: P = 0.090).BBB impairment and infiltration of T cells and B cells may contribute to the pathophysiology of residual schizophrenia, while microglial activation seems to play a role in paranoid schizophrenia. The identification of diverse immune endophenotypes may facilitate the development of distinct anti-inflammatory schizophrenia therapies to normalize BBB function, (auto)antibody production or microglial activity.     

Dysregulation of DGCR6 and DGCR6L: psychopathological outcomes in chromosome 22q11.2 deletion syndrome

Chromosome 22q11.2 deletion syndrome (22q11DS) is the most common microdeletion syndrome in humans. It is typified by highly variable symptoms, which might be explained by epigenetic regulation of genes in the interval. Using computational algorithms, our laboratory previously predicted that DiGeorge critical region 6 (DGCR6), which lies within the deletion interval, is imprinted in humans. Expression and epigenetic regulation of this gene have not, however, been examined in 22q11DS subjects. The purpose of this study was to determine if the expression levels of DGCR6 and its duplicate copy DGCR6L in 22q11DS subjects are associated with the parent-of-origin of the deletion and childhood psychopathologies. Our investigation showed no evidence of parent-of-origin-related differences in expression of both DGCR6 and DGCR6L. However, we found that the variability in DGCR6 expression was significantly greater in 22q11DS children than in age and gender-matched control individuals. Children with 22q11DS who had anxiety disorders had significantly lower DGCR6 expression, especially in subjects with the deletion on the maternal chromosome, despite the lack of imprinting. Our findings indicate that epigenetic mechanisms other than imprinting contribute to the dysregulation of these genes and the associated childhood psychopathologies observed in individuals with 22q11DS. Further studies are now needed to test the usefulness of DGCR6 and DGCR6L expression and alterations in the epigenome at these loci in predicting childhood anxiety and associated adult-onset pathologies in 22q11DS subjects.     

Autonomic response to upright tilt in people with and without Down syndrome

This study examined whether the autonomic response to passive upright tilt as evidenced by changes in measures of heart rate and blood pressure variability differs between individuals with DS and without DS. Beat-to-beat blood pressure was measured in 26 individuals with Down syndrome (DS) and 11 individuals without DS during 5 min of rest and 5 min of upright tilt. Dependent variables included heart rate, blood pressure, frequency component measures of heart rate and blood pressure variability, and baroreflex sensitivity. The normalized high frequency (HF) power, normalized low frequency (LF) power, and LF/HF of heart rate variability, as well as the LF of blood pressure variability were reduced in persons with DS in response to upright tilt (p < 0.05). This was accompanied by smaller change in baroreflex sensitivity (p < 0.05) in individuals with DS. Blood pressure responses to upright tilt were also reduced in individuals with DS (p < 0.05), but the heart rate response did not differ between groups. Individuals with DS show less vagal withdrawal and sympatho-excitation in response to passive upright tilt. These effects may be partially mediated by smaller change in baroreflex sensitivity in individuals with DS. The results support the hypothesis of altered autonomic modulation in people with DS.     

The bone tissue of children and adolescents with Down syndrome is sensitive to mechanical stress in certain skeletal locations: A 1-year physical training program study

The systemic complications of Down syndrome (DS) attenuate the osteogenic response to physical activity in DS patients. Through an interventional study we showed the effects of physical training on development of bone mineral content (BMC) and density (BMD) as well as on quantitative bone ultrasound (QUS) parameters in individuals with DS. A total of 42 children with DS were randomly assigned to either an exercising (DS-E, n = 20, age 16 ± 1.8 years) or non-exercising group (DS-NE, n = 22, age 16.9 ± 1.5 years). DS-E group was assigned to a program of osteogenic activities with 60 min sessions twice a week, over 12 month period. Bone mass measures were performed by dual X-ray absorpsiometry (DXA) at the spine and hip, and ultrasound attenuation (BUA) and velocity (SOS) assessed from the calcaneus by QUS device. All bone parameters had evolved with age, except for neck BMD. One year of training increased BMC values at lumbar spine (7%, p < .005) and total hip (10%, p < .05), and BMD values only at lumbar spine (4%, p < .05). Changes in BUA and SOS values were not evident following training. Trained individuals increased their motor skills measured through Eurofit tests.It was concluded that a program of osteogenic physical training may induce bone improvement in children with DS, but with a lower magnitude than that reported in the specialized literature for individuals without DS.     

Cortisol awakening response in patients with psychosis: Systematic review and meta-analysis

The cortisol awakening response (CAR), defined as the increase in cortisol release in response to waking up, shows associations with social and environmental risk factors of schizophrenia and has been studied as a potential biomarker in schizophrenia. We report a systematic review and meta-analysis of 11 studies and 879 participants focusing on the CAR of patients with schizophrenia, first-episode psychosis, and at-risk mental states. Random-effects meta-analysis showed that CAR is attenuated in patients with psychosis compared to healthy controls (g = ⿿0.426, 95% CI ⿿0.585 to ⿿0.267, p < 0.001, 11 between-group comparisons, n = 879). Subgroup analysis showed flattened CAR in patients with schizophrenia (g = ⿿0.556, 95% CI ⿿1.069 to ⿿0.044, p < 0.05, 2 between-group comparisons, n = 114) and first-episode psychosis (g = ⿿0.544, 95% CI ⿿0.731 to ⿿0.358, p < 0.001, 6 between-group comparisons, n = 505), but not in individuals with at-risk mental states. These distinctive alterations of hypothalamic-pituitary-adrenal axis function may have important implications for CAR as a marker for transition risk. However, the lack of objective verification of sampling adherence in these studies may limit the interpretation of the results.