Search

Evidence from human genetic pain disorders shows that voltage-gated sodium channel α-subtypes Nav1.7, Nav1.8 and Nav1.9 are important in the peripheral signalling of pain. Nav1.7 is of particular interest because individuals with Nav1.7 loss-of-function mutations are congenitally insensitive to acute and chronic pain, and there is considerable hope that phenocopying these effects with a pharmacological antagonist will produce a new class of analgesic drug. However, studies in these rare individuals do not reveal how and where voltage-gated sodium channels contribute to pain signalling, which is of critical importance for drug development. More than a decade of research utilizing rodent genetic models and pharmacological tools to study voltage-gated sodium channels in pain has begun to unravel the role of different subtypes. Here, we review the contribution of individual channel subtypes in three key physiological processes necessary for transmission of sensory information to the CNS: transduction of stimuli at peripheral nerve terminals, axonal transmission of action potentials and neurotransmitter release from central terminals. These data suggest that drugs seeking to recapitulate the analgesic effects of loss of function of Nav1.7 will need to be brain-penetrant - which most of those developed to date are not.

Radiating pain is a significant feature of chronic musculoskeletal pain conditions such as radiculopathies, repetitive motion disorders and whiplash associated disorders. It is reported to be caused by the development of mechanically-sensitive ectopic receptive fields along intact nociceptor axons at sites of peripheral neuroinflammation (neuritis). Since inflammation disrupts axonal transport, we have hypothesised that anterogradely-transported mechanically sensitive ion channels accumulate at the site of disruption, which leads to axonal mechanical sensitivity (AMS). In this study, we have characterised the mechanical properties of the ectopic axonal receptive fields in the rat and have examined the contribution of mechanically sensitive ion channels to the development of AMS following neuritis and vinblastine-induced axonal transport disruption. In both models, there was a positive force–discharge relationship and mechanical thresholds were low (∼9 mN/mm2). All responses were attenuated by Ruthenium Red and FM1-43, which block mechanically sensitive ion channels. In both models, the transport of TRPV1 and TRPA1 was disrupted, and intraneural injection of agonists of these channels caused responses in neurons with AMS following neuritis but not vinblastine treatment. In summary, these data support a role for mechanically sensitive ion channels in the development of AMS.

Nav1.7 is a promising drug target for the treatment of pain because individuals with Nav1.7 loss-of-function mutations are insensitive to pain and do not have other serious neurological deficits. However, current peripherally restricted Nav1.7 inhibitors have not performed well in clinical pain trials, which may reflect a lack of understanding of the function of Nav1.7 in the transmission of nociceptive information. Although numerous studies have reported that Nav1.7 has a moderate role in peripheral transduction, the precise contribution of Nav1.7 to axonal propagation in nociceptors is not clearly defined, particularly for afferents innervating deep structures.In this study, we examined the contribution of Nav1.7 to axonal propagation in nociceptors utilising sodium channel blockers in in vivo electrophysiological and calcium imaging recordings from L4 in the mouse. Using the sodium channel blocker TTX (1-10μM) to inhibit Nav1.7 and other TTX-S sodium channels along the sciatic nerve, we first showed that around 2/3rds of nociceptive neurons innervating the skin, but a lower proportion innervating the muscle (45%), are blocked by TTX. In contrast, nearly all large-sized A-fibre cutaneous afferents (95-100%) were blocked by axonal TTX. Characterisation of TTX resistant cutaneous nociceptors revealed that many were polymodal (57%) and capsaicin sensitive (57%).Next, we examined the role of Nav1.7 in axonal propagation in nociceptive neurons by applying the selective channel blocker PF-05198007 (300nM-1μM) to the sciatic nerve between stimulating and recording sites. 100-300nM PF-05198007 blocked propagation in 63% of C-fibre sensory neurons, whereas similar concentrations did not affect propagation in rapidly conducting A-fibre neurons. We conclude that Nav1.7 has an essential contribution to axonal propagation in only around 2/3rds of nociceptive C-fibre neurons, and a lower proportion (≤45%) of nociceptive neurons innervating muscle.

Local nerve inflammation (neuritis) leads to ongoing activity and axonal mechanical sensitivity (AMS) along intact nociceptor axons and disrupts axonal transport. This phenomenon forms the most feasible cause of radiating pain, such as sciatica. We have previously shown that axonal transport disruption without inflammation or degeneration also leads to AMS but does not cause ongoing activity at the time point when AMS occurs, despite causing cutaneous hypersensitivity. However, there have been no systematic studies of ongoing activity during neuritis or noninflammatory axonal transport disruption. In this study, we present the time course of ongoing activity from primary sensory neurons following neuritis and vinblastine-induced axonal transport disruption. Whereas 24% of C/slow Aδ-fiber neurons had ongoing activity during neuritis, few ( NEW & NOTEWORTHY Many patients with radiating pain lack signs of nerve injury on clinical examination but may have neuritis, which disrupts axonal transport. We have shown that axonal transport disruption does not induce ongoing activity in primary sensory neurons but does cause transient axonal mechanical sensitivity. The present data complete a profile of key axonal sensitivities following axonal transport disruption. Collectively, this profile supports that an active peripheral process is necessary for maintained axonal sensitivities.

Ann Bishop was an eminent protozoologist and parasitologist who spent almost her entire career in Cambridge where she was a Fellow of Girton College for nearly 60 years. Her main work was concerned with the development of drug resistance in the protozoan parasites that cause the disease malaria, still among the most important agents of mortality in the world today.

With the rate of change accelerating in both technological development and in the spread of global markets, very few cost cutting businesses will survive in a value added marketplace. Information sharing over networks has a lot to offer the Industry by way of eliminating delays from the construction process and inventory from the Supply Chain. The most significant change by 2005 will be in networking and communications. Discovering design flaws at the design stage rather than when the building is in use must be very attractive to clients of the Construction Industry. Construction firms must have some sort of IT Strategy or clear view of how to exploit IT to support their businesses. Large companies need to act as coaches and mentors to smaller ones. The Industry cannot maximise its IT benefits unless all the players participate.

Onchocerca volvulus is a filarial worm, transmitted by blackflies (Diptera: Simulidae), which causes severe disease and blindness in Africa and parts of South America. The worms are threadlike; the male is usually only a few inches long, but the female grows up to 2 feet ( ca. 0.61 m) in length. They lie paired, coiled and knotted together in nodules under the skin. The females produce millions of microscopic larvae that swim in the tissue spaces of the skin, waiting for a blackfly to pick them up and transfer them to a new host. In heavy infections they can reach a density of a hundred or more in every milligram of skin. They cause irritation, severe dermatitis and, in the eye, inflammation, fibrosis and blindness. In the past, blackflies have driven the people away from many fertile valleys of the Volta River basin. Their immature stages develop only in fast-flowing stretches of rivers, and so control methods rely on killing the larvae by aerial spraying of selected targets along river courses.

Cecil Arthur Hoare was born on 6 March 1892 of a British father, Arthur Stowell Hoare, of Middlesex, and a Russian-born mother, Aimée Challet of Vitebsk (Bielorussia). Arthur Hoare was a journalist, working as a foreign correspondent first in Holland and then in France. Aimée was a professional singer, who graduated from the Kiev Conservatoire and later travelled widely in Europe with various operatic companies. Cecil’s parents met and married in France, and later moved to Holland where they lived until 1898; they separated when Cecil was 6 years of age. On the paternal side the Hoares were mainly business people connected with banking; on the maternal side the relations belonged to the Russian intelligentsia: lawyers, doctors and engineers.

Woodrow Wilson spoke of the “little legislatures of Congress,” in referring to House and Senate standing committees. Perhaps it is not out of place, then, to call subcommittees the “miniature legislatures.” Little systematic academic attention has been given them since Burton French's discussion in this Review in 1915. They are worth understanding, however, for subcommittees often leave an indelible mark on legislation. As one Congressional staff member stated, “Given an active subcommittee chairman working in a specialized field with a staff of his own, the parent committee can do no more than change the grammar of a subcommittee report.” This article deals with the reasons for the existence and growth of subcommittees, with the variety of ways in which they are organized, and with the issues and methods involved in their control. Conference committees are outside the scope of this study.

n/a

The seniority system ordinarily rates no more than two or three pages in books devoted to Congress. There is likely to be a brief description and a weighing of the arguments, pro and con, followed generally by the conclusion that the system is a poor one; occasionally an author will defend it stoutly. Regardless of the conclusions, the analyses are rarely thorough. This article attempts to fill a gap in the literature on Congress by describing and analyzing various aspects of its seniority system.It is well to remember at the outset that very few human institutions ignore seniority entirely. Champ Clark, in his autobiography, noted that it is observed in all the affairs of life:No sane man would for one moment think of making a graduate from West Point a full general, or one from Annapolis an admiral, or one from any university or college chief of a great newspaper, magazine or business house. A priest or a preacher who has just taken orders is not immediately made a bishop, archbishop or cardinal. In every walk of life “men must tarry at Jericho till their beards are grown.”

Also available in an electronic version via the Internet at: http://nla.gov.au/nla.pic-vn3117865; Published in: The Graphic. Christmas number, 1881, p. 23., Graphic (London, England)