In pursuit of P2X3 antagonists: novel therapeutics for chronic pain and afferent sensitization

Treating pain by inhibiting ATP activation of P2X3-containing receptors heralds an exciting new approach to pain management, and Afferent's program marks the vanguard in a new class of drugs poised to explore this approach to meet the significant unmet needs in pain management. P2X3 receptor subunits are expressed predominately and selectively in so-called C- and Aδ-fiber primary afferent neurons in most tissues and organ systems, including skin, joints, and hollow organs, suggesting a high degree of specificity to the pain sensing system in the human body. P2X3 antagonists block the activation of these fibers by ATP and stand to offer an alternative approach to the management of pain and discomfort. In addition, P2X3 is expressed pre-synaptically at central terminals of C-fiber afferent neurons, where ATP further sensitizes transmission of painful signals. As a result of the selectivity of the expression of P2X3, there is a lower likelihood of adverse effects in the brain, gastrointestinal, or cardiovascular tissues, effects which remain limiting factors for many existing pain therapeutics. In the periphery, ATP (the factor that triggers P2X3 receptor activation) can be released from various cells as a result of tissue inflammation, injury or stress, as well as visceral organ distension, and stimulate these local nociceptors. The P2X3 receptor rationale has aroused a formidable level of investigation producing many reports that clarify the potential role of ATP as a pain mediator, in chronic sensitized states in particular, and has piqued the interest of pharmaceutical companies. P2X receptor-mediated afferent activation has been implicated in inflammatory, visceral, and neuropathic pain states, as well as in airways hyperreactivity, migraine, itch, and cancer pain. It is well appreciated that oftentimes new mechanisms translate poorly from models into clinical efficacy and effectiveness; however, the breadth of activity seen from P2X3 inhibition in models offers a realistic chance that this novel mechanism to inhibit afferent nerve sensitization may find its place in the sun and bring some merciful relief to the torment of persistent discomfort and pain. The development philosophy at Afferent is to conduct proof of concept patient studies and best identify target patient groups that may benefit from this new intervention

Reproduction in the Female Mithun

Mithun is a domesticated beef bovine species in Himalayan foothills of Southeast Asia. It inhabits at an altitude from 300 to 3000 m MSL, often under extensive grazing system. Mithun is a very fertile animal, able to produce one calf/year. Mithun can interbreed with other bovine species, but male offspring are sterile. This chapter intent is to gather and discuss available information on several aspects of reproduction in female Mithun. The morphology of the reproductive organs is different from cattle and has a longer reproductive tract and pregnancies compared to cattle. Although its estrus period is longer than in cow, Mithun usually displays silent heats, requiring a breeding bull for heat detection. Seasonal fluctuations on reproductive pattern have been reported, which are related to forage availability and quality. Calving in summer takes longer to resumption of cyclic ovarian activity than calving in winter. As Mithun is an important socio-cultural-religious-economic asset in India, to counter some short comings, new breeding strategies have been introduced like multiple ovulation and embryo transfer technology. A good understanding of different aspects of reproduction is crucial to support effective reproductive managements to enhance socio-economic status and cultural importance of tribals to preserve Mithun germplasm to be used in future

Soft Robot-Assisted Minimally Invasive Surgery and Interventions: Advances and Outlook

Since the emergence of soft robotics around two decades ago, research interest in the field has escalated at a pace. It is fuelled by the industry's appreciation of the wide range of soft materials available that can be used to create highly dexterous robots with adaptability characteristics far beyond that which can be achieved with rigid component devices. The ability, inherent in soft robots, to compliantly adapt to the environment, has significantly sparked interest from the surgical robotics community. This article provides an in-depth overview of recent progress and outlines the remaining challenges in the development of soft robotics for minimally invasive surgery

Review of visceroptosis and allied abdominal conditions associated with chronic invalidism

The condition in which an absence of well -being and a lack of energy accompanies persistent abdominal symptoms of no known pathology, is one worthy of investigation. Never leading to a fatal termination it nevertheless assumes considerable importance from the mass of suffering and the loss of economic efficiency it produces.Not that it has failed to receive consideration in the past ; on the contrary, a vast literature has accumulated around this one condition. The magnitude of this literature is not obvious at first sight, and only becomes so when it is realised that conditions as diverse as nervous dyspepsia, nephroptosis, gastroptosis, visceroptosis, autointoxication, intestinal stasis, chronic a.p?oendicitis caecum mobile, and others too numerous to mention, merely re,?resent different interpretations of a single symptom complex. This view is forced upon one by an unprejudiced study of the clinical material as it presents itself in general practice, and the conclusion seems inevitable that some common whole must underlie these diverse manifestations.In the past many investigators have come to the same conclusion. This they reached by an intensive and specialised study of one side of the problem, and for that reason, presumably, failed to obtain the general assent the facts deserved. G It has, therefore, seemed to me worth while to approach the problem from the wide angle of general practice. The latter offers a very special facility for the study of the condition, in that the genesis, progress and termination can be followed by one observer in a way not possible in any other branch of medicine

New Robotic Technologies in Cancer Colon Screening

Colorectal cancer (CRC) is the 3rd most common cause of cancer death worldwide. Regular screening of the asymptomatic population can drastically reduce the mortality rate. CRC screening includes several proceedings although the gold standard remains optical colonoscopy (OC), which is unpleasant, causes pain and discomfort. New technologies exemplified by capsule endoscopy (CE) constitute alternative painless solutions and despite their limitations, e.g., passive locomotion and absence of on-board instrumentation, are being increasingly used for CRC screening. Research and development centres are investigating novel advanced robotic technologies for diagnostic and therapeutic use. These include wireless communication, active locomotion, sensors, diagnostic, and therapeutic instruments. This review describes the traditional OC procedure and the existing robotic technologies for CRC