Telemedicine is helping the parents of children with neurodevelopmental disorders living in remote and deprived areas.

Telecommunication technologies are advancing rapidly with huge investment to improve infrastructure in rural areas. Telemedicine brings the benefits of telecommunication to healthcare, especially in resource-limited and remote communities. The recent literature on telemedicine in paediatrics will be reviewed, with particular focus on its application to help children with neurodevelopmental disorders and their families living in remote regions and/or low-income countries, and gaps identified for future research. Studies show that telemedicine can enable a family's access to appropriately qualified help that physically may only be available hundreds of miles away, helping to overcome geographic barriers. Telemedicine can also train parents and equip them with the knowledge and skills to better care for their children. Despite some technological barriers to implementation, telemedicine can help transform all stages of autism treatment. However, more studies are required in low- and middle-income countries to fully elucidate the benefits offered by telemedicine to autistic children and their families.

GRECOS Project (Genotyping Recurrence Risk of Stroke): The Use of Genetics to Predict the Vascular Recurrence After Stroke.

BACKGROUND AND PURPOSE: Vascular recurrence occurs in 11% of patients during the first year after ischemic stroke (IS) or transient ischemic attack. Clinical scores do not predict the whole vascular recurrence risk; therefore, we aimed to find genetic variants associated with recurrence that might improve the clinical predictive models in IS. METHODS: We analyzed 256 polymorphisms from 115 candidate genes in 3 patient cohorts comprising 4482 IS or transient ischemic attack patients. The discovery cohort was prospectively recruited and included 1494 patients, 6.2% of them developed a new IS during the first year of follow-up. Replication analysis was performed in 2988 patients using SNPlex or HumanOmni1-Quad technology. We generated a predictive model using Cox regression (GRECOS score [Genotyping Reurrence Risk of Stroke]) and generated risk groups using a classification tree method. RESULTS: The analyses revealed that rs1800801 in the MGP gene (hazard ratio, 1.33; P=9×10-03), a gene related to artery calcification, was associated with new IS during the first year of follow-up. This polymorphism was replicated in a Spanish cohort (n=1.305); however, it was not significantly associated in a North American cohort (n=1.683). The GRECOS score predicted new IS (P=3.2×10-09) and could classify patients, from low risk of stroke recurrence (1.9%) to high risk (12.6%). Moreover, the addition of genetic risk factors to the GRECOS score improves the prediction compared with previous Stroke Prognosis Instrument-II score (P=0.03). CONCLUSIONS: The use of genetics could be useful to estimate vascular recurrence risk after IS. Genetic variability in the MGP gene was associated with vascular recurrence in the Spanish population.

The impact of pre- and post-natal psycho-educational intervention on the construction of parenthood.

A pilot study was conducted to assess the merits and feasibility of a standardized postnatal psycho-educational interview on mothers' mental wellbeing, self-efficacy, and mother-child and couple relationships. A comparison of prenatal psycho-educational interview (n = 23) vs. pre- and post-natal psycho-educational interviews (n = 26) was carried out. Parental self-efficacy and the mother-child relationship were significantly improved for the group who received a post-natal interview at 2 and 3 months postpartum in addition to a prenatal interview. Pre- and post-natal interviews improve the construction of parenthood.

Clinical and psychological effects of excessive screen time on children.

Over recent years, screen time has become a more complicated concept, with an ever-expanding variety of electronic media devices available throughout the world. Television remains the predominant type of screen-based activity among children. However, computer use, video games and ownership of devices, such as tablets and smart phones, are occurring from an increasingly young age. Screen time, in particular, television viewing, has been negatively associated with the development of physical and cognitive abilities, and positively associated with obesity, sleep problems, depression and anxiety. The physiological mechanisms that underlie the adverse health outcomes related to screen time and the relative contributions of different types of screen and media content to specific health outcomes are unclear. This review discusses the positive and negative effects of screen time on the physiological and psychological development of children. Furthermore, recommendations are offered to parents and clinicians.

Genes involved in hemorrhagic transformations that follow recombinant t-PA treatment in stroke patients.

AIM: Despite the benefits of recombinant t-PA (rt-PA) for stroke patients some of them suffer from adverse hemorrhagic transformations (HTs) following treatment. Our objective is to study the transcriptomics of HTs patients. METHODS: We studied by microarrays 11 blood samples from patients with stroke that had received rt-PA of whom six of them had suffered a HT. For replication step RNA was collected from 14 new subjects (seven with HT, seven without) and then analyzed by real-time PCR. Four proteins were measured by ELISA in 72 new subjects to analyze their role as potential protein biomarkers. RESULTS: The microarray analysis revealed that 14 genes were altered among the HT patients. The replication study confirmed these results for six genes. Two of them (BCL2 and OLFM4) are associated with apoptosis, whereas the other four (LTF, LCN2 [also known as NGAL], CEACAM8 and CRISP3) are involved in the regulation of neutrophil processes. CONCLUSION: Our data revealed that genes related to apoptosis and neutrophil regulation pathways could be associated with HTs after rt-PA.

IL1B and VWF variants are associated with fibrinolytic early recanalization in patients with ischemic stroke.

BACKGROUND AND PURPOSE: There is a great interindividual variability among patients with acute ischemic stroke regarding the response to intravenous tissue-type plasminogen activator treatment. The aim of this study was to identify genetic variants associated with recanalization, and thus treatment efficacy, after tissue-type plasminogen activator administration. METHODS: A total of 140 single nucleotide polymorphisms from 97 candidate genes were successfully genotyped by SNPlex in 2 cohorts, accounting for 497 prospectively recruited tissue-type plasminogen activator-treated patients, of whom 33% recanalized during tissue-type plasminogen activator infusion. Functional studies were then performed, including assessment of interleukin 1B mRNA levels and von Willebrand factor, FIII, FVII, FVIII, and FX protein activity. RESULTS: After replication, the following single nucleotide polymorphisms were associated with early recanalization: rs1143627 in IL1B gene (CC: 53.1% of recanalization, A-carriers: 32.7%; P=0.022; replication cohort: P=0.046), rs16944 in IL1B gene (AA: 50% of recanalization, G-carriers: 32%; P=0.038; replication cohort: P=0.049), and rs1063856 in the vWF gene (GG: 53.8% of recanalization, A-carriers: 31.5%; P=0.006; replication cohort: P=0.046). The functional studies revealed an association between the rs1063856 single nucleotide polymorphisms in vWF and FVIII activity (AA: 115.93%, AG: 156.07%, GG: 83.42%; P=0.005). CONCLUSIONS: Three single nucleotide polymorphisms were associated with tissue-type plasminogen activator efficacy in the Spanish population, and their mechanism of action might be associated with the activity of coagulation factors.

Role of the MMP9 gene in hemorrhagic transformations after tissue-type plasminogen activator treatment in stroke patients.

BACKGROUND AND PURPOSE: Despite the benefits of tissue-type plasminogen activator treatment, some stroke patients experience adverse hemorrhagic transformations (HT). Plasma protein levels of MMP9 have been associated with HT occurrence. We aimed to analyze the association of the MMP9 gene with HT occurrence. METHODS: We analyzed the MMP9 gene in blood samples from 885 stroke patients treated with tissue-type plasminogen activator by tag-SNP, imputed SNP, direct sequencing, and RNA expression. RESULTS: We did not observe any significant association between MMP9 genetic variations or MMP9 expression and HT occurrence. Moreover, no association was found between MMP9 expression and MMP9 polymorphisms. CONCLUSIONS: Genetic variations in the MMP9 gene are not associated with HT occurrence in tissue-type plasminogen activator-treated patients.

TTC7B emerges as a novel risk factor for ischemic stroke through the convergence of several genome-wide approaches.

We hereby propose a novel approach to the identification of ischemic stroke (IS) susceptibility genes that involves converging data from several unbiased genetic and genomic tools. We tested the association between IS and genes differentially expressed between cases and controls, then determined which data mapped to previously reported linkage peaks and were nominally associated with stroke in published genome-wide association studies. We first performed gene expression profiling in peripheral blood mononuclear cells of 20 IS cases and 20 controls. Sixteen differentially expressed genes mapped to reported whole-genome linkage peaks, including the TTC7B gene, which has been associated with major cardiovascular disease. At the TTC7B locus, 46 tagging polymorphisms were tested for association in 565 Portuguese IS cases and 520 controls. Markers nominally associated in at least one test and defining associated haplotypes were then examined in 570 IS Spanish cases and 390 controls. Several polymorphisms and haplotypes in the intron 5-intron 6 region of TTC7B were also associated with IS risk in the Spanish and combined data sets. Multiple independent lines of evidence therefore support the role of TTC7B in stroke susceptibility, but further work is warranted to identify the exact risk variant and its pathogenic potential.

A predictive clinical-genetic model of tissue plasminogen activator response in acute ischemic stroke.

OBJECTIVE: Wide interindividual variability exists in response to tissue plasminogen activator (t-PA) treatment in the acute phase of ischemic stroke. We aimed to find genetic variations associated with hemorrhagic transformation (HT) and mortality rates after t-PA. We then generated a clinical-genetic model for predicting t-PA response. METHODS: Our prospective study used SNPlex to genotype 140 single nucleotide polymorphisms (SNPs) from 97 candidate genes in 3 patient cohorts. The cohorts included 1,172 patients who were treated with t-PA; 20.9% of them developed HT as evaluated by systematic brain computed tomography scan, and 10.6% died. A predictive model was generated by logistic regression (LR). Functional studies included real time quantitative polymerase chain reaction, nephelometry, and Western blot for alpha-2-macroglobulin (A2M) and activated partial thromboplastin time measurement for coagulation factor XII (FXII). RESULTS: Replication analysis revealed that the SNP rs669 (Val1000Ile) in A2M was associated with HT, and rs1801020 (-4C>T) of F12 was associated with in-hospital death. The rs669 SNP withstood Bonferroni correction for HT (p < 3.57E-4). LR-based scores predicted HT occurrence (p = 9.13E-15) and in-hospital mortality (p = 8.7E-9) and were validated in an independent cohort. Val1000Ile modified A2M serum levels at baseline and after t-PA infusion, but not mRNA expression or protein structure; -4C>T affected FXII activity both prior to and after t-PA treatment. INTERPRETATION: Two functional polymorphisms were consistently associated with t-PA safety. Our validated LR-based score predicts t-PA safety in the Spanish population.

MMP-2/MMP-9 plasma level and brain expression in cerebral amyloid angiopathy-associated hemorrhagic stroke.

Cerebral amyloid angiopathy (CAA) is one of the main causes of intracerebral hemorrhage (ICH) in the elderly. Matrix metalloproteinases (MMPs) have been implicated in blood-brain barrier disruption and ICH pathogenesis. In this study, we determined the levels MMP-2 and MMP-9 in plasma and their brain expression in CAA-associated hemorrhagic stroke. Although MMP-2 and MMP-9 plasma levels did not differ among patients and controls, their brain expression was increased in perihematoma areas of CAA-related hemorrhagic strokes compared with contralateral areas and nonhemorrhagic brains. In addition, MMP-2 reactivity was found in ß-amyloid (Aß)-damaged vessels located far from the acute ICH and in chronic microbleeds. MMP-2 expression was associated to endothelial cells, histiocytes and reactive astrocytes, whereas MMP-9 expression was restricted to inflammatory cells. In summary, MMP-2 expression within and around Aß-compromised vessels might contribute to the vasculature fatal fate, triggering an eventual bleeding.

Brain perihematoma genomic profile following spontaneous human intracerebral hemorrhage.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) represents about 15% of all strokes and is associated with high mortality rates. Our aim was to identify the gene expression changes and biological pathways altered in the brain following ICH. METHODOLOGY/PRINCIPAL FINDINGS: Twelve brain samples were obtained from four deceased patients who suffered an ICH including perihematomal tissue (PH) and the corresponding contralateral white (CW) and grey (CG) matter. Affymetrix GeneChip platform for analysis of over 47,000 transcripts was conducted. Microarray Analysis Suite 5.0 was used to process array images and the Ingenuity Pathway Analysis System was used to analyze biological mechanisms and functions of the genes. We identified 468 genes in the PH areas displaying a different expression pattern with a fold change between -3.74 and +5.16 when compared to the contralateral areas (291 overexpressed and 177 underexpressed). The top genes which appeared most significantly overexpressed in the PH areas codify for cytokines, chemokines, coagulation factors, cell growth and proliferation factors while the underexpressed codify for proteins involved in cell cycle or neurotrophins. Validation and replication studies at gene and protein level in brain samples confirmed microarray results. CONCLUSIONS: The genomic responses identified in this study provide valuable information about potential biomarkers and target molecules altered in the perihematomal regions.

A large screening of angiogenesis biomarkers and their association with neurological outcome after ischemic stroke.

BACKGROUND: The induction of angiogenesis after stroke may enhance neurorestorative processes. Our aim was to examine the endogenous angiogenesis balance and their association with long-term clinical outcome in ischemic stroke patients. METHODS: A total of 109 stroke subjects were included in the study. Firstly, plasma samples were obtained from control subjects (n = 26) and tPA-treated stroke patients (n = 29) at baseline (within 3h of symptoms onset), 1, 2, 12, 24h after tPA treatment, at discharge and 3 months after the ischemic event. Angiogenic promoters (PDGF-AA, PDGF-BB, HGF, FGF, KGF, HB-EGF, TPO, VEGF, VEGFR-1, VEGFR-2 and SDF-1α) and inhibitors (endostatin, angiostatin, thrombospondin-1 and thrombospondin-2) were analyzed by Searchlight(®) technology or ELISA. Additionally, baseline and 24h endostatin plasma level was determined in a new set of stroke patients (n = 80). Clinical parameters (NIHSS, mRS, mortality and hemorrhagic transformation events) were assessed to evaluate outcome. RESULTS: Baseline PDGF-BB, endostatin and thrombospondin-2 levels were higher in stroke patients than in controls (p < 0.05). A pro-angiogenic balance was associated with lower NIHSS scores and less intracranial hemorrhagic complications. Interestingly, a high baseline endostatin level was associated to long-term functional dependency (mRS > 2; p = 0.004). Finally, a baseline endostatin cut-off point of 184 ng/mL was an independent predictor of functional dependency at three months in the multiple logistic regression with an odds ratio of 8.9 (95% CI: 2.7-28.8; p = 0.0002). CONCLUSIONS: Our results indicate that an early pro-angiogenic balance is associated with mild short-term neurological deficit, while an acute anti-angiogenesis status determined by high endostatin plasma level predicts a worse long-term functional outcome.

ACE variants and risk of intracerebral hemorrhage recurrence in amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is a well-established cause of lobar intracerebral hemorrhage (ICH). The aim of the authors was to investigate the influence of clinical characteristics and genetic variants in the ACE, LRP, MMP9, Tafi, VEGFA, CYP11B2, A2M and APOE on ICH recurrence in a cohort of CAA-related ICH patients. Sixty patients were enrolled and new symptomatic ICHs in the 36 mo following the index event were recorded. Leukoaraiosis degree, microbleeds count and variants in the APOE and ACE were associated with ICH recurrence. The rs4311 variant of the ACE was an independent risk factor (p = 0.001), resisting Bonferroni correction. Moreover, carriers of ε2 of the APOE and TT of the rs4311 of the ACE reached 100% recurrence before 18 mo (p < 0.001). Finally, ACE protein level was measured in serum of controls and depended on the rs4311 genotypes, TT carriers presenting higher level than CC carriers (p = 0.012). These results suggest that variants in the ACE are associated with CAA-related ICH recurrence, possibly by modulating ACE protein level.

CD40-1C>T polymorphism (rs1883832) is associated with brain vessel reocclusion after fibrinolysis in ischemic stroke.

AIMS: To find genetic predictors of reocclusion after successful fibrinolytic therapy during the acute phase of ischemic stroke. PATIENTS & METHODS: This was a case-case prospective study analyzing 236 polymorphisms in a cohort of 222 patients treated with tissue plasminogen activator, from which 16 patients suffered a reocclusion event (7.2%). A predictive scale was generated using independent polymorphisms with a dominant/recessive model and tandem occlusion, weighted by their beta-coefficients in logistic regression. RESULTS: Using a dominant/recessive model, the rs1800801 SNP from the MGP gene (odds ratio [OR]: 15.25; 95% CI: 2.23-104.46; adjusted p = 0.006) and the rs1883832 SNP from CD40 gene (OR: 0.077; 95% CI: 0.009-0.66; adjusted p = 0.019) were independently associated with reocclusion after logistic regression adjustment by clinical predictors. In an additive model, only the rs1883832 SNP (OR: 4.43; 95% CI: 1.62-12.15; adjusted p = 0.004) was related to reocclusion occurrence. The predictive model that was generated stratified the reocclusion risk from less than 1% to more than 70%. Reocclusions were associated with neurological worsening at 24 h (patients with reocclusion: 26.7%, versus patients without reocclusion: 4.9%; p = 0.002), as it was seen for MGP -7A>G (AA: 17.2% vs AG+GG: 4.5%; p = 0.027), but not for CD40 1C>T (CC: 4.5% vs CT+TT: 7.7%; p = 0.565). There was an association between CD40 -1C>T genotype and CD40 transcriptional activity in peripheral blood mononuclear cells (median expression values TT: 65.75%, CT: 70.80%, CC: 96.00%; p = 0.023). However, CD40 soluble fraction was not a useful biomarker of reocclusion status. CONCLUSION: An association was found between MGP -7A>G and CD40 -1C>T polymorphisms, and reocclusion risk. The predictive scale that was generated permits the stratification of patients by their reocclusion risk with higher accuracy than clinical parameters alone.

Association of a genetic variant in the ALOX5AP with higher risk of ischemic stroke: a case-control, meta-analysis and functional study.

BACKGROUND: Variants in the 5-lipoxygenase-activating protein (ALOX5AP) and phosphodiesterase 4D (PDE4D) genes have first been associated with ischemic stroke (IS) through whole-genome linkage screens. However, association studies obtained conflicting results. We aimed to investigate the contribution of selected single nucleotide polymorphisms (SNPs) in these genes for the first time in a large Iberian population. METHODS: A case-control design was used to analyze one SNP in ALOX5AP and five SNPs in PDE4D in a total of 1,092 IS patients and 781 healthy controls of two different subsets from Spain and Portugal. The analysis was adjusted for confounding variables and the results were integrated in a meta-analysis of all case-control studies. In addition, ALOX5AP gene expression levels were determined in controls and IS cases. RESULTS: A first meta-analysis of both subsets showed that the T allele of the SG13S114 SNP in ALOX5AP was a risk factor for IS after Bonferroni correction [OR = 1.22 (1.06-1.40); p = 0.006]. A second meta-analysis of white populations confirmed these results [OR = 1.18 (1.07-1.31); p = 0.001]. ALOX5AP gene expression analysis in a subset of controls and cases revealed that the SG13S114 genotypes modulate mRNA levels of ALOX5AP (p = 0.001) and mRNA levels were higher in IS cases (2.8 +/- 2.4%) than in controls (1.4 +/- 1.3%; p = 0.003). No association of the variants in PDE4D with IS was observed in our study. CONCLUSIONS: The ALOX5AP SG13S114 variant is an independent risk factor for IS in the Iberian population and is associated with ALOX5AP expression levels. The role of this gene in stroke merits further investigation.

KCNK17 genetic variants in ischemic stroke.

BACKGROUND: Genetic factors contribute to the development of ischemic stroke (IS). In order to identify susceptibility variants, we analyzed single nucleotide polymorphisms (SNPs) that had been previously linked to stroke in a genome-wide association study. METHODS: We analyzed 12 SNPs in a White population comprising IS patients and healthy controls. The analysis was adjusted for confounding variables and stratified by stroke etiology. Functional studies were then performed to elucidate the role of these variants in IS. RESULTS: In a preliminary analysis of 268 controls and 531 IS cases, the rs10947803 SNP of KCNK17 (p=0.012) and the rs7506045 of IMPA2 (p=0.040) were associated with IS, although only the KCNK17 gene was an independent risk factor for IS. In a second phase, analysis of 271 new IS cases revealed that the A allele of rs10947803 was associated with stroke after correction for Bonferroni (OR=1.48; 95% CI, 1.14-1.91, p=0.003). Gene expression analysis revealed that KCNK17 mRNA levels were higher in the IS cases in the acute phase than in controls (14+/-78% vs. 91+/-41, p=0.002) but not in the chronic phase (56+/-57%; p=0.230). Moreover, RNA levels depended on the alleles of the rs10947803 SNP in the control group (p=0.021) and in the chronic phase (p=0.033). CONCLUSIONS: The A allele of the rs10947803 variant of KCNK17 was associated with increased risk of IS and increased levels of KCNK17 gene expression. The role of this potassium channel gene in IS opens diagnostic and therapeutic expectations and merits further investigation.

CADASIL management or what to do when there is little one can do.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare disease that leads to migraine, mood disorders, recurrent lacunar strokes and early vascular dementia. This autosomal-dominant condition is caused by mutations in the NOTCH3 gene and is characterized by degeneration of vascular smooth muscle cells. At present, no evidence-based treatment for CADASIL is available and only relief of symptoms can be offered to patients. This review focuses on an update of CADASIL management, based on the recent clinical and basic evidence, and discusses possible new treatment targets for CADASIL.

Genetics of stroke: a review of recent advances.

Stroke is a multifactorial disease responsible for nearly 10% of deaths each year in industrialized countries. While some monogenic forms of stroke have been described, the vast majority result from the common polygenic form of the disease. Progress in molecular genetics has allowed the identification, through genome-wide linkage analysis, of various candidate genes, including the genes encoding PDE4D and ALOX5AP. Since then, genetic research has been extensively performed from single candidate genes to whole-genome scan studies, in parallel with the development of high-throughput technologies in molecular diagnostics. Additionally, the safety and efficacy of tissue plasminogen activator, the only approved therapy for the acute phase of stroke, is modulated by genetic background associated with the occurrence of hemorrhagic transformations and with the revascularization of the cerebral arteries. In the near future, understanding the contribution of stroke genetic factors will lead to improvements in prevention and treatments for neurovascular diseases.

Association between ESR2 genetic variants and risk of myocardial infarction.

BACKGROUND: Environmental and genetic factors contribute to the development of complex diseases such as myocardial infarction (MI), the leading cause of death in men and women. Women develop MI approximately 10 years later than men, a difference that could be explained by the genes coding for the estrogen receptors. Single nucleotide polymorphisms (SNPs) in the ESR2 gene may affect susceptibility for MI in a sex-dependent manner. METHODS: A nested case-control design was used to analyze 3 polymorphisms of the ESR2 gene and their associated haplotypes in 710 myocardial infarction cases from the REGICOR (Registre Gironí del Corazón) study and 2379 controls randomly selected in a representative population of a Spanish cross-sectional study. RESULTS: The rs1271572 T allele was significantly more common in patients who developed MI (P < 0.001). No association was observed for rs1256049 or rs4986938. Assuming a dominant model of inheritance, the association, as determined by logistic multivariate regression after adjustment for conventional cardiac risk factors, remained statistically significant in men [odds ratio (OR) 1.65, 95% CI 1.18-2.30; P = 0.003) but not in women (P = 0.754). A very common haplotype encompassing the rs1271572 variant was also associated with the risk of MI in the overall population (OR 1.41, 95% CI 1.06-1.87; P = 0.020) and in men (OR 1.57, 95% CI 1.12-2.21; P = 0.009). CONCLUSIONS: The rs1271572 SNP T variant was associated with increased risk of MI in a Spanish population, and this association was found to be limited to men only. Sex differences in the genetic risk merit further investigation.