Genetics of asthma: a molecular biologist perspective

Asthma belongs to the category of classical allergic diseases which generally arise due to IgE mediated hypersensitivity to environmental triggers. Since its prevalence is very high in developed or urbanized societies it is also referred to as "disease of civilizations". Due to its increased prevalence among related individuals, it was understood quite long back that it is a genetic disorder. Well designed epidemiological studies reinforced these views. The advent of modern biological technology saw further refinements in our understanding of genetics of asthma and led to the realization that asthma is not a disorder with simple Mendelian mode of inheritance but a multifactorial disorder of the airways brought about by complex interaction between genetic and environmental factors. Current asthma research has witnessed evidences that are compelling researchers to redefine asthma altogether. Although no consensus exists among workers regarding its definition, it seems obvious that several pathologies, all affecting the airways, have been clubbed into one common category called asthma. Needless to say, genetic studies have led from the front in bringing about these transformations. Genomics, molecular biology, immunology and other interrelated disciplines have unearthed data that has changed the way we think about asthma now. In this review, we center our discussions on genetic basis of asthma; the molecular mechanisms involved in its pathogenesis. Taking cue from the existing data we would briefly ponder over the future directions that should improve our understanding of asthma pathogenesis

Danger- and pathogen-associated molecular patterns recognition by pattern-recognition receptors and ion channels of the transient receptor potential family triggers the inflammasome activation in immune cells and sensory neurons.

An increasing number of studies show that the activation of the innate immune system and inflammatory mechanisms play an important role in the pathogenesis of numerous diseases. The innate immune system is present in almost all multicellular organisms and its activation occurs in response to pathogens or tissue injury via pattern-recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Intracellular pathways, linking immune and inflammatory response to ion channel expression and function, have been recently identified. Among ion channels, the transient receptor potential (TRP) channels are a major family of non-selective cation-permeable channels that function as polymodal cellular sensors involved in many physiological and pathological processes.In this review, we summarize current knowledge of interactions between immune cells and PRRs and ion channels of TRP families with PAMPs and DAMPs to provide new insights into the pathogenesis of inflammatory diseases. TRP channels have been found to interfere with innate immunity via both nuclear factor-kB and procaspase-1 activation to generate the mature caspase-1 that cleaves pro-interleukin-1ß cytokine into the mature interleukin-1ß.Sensory neurons are also adapted to recognize dangers by virtue of their sensitivity to intense mechanical, thermal and irritant chemical stimuli. As immune cells, they possess many of the same molecular recognition pathways for danger. Thus, they express PRRs including Toll-like receptors 3, 4, 7, and 9, and stimulation by Toll-like receptor ligands leads to induction of inward currents and sensitization in TRPs. In addition, the expression of inflammasomes in neurons and the involvement of TRPs in central nervous system diseases strongly support a role of TRPs in inflammasome-mediated neurodegenerative pathologies. This field is still at its beginning and further studies may be required.Overall, these studies highlight the therapeutic potential of targeting the inflammasomes in proinflammatory, autoinflammatory and metabolic disorders associated with undesirable activation of the inflammasome by using specific TRP antagonists, anti-human TRP monoclonal antibody or different molecules able to abrogate the TRP channel-mediated inflammatory signals

Evaluation of proximal protection devices during carotid artery stenting as the first choice for embolic protection

Aims: To assess the use of proximal protection devices in consecutive patients as the preferred means of cerebral embolic protection for primary carotid stenting. Methods and results: This was a prospective single-centre study to evaluate the technical and clinical success of proximal protection devices as the first choice for embolic protection in symptomatic (≥50%) and asymptomatic (≥70%) carotid stenosis. Proximal protection devices were used for embolic protection in 124 consecutive patients. No patients were excluded for anatomical reasons. The GORE® Flow Reversal System (W.L. Gore, Flagstaff, AZ, USA) was used in 92 patients, and the Mo.Ma Ultra device (Medtronic, Minneapolis, MN, USA) in 32 patients. Follow-up duration was 30 days. Mean age was 71±8 years. Seventy-five percent of patients were male (n=93). Twenty-six of 124 (21%) treated stenoses were symptomatic. Technical success was achieved in 122 of 124 cases (98%). Due to anatomical conditions, in two patients flow reversal could not be established. In both cases additional distal filter devices were used. Carotid stenting was successful in 124 lesions (100%). Ten patients (8.1%) had contraindications to flow reversal (three high-grade ostial stenoses of the external carotid artery, seven contralateral occlusions of the internal carotid artery) in none of whom complications occurred. There were no procedural neurologic events. Within 30 days of follow-up, one patient had an ischaemic stroke (on day 11). Conclusions: Proximal protection is a safe method as the first choice for embolic protection. It can be used with a high rate of technical success