Towards precision medicine: The application of omics technologies in asthma management

Asthma is a chronic obstructive respiratory disease characterised by bronchial inflammation. Its biological and clinical features have been widely explored and a number of pharmacological treatments are currently available. Currently several aspects of asthma pathophysiological background remain unclear, and this is represent a limitation for the traditional asthma phenotype approach. In this scenario, the identification of new molecular and clinical biomarkers may be helpful in order to better understand the disease, define specific diagnostic tools and highlight relevant novel targets for pharmacological treatments. Omics technologies offer innovative research tools for addressing the above mentioned goals. However, there is still a lot to do both in the fields of basic research and in the clinical application. Recently, genome-wide association studies, microRNAs and proteomics are contributing to enrich the available data for the identification of new asthma biomarkers. A precise approach to the patient with asthma, particularly with severe uncontrolled asthma, requires new and specific therapeutic targets, but also proper tools able to drive the clinician in tailoring the treatment. On the other hand, there is a need of predictors to treatment's response, particularly in the field of biological drugs, whose sustainability implies a correct and precise selection of the patients. Translating acquired omics knowledge in clinical practice may address the unmet needs described above, but large-scale studies are required in order to confirm their relevance and effectiveness in daily practice. Thus in our opinion the application of omics is still lagging in the real-life setting

Precision Medicine in Targeted Therapies for Severe Asthma: Is There Any Place for "omics" Technology?

According to the current guidelines, severe asthma still represents a controversial topic in terms of definition and management. The introduction of novel biological therapies as a treatment option for severe asthmatic patients paved the way to a personalized approach, which aims at matching the appropriate therapy with the different asthma phenotypes. Traditional asthma phenotypes have been decomposing by an increasing number of asthma subclasses based on functional and physiopathological mechanisms. This is possible thanks to the development and application of different omics technologies. The new asthma classification patterns, particularly concerning severe asthma, include an increasing number of endotypes that have been identified using new omics technologies. The identification of endotypes provides new opportunities for the management of asthma symptoms, but this implies that biological therapies which target inflammatory mediators in the frame of specific patterns of inflammation should be developed. However, the pathway leading to a precision approach in asthma treatment is still at its beginning. The aim of this review is providing a synthetic overview of the current asthma management, with a particular focus on severe asthma, in the light of phenotype and endotype approach, and summarizing the current knowledge about "omics" science and their therapeutic relevance in the field of bronchial asthma

Lyman- \u3b1 Forest Constraints on Primordial Black Holes as Dark Matter

The renewed interest in the possibility that primordial black holes (PBHs) may constitute a significant part of dark matter has provided motivation for revisiting old observational constraints, as well as developing new ones. We present new limits on the PBH abundance, from a comprehensive analysis of high-resolution high-redshift Lyman-\u3b1 forest data. Poisson fluctuations in the PBH number density induce a small-scale power enhancement which departs from the standard cold dark matter prediction. Using a grid of hydrodynamic simulations exploring different values of astrophysical parameters, we obtain a marginalized upper limit on the PBH mass of fPBHMPBH 3c60M at 2\u3c3, when a Gaussian prior on the reionization redshift is imposed, preventing its posterior distribution from peaking on very high values, which are disfavored by the most recent estimates obtained both through cosmic microwave background and intergalactic medium observations. Such a bound weakens to fPBHMPBH 3c170M when a conservative flat prior is instead assumed. Both limits significantly improve on previous constraints from the same physical observable. We also extend our predictions to nonmonochromatic PBH mass distributions, ruling out large regions of the parameter space for some of the most viable PBH extended mass functions

Loss of heterozygosity of TRIM3 in malignant gliomas

<p>Abstract</p> <p>Background</p> <p>Malignant gliomas are frequent primary brain tumors associated with poor prognosis and very limited response to conventional chemo- and radio-therapies. Besides sharing common growth features with other types of solid tumors, gliomas are highly invasive into adjacent brain tissue, which renders them particularly aggressive and their surgical resection inefficient. Therefore, insights into glioma formation are of fundamental interest in order to provide novel molecular targets for diagnostic purposes and potential anti-cancer drugs. Human <it>Tripartite motif protein 3 </it>(<it>TRIM3</it>) encodes a structural homolog of <it>Drosophila brain tumor </it>(<it>brat</it>) implicated in progenitor cell proliferation control and cancer stem cell suppression. <it>TRIM3 </it>is located within the loss of allelic heterozygosity (LOH) hotspot of chromosome segment 11p15.5, indicating a potential role in tumor suppression. ...</p> <p>Methods</p> <p>Here we analyze 70 primary human gliomas of all types and grades and report somatic deletion mapping as well as single nucleotide polymorphism analysis together with quantitative real-time PCR of chromosome segment 11p15.5.</p> <p>Results</p> <p>Our analysis identifies LOH in 17 cases (24%) of primary human glioma which defines a common 130 kb-wide interval within the <it>TRIM3 </it>locus as a minimal area of loss. We further detect altered genomic dosage of <it>TRIM3 </it>in two glioma cases with LOH at 11p15.5, indicating homozygous deletions of <it>TRIM3</it>.</p> <p>Conclusion</p> <p>Loss of heterozygosity of chromosome segment 11p15.5 in malignant gliomas suggests <it>TRIM3 </it>as a candidate brain tumor suppressor gene.</p

Brain hemodynamic intermediate phenotype links Vitamin B12 to cognitive profile of healthy and mild cognitive impaired subjects

Vitamin B12, folate, and homocysteine are implicated in pivotal neurodegenerative mechanisms and partake in elders' mental decline. Findings on the association between vitamin-related biochemistry and cognitive abilities suggest that the structural and functional properties of the brain may represent an intermediate biomarker linking vitamin concentrations to cognition. Despite this, no previous study directly investigated whether vitamin B12, folate, and homocysteine levels are sufficient to explain individual neuropsychological profiles or, alternatively, whether the activity of brain regions modulated by these compounds better predicts cognition in elders. Here, we measured the relationship between vitamin blood concentrations, scores at seventeen neuropsychological tests, and brain activity of sixty-five elders spanning from normal to Mild Cognitive Impairment. We then evaluated whether task-related brain responses represent an intermediate phenotype, providing a better prediction of subjects' neuropsychological scores, as compared to the one obtained considering blood biochemistry only. We found that the hemodynamic activity of the right dorsal anterior cingulate cortex was positively associated (p value &lt; 0 05 cluster corrected) with vitamin B12 concentrations, suggesting that elders with higher B12 levels had a more pronounced recruitment of this salience network region. Crucially, the activity of this area significantly predicted subjects' visual search and attention abilities (p value = 0 0023), whereas B12 levels per se failed to do so. Our results demonstrate that the relationship between blood biochemistry and elders' cognitive abilities is revealed when brain activity is included into the equation, thus highlighting the role of brain imaging as intermediate phenotype.Vitamin B12, folate, and homocysteine are implicated in pivotal neurodegenerative mechanisms and partake in elders' mental decline. Findings on the association between vitamin-related biochemistry and cognitive abilities suggest that the structural and functional properties of the brain may represent an intermediate biomarker linking vitamin concentrations to cognition. Despite this, no previous study directly investigated whether vitamin B12, folate, and homocysteine levels are sufficient to explain individual neuropsychological profiles or, alternatively, whether the activity of brain regions modulated by these compounds better predicts cognition in elders. Here, we measured the relationship between vitamin blood concentrations, scores at seventeen neuropsychological tests, and brain activity of sixty-five elders spanning from normal to Mild Cognitive Impairment. We then evaluated whether task-related brain responses represent an intermediate phenotype, providing a better prediction of subjects' neuropsychological scores, as compared to the one obtained considering blood biochemistry only. We found that the hemodynamic activity of the right dorsal anterior cingulate cortex was positively associated (p value &lt; 0 05 cluster corrected) with vitamin B12 concentrations, suggesting that elders with higher B12 levels had a more pronounced recruitment of this salience network region. Crucially, the activity of this area significantly predicted subjects' visual search and attention abilities (p value = 0 0023), whereas B12 levels per se failed to do so. Our results demonstrate that the relationship between blood biochemistry and elders' cognitive abilities is revealed when brain activity is included into the equation, thus highlighting the role of brain imaging as intermediate phenotype

Quantitative Organization of GABAergic Synapses in the Molecular Layer of the Mouse Cerebellar Cortex

In the cerebellar cortex, interneurons of the molecular layer (stellate and basket cells) provide GABAergic input to Purkinje cells, as well as to each other and possibly to other interneurons. GABAergic inhibition in the molecular layer has mainly been investigated at the interneuron to Purkinje cell synapse. In this study, we used complementary subtractive strategies to quantitatively assess the ratio of GABAergic synapses on Purkinje cell dendrites versus those on interneurons. We generated a mouse model in which the GABAA receptor α1 subunit (GABAARα1) was selectively removed from Purkinje cells using the Cre/loxP system. Deletion of the α1 subunit resulted in a complete loss of GABAAR aggregates from Purkinje cells, allowing us to determine the density of GABAAR clusters in interneurons. In a complementary approach, we determined the density of GABA synapses impinging on Purkinje cells using α-dystroglycan as a specific marker of inhibitory postsynaptic sites. Combining these inverse approaches, we found that synapses received by interneurons represent approximately 40% of all GABAergic synapses in the molecular layer. Notably, this proportion was stable during postnatal development, indicating synchronized synaptogenesis. Based on the pure quantity of GABAergic synapses onto interneurons, we propose that mutual inhibition must play an important, yet largely neglected, computational role in the cerebellar cortex

Randomized trial on the effects of a combined physical/cognitive training in aged MCI subjects: the Train the Brain study

Age-related cognitive impairment and dementia are an increasing societal burden. Epidemiological studies indicate that lifestyle factors, e.g. physical, cognitive and social activities, correlate with reduced dementia risk; moreover, positive effects on cognition of physical/cognitive training have been found in cognitively unimpaired elders. Less is known about effectiveness and action mechanisms of physical/cognitive training in elders already suffering from Mild Cognitive Impairment (MCI), a population at high risk for dementia. We assessed in 113 MCI subjects aged 65-89 years, the efficacy of combined physical-cognitive training on cognitive decline, Gray Matter (GM) volume loss and Cerebral Blood Flow (CBF) in hippocampus and parahippocampal areas, and on brain-blood-oxygenation-level-dependent (BOLD) activity elicited by a cognitive task, measured by ADAS-Cog scale, Magnetic Resonance Imaging (MRI), Arterial Spin Labeling (ASL) and fMRI, respectively, before and after 7 months of training vs. usual life. Cognitive status significantly decreased in MCI-no training and significantly increased in MCI-training subjects; training increased parahippocampal CBF, but no effect on GM volume loss was evident; BOLD activity increase, indicative of neural efficiency decline, was found only in MCI-no training subjects. These results show that a non pharmacological, multicomponent intervention improves cognitive status and indicators of brain health in MCI subjects

Involvement of cerebellum in emotional behavior.

The present study was carried out to search whether organophosphate pesticides affect the mechanical properties of the thoracic aorta. Wistar female rats (aged 6-8 weeks) were assigned randomly to a control group and groups treated with either dichlorvos or chlorpyriphos for 90 days at a dose of 5 mg/kg/day. After that period, animals were killed and thoracic aorta strips in longitudinal direction were isolated. The stress, strain and elastic modulus were obtained from the strips. Our results showed that chronic administration of chlorpyriphos and dichlorvos caused downward shift of the stress-strain relations compared to the control curve. The elastic modulus-stress curve revealed distinct characteristics in the low and high stress regions. A power function was used to simulate the low stress region while a line was fit to the high stress region. Curve fitting procedure illustrated that both pesticides influenced mainly the high stress region, but they had diverse effects at the low stress region. The results also imply that chlorpyriphos and dichlorvos decrease the strength of the aorta and therefore might influence the response of the aorta to mechanical loading induced by blood pressure

LA NEURORIABILITAZIONE VISIVA CON SISTEMI PRISMATICI COME TECNICA INDISPENSABILE NELLA RIABILITAZIONE DEL TRAUMATIZZATO CRANICO CON ALTERAZIONI DEL CAMPO VISIVO. DESCRIZIONE DI UN PROGETTO DI TUTELA INTEGRATA IN AMBITO INAIL

Gli Autori prendono spunto da un grave infortunio sul lavoro che ha causato importanti danni a livello craniofaciale con interessamento del sistema visivo, dell’apparato locomotore ed endocrino, che ha portato all’ideazione di un progetto riabilitativo integrato pluridisciplinare. Gli Autori iniziano con un breve accenno all’etiologia dell’emianopsia e proseguono con un approfondimento delle diverse strategie riabilitative correlate alla neuroriabilitazione visiva. Dopo aver illustrato l’esame obiettivo dell’infortunato, soffermandosi sulle lesioni del sistema visivo (le alterazioni dell’apparato endocrino e locomotore e il loro trattamento saranno solamente accennati a proposito dei problemi riabilitativi, poiché non fanno parte nella ricerca), descrivono l’organizzazione e l’attuazione del progetto riabilitativo individualizzato ed in particolare la neuroriabilitazione visiva di tipo sostitutivo con sistemi prismatici. Agli Autori preme mettere in risalto, in accordo con la più recente Letteratura, che la precoce neuroriabilitazione visiva dell’emianopsia, in questo caso eseguita con sistemi prismatici, avendo assicurato un ampliamento del campo visivo, ha indotto impulsi positivi su tutto il trattamento riabilitativo. Nel caso descritto, infatti, il miglioramento via via acquisito delle abilità visive ha procurato nell’infortunato un immediato benessere psicologico, ha portato ad una più celere ripresa della stabilità posturale e della deambulazione, tanto da consentire allo stesso di partecipare ad un programma di riqualificazione professionale e di essere in seguito reinserito in ambito lavorativo. Gli Autori concludono, in accordo con la più recente Letteratura, che nei gravi traumi cranici è facile ritrovare alterazioni del sistema visivo e che il loro precoce trattamento è fondamentale per la riabilitazione di eventuali lesioni a livello di aree non visive o di altri apparati. Infine, non tralasciando il ruolo fondamentale della famiglia nei programmi riabilitativi, pongono l’accento sull’importanza della visione unitaria nel lavoro funzionale dell’Equipe Multidisciplinare nell’approccio al soggetto disabile, ai fini del suo effettivo reinserimento familiare, sociale, e lavorativo

La neuroriabilitazione visiva con sistemi prismatici come tecnica indispensabile per il traumatizzato cranico con alterazioni del campo visivo. Descrizione di un progetto di tutela integrata in ambito Inail

Gli autori prendono spunto da un grave infortunio sul lavoro che ha causato importanti danni al livello cranio facciale con interessamento del sistema visivo, dell’apparato locomotore ed endocrino, che ha portato all’ideazione di un progetto riabilitativo integrato pluridisciplinare. Gli Autori iniziano con un breve accenno all’eziologia dell’emianopsia e proseguono con approfondimento delle diverse strategie riabilitative correlate alla neuroriabilitazione visiva. Dopo aver illustrato l’esame obiettivo dell’infortunato, soffermandosi sulle lesioni del sistema visivo, descrivono l’organizzazione e l’attuazione del progetto riabilitativo individualizzato e in particolare la neuroriabilitazione visiva di tipo sostitutivo con sistemi prismatici. Agli autori preme metter in risalto, in accordo con la più recente letteratura, che la precoce neuroriabilitazione visiva e dell’emianopsia, in questo caso eseguita con sistemi prismatici, avendo assicurato un ampliamento del campo visivo, ha indotto impulsi positivi su tutto il trattamento riabilitativo. Nel caso descritto, infatti, il miglioramento via via acquisito delle abilità visive ha procurato nell’infortunato un immediato benessere psicologico, ha portato ad una più celere ripresa della stabilità posturale e della deambulazione, tanto da consentire allo stesso di partecipare ad un programma di riqualificazione professionale e di essere in seguito rinserito in ambito lavorativo. Gli Autori concludono, in accordo con la più recente letteratura, che nei gravi traumi cranici è facile trovare alterazioni del sistema visivo e che il precoce trattamento è fondamentale per la riabilitazione di eventuali lesioni a livello di aree non visive e di altri apparati. Infine, non tralasciando il ruolo fondamentale della famiglia, nei programmi riabilitativi, pongono l’accento sull’importanza della visione unitaria del lavoro funzionale dell’equipe multidisciplinare, nell’approccio al soggetto disabile, ai fini del suo effettivo rinserimento familiare, sociale e lavorativo