2014 Round-up
despite the virtual disappearance of this bacterium in developed countries. In 2010, a N meningitidis serogroup A polysaccharide–tetanus toxoid conjugate vaccine (PsA-TT) developed by the Meningitis Vaccine Project (MVP) was deployed in Burkina Faso and largely reduced the carrier rate and incidence of meningitis. Although these results were encouraging, some researchers have argued that the reduction might have been due to the falling incidence of serogroup A disease before the introduction of the vaccine. Now, Doumagoum Daugla and colleagues5 have provided persuasive evidence for the effectiveness of PsA-TT, assessed during an ongoing epidemic in Chad. Approximately 1·8 million individuals aged 1–29 years received one dose of PsA–TT during a vaccination campaign in three regions of Chad in 2011. The incidence and carrier rates of meningitis during the 2012 meningitis season in these regions were markedly reduced when compared with unvaccinated regions, with a 94% difference in crude incidence. This study provides
compelling evidence for the effectiveness of PsA-TT and shows the importance, will, and resolve of organisations such as MPV to address major global health concerns. Kiran T Thakur, Justin C McArthur, *Arun Venkatesan Division of Neuroinfectious Disease and Neuroimmunology, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA [email protected] We declare no competing interests. 1 2
3 4 5
Boulware DR, Meya DB, Muzoora C, et al. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med 2014; 370: 2487–98. Frohman EM, Monaco MC, Remington G, et al. JC virus in CD34+ and CD19+ cells in patients with multiple sclerosis treated with natalizumab. JAMA Neurol 2014; 71: 596–602. Moda F, Gambetti P, Notari S, et al. Prions in the urine of patients with variant Creutzfeldt-Jakob disease. N Engl J Med 2014; 371: 530–39. Orrú CD, Bongianni M, Tonoli G et al. A test for Creutzfeldt-Jakob disease using nasal brushings. N Engl J Med 2014; 371: 519–29. Daugla DM, Gami JP, Gamougam K, et al. Effect of a serogroup A meningococcal conjugate vaccine (PsA–TT) on serogroup A meningococcal meningitis and carriage in Chad: a community study. Lancet 2014; 383: 40–47.
Pain: from new perspectives to novel treatments
Judith Haeusler/Cultura/Science Photo Library
During the past year, important advances in pain research have included changed perspectives and new insights, the development of sophisticated methods, and the discovery of pain mechanisms and novel drug targets. One of the most remarkable changes in perspective has taken place in the study of fibromyalgia—a chronic pain condition of still unknown causation, which affects millions of patients worldwide. The journey started with the first description of small-calibre nerve fibre pathology
22
in patients with fibromyalgia1 in 2013, and has been successfully carried forward by the work of Jordi Serra and colleagues,2 who used microneurography, the most precise and objective neurophysiological method available so far to study small-fibre function. A comparison of patients with fibromyalgia with patients affected by idiopathic small-fibre neuropathy revealed that the normally silent mechano-insensitive C-nociceptors are spontaneously active in patients with fibromyalgia and respond to mechanical stimulation with prolonged firing, suggesting that they are pathologically sensitive. These nerve fibres also showed enhanced activity-dependent slowing of their conduction velocity after stimulation at 0·25 Hz. Not only do these findings build on previous reports about the potential contribution of peripheral C-nociceptors to fibromyalgia pathophysiology, they also underline the need to distinguish idiopathic smallfibre neuropathy from other painful conditions with small-nerve-fibre pathology, since clearly distinct activity profiles and slowing properties were seen in fibromyalgia compared with patients with small-fibre neuropathy. New insights into the pathophysiology of pain behaviour in experimental animals were reported by Robert Sorge and colleagues.3 By systematic www.thelancet.com/neurology Vol 14 January 2015
2014 Round-up
investigation of the chance observation that laboratory rodents showed less pain behaviour in the presence of a male researcher, the group managed to identify odour-induced stress analgesia.3 In two pain models, the mere presence of a male experimenter or his T-shirt, bedding material from unfamiliar male rodents, or secretions from the human axilla led to a measurable stress reaction with stress-induced analgesia in the experimental animals. (E)-3-methyl-2-hexenoic acid, androstenone, and androstadienone were identified as the compounds underlying these effects. These findings will have a substantial effect on the interpretation of previously acquired behavioural data, and on future experimental pain research. Although sex differences in experimental animals were already regarded as crucial, researchers will now have to think of the composition of their research teams as a major confounding factor. One of the emerging methods in experimental pain research is optogenetics. Classical optogenetic experiments are based on the generation of transgenic animals that are suitable for remote manipulation via optic systems attached to their bodies. In a recent report,4 Shrivats Iyer and colleagues present the first data for a new virus-based approach to the intraneural delivery of excitatory and inhibitory opsins, which allow bidirectional control of nociceptors in non-transgenic, freely moving mice. Pain was induced by transcutaneous optic activation of excitatory opsins released by intraneurally injected adeno-associated viruses. Pain behaviour was dose dependent, and the activated neurons could be traced and characterised up to their endings in the spinal cord and skin. In turn, pain was attenuated after optic activation if an inhibitory opsin was given. Even established neuropathic hyperalgesia after nerve injury could be reversed. Therefore, the new strategy not only bypasses the need to generate transgenic mice for optogenetic experiments, but also enables remote nociceptor manipulation through transdermal control. Brittany Wright and colleagues5 have made remarkable progress in ongoing efforts to improve understanding of the underlying mechanisms of pain. Instead of focusing on a single receptor, the group investigated the phosphatidylinositol-4,5-bisphosphate (PIP₂) pathway, which is an intracellular convergence point for many different receptors. They established that phosphatidylinositol-4-phosphate 5-kinase type 1C (PIP5K1C) is the major source of PIP₂ in dorsal root www.thelancet.com/neurology Vol 14 January 2015
ganglion neurons. By use of various complementary experimental approaches, including the assessment of heterozygous Pip5k1c+/- mice, PIP5K1C was confirmed as the major source of PIP₂, and PIP₂ as a key substrate for nociception. Intrathecal and intraplantar application of a specific small-molecule inhibitor attenuated pain behaviour in the experimental animals by reduction of neuronal PIP₂ expression, which identifies PIP5K1C as a novel target for analgesic treatment. The successful translation of preclinical data to analgesics was shown in a multicentre, placebocontrolled, double-blind, randomised, phase 2 clinical trial.6 By taking advantage of the newly discovered role of the angiotensin II type 2 receptor (AT₂R) in pain perception, Andrew Rice and colleagues6 showed that patients with postherpetic neuralgia reported a substantial decrease in pain ratings when treated with the orally administered AT₂R antagonist EMA401. The remarkably well-tolerated compound—the first drug to be tested for an AT₂R-bound mechanism in humans— significantly reduced pain intensity during an observation time of 28 days in this chronic and difficult-to-treat pain disorder. The study is an impressive example of how basic science can lay the groundwork for the successful clinical application of a new compound, while contributing to understanding of pain pathophysiology. This selection of pioneering work from 2014 represents the dynamism, variety, and efficacy in pain research and gives us reason to look forward with confidence to exciting future endeavours. Nurcan Üçeyler, *Claudia Sommer Department of Neurology, University of Würzburg, 97080 Würzburg, Germany [email protected] NÜ has received speaker’s fees from Astellas and consulting fees from Grünenthal GmbH. CS has received consulting fees and speaker’s fees from Astellas and Pfizer. 1 2 3
4
5 6
Üçeyler N, Zeller D, Kahn AK, et al. Small fibre pathology in patients with fibromyalgia syndrome. Brain 2013; 136: 1857–67. Serra J, Collado A, Sola R, et al. Hyperexcitable C nociceptors in fibromyalgia. Ann Neurol 2014; 75: 196–208. Sorge RE, Martin LJ, Isbester KA, et al. Olfactory exposure to males, including men, causes stress and related analgesia in rodents. Nat Methods 2014; 11: 629–32. Iyer SM, Montgomery KL, Towne C, et al. Virally mediated optogenetic excitation and inhibition of pain in freely moving nontransgenic mice. Nat Biotechnol 2014; 32: 274–78. Wright BD, Loo L, Street SE, et al. The lipid kinase PIP5K1C regulates pain signaling and sensitization. Neuron 2014; 82: 836–47. Rice AS, Dworkin RH, McCarthy TD, et al. EMA401, an orally administered highly selective angiotensin II type 2 receptor antagonist, as a novel treatment for postherpetic neuralgia: a randomised, double-blind, placebo-controlled phase 2 clinical trial. Lancet 2014; 383: 1637–47.
23
despite the virtual disappearance of this bacterium in developed countries. In 2010, a N meningitidis serogroup A polysaccharide–tetanus toxoid conjugate vaccine (PsA-TT) developed by the Meningitis Vaccine Project (MVP) was deployed in Burkina Faso and largely reduced the carrier rate and incidence of meningitis. Although these results were encouraging, some researchers have argued that the reduction might have been due to the falling incidence of serogroup A disease before the introduction of the vaccine. Now, Doumagoum Daugla and colleagues5 have provided persuasive evidence for the effectiveness of PsA-TT, assessed during an ongoing epidemic in Chad. Approximately 1·8 million individuals aged 1–29 years received one dose of PsA–TT during a vaccination campaign in three regions of Chad in 2011. The incidence and carrier rates of meningitis during the 2012 meningitis season in these regions were markedly reduced when compared with unvaccinated regions, with a 94% difference in crude incidence. This study provides
compelling evidence for the effectiveness of PsA-TT and shows the importance, will, and resolve of organisations such as MPV to address major global health concerns. Kiran T Thakur, Justin C McArthur, *Arun Venkatesan Division of Neuroinfectious Disease and Neuroimmunology, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA [email protected] We declare no competing interests. 1 2
3 4 5
Boulware DR, Meya DB, Muzoora C, et al. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med 2014; 370: 2487–98. Frohman EM, Monaco MC, Remington G, et al. JC virus in CD34+ and CD19+ cells in patients with multiple sclerosis treated with natalizumab. JAMA Neurol 2014; 71: 596–602. Moda F, Gambetti P, Notari S, et al. Prions in the urine of patients with variant Creutzfeldt-Jakob disease. N Engl J Med 2014; 371: 530–39. Orrú CD, Bongianni M, Tonoli G et al. A test for Creutzfeldt-Jakob disease using nasal brushings. N Engl J Med 2014; 371: 519–29. Daugla DM, Gami JP, Gamougam K, et al. Effect of a serogroup A meningococcal conjugate vaccine (PsA–TT) on serogroup A meningococcal meningitis and carriage in Chad: a community study. Lancet 2014; 383: 40–47.
Pain: from new perspectives to novel treatments
Judith Haeusler/Cultura/Science Photo Library
During the past year, important advances in pain research have included changed perspectives and new insights, the development of sophisticated methods, and the discovery of pain mechanisms and novel drug targets. One of the most remarkable changes in perspective has taken place in the study of fibromyalgia—a chronic pain condition of still unknown causation, which affects millions of patients worldwide. The journey started with the first description of small-calibre nerve fibre pathology
22
in patients with fibromyalgia1 in 2013, and has been successfully carried forward by the work of Jordi Serra and colleagues,2 who used microneurography, the most precise and objective neurophysiological method available so far to study small-fibre function. A comparison of patients with fibromyalgia with patients affected by idiopathic small-fibre neuropathy revealed that the normally silent mechano-insensitive C-nociceptors are spontaneously active in patients with fibromyalgia and respond to mechanical stimulation with prolonged firing, suggesting that they are pathologically sensitive. These nerve fibres also showed enhanced activity-dependent slowing of their conduction velocity after stimulation at 0·25 Hz. Not only do these findings build on previous reports about the potential contribution of peripheral C-nociceptors to fibromyalgia pathophysiology, they also underline the need to distinguish idiopathic smallfibre neuropathy from other painful conditions with small-nerve-fibre pathology, since clearly distinct activity profiles and slowing properties were seen in fibromyalgia compared with patients with small-fibre neuropathy. New insights into the pathophysiology of pain behaviour in experimental animals were reported by Robert Sorge and colleagues.3 By systematic www.thelancet.com/neurology Vol 14 January 2015
2014 Round-up
investigation of the chance observation that laboratory rodents showed less pain behaviour in the presence of a male researcher, the group managed to identify odour-induced stress analgesia.3 In two pain models, the mere presence of a male experimenter or his T-shirt, bedding material from unfamiliar male rodents, or secretions from the human axilla led to a measurable stress reaction with stress-induced analgesia in the experimental animals. (E)-3-methyl-2-hexenoic acid, androstenone, and androstadienone were identified as the compounds underlying these effects. These findings will have a substantial effect on the interpretation of previously acquired behavioural data, and on future experimental pain research. Although sex differences in experimental animals were already regarded as crucial, researchers will now have to think of the composition of their research teams as a major confounding factor. One of the emerging methods in experimental pain research is optogenetics. Classical optogenetic experiments are based on the generation of transgenic animals that are suitable for remote manipulation via optic systems attached to their bodies. In a recent report,4 Shrivats Iyer and colleagues present the first data for a new virus-based approach to the intraneural delivery of excitatory and inhibitory opsins, which allow bidirectional control of nociceptors in non-transgenic, freely moving mice. Pain was induced by transcutaneous optic activation of excitatory opsins released by intraneurally injected adeno-associated viruses. Pain behaviour was dose dependent, and the activated neurons could be traced and characterised up to their endings in the spinal cord and skin. In turn, pain was attenuated after optic activation if an inhibitory opsin was given. Even established neuropathic hyperalgesia after nerve injury could be reversed. Therefore, the new strategy not only bypasses the need to generate transgenic mice for optogenetic experiments, but also enables remote nociceptor manipulation through transdermal control. Brittany Wright and colleagues5 have made remarkable progress in ongoing efforts to improve understanding of the underlying mechanisms of pain. Instead of focusing on a single receptor, the group investigated the phosphatidylinositol-4,5-bisphosphate (PIP₂) pathway, which is an intracellular convergence point for many different receptors. They established that phosphatidylinositol-4-phosphate 5-kinase type 1C (PIP5K1C) is the major source of PIP₂ in dorsal root www.thelancet.com/neurology Vol 14 January 2015
ganglion neurons. By use of various complementary experimental approaches, including the assessment of heterozygous Pip5k1c+/- mice, PIP5K1C was confirmed as the major source of PIP₂, and PIP₂ as a key substrate for nociception. Intrathecal and intraplantar application of a specific small-molecule inhibitor attenuated pain behaviour in the experimental animals by reduction of neuronal PIP₂ expression, which identifies PIP5K1C as a novel target for analgesic treatment. The successful translation of preclinical data to analgesics was shown in a multicentre, placebocontrolled, double-blind, randomised, phase 2 clinical trial.6 By taking advantage of the newly discovered role of the angiotensin II type 2 receptor (AT₂R) in pain perception, Andrew Rice and colleagues6 showed that patients with postherpetic neuralgia reported a substantial decrease in pain ratings when treated with the orally administered AT₂R antagonist EMA401. The remarkably well-tolerated compound—the first drug to be tested for an AT₂R-bound mechanism in humans— significantly reduced pain intensity during an observation time of 28 days in this chronic and difficult-to-treat pain disorder. The study is an impressive example of how basic science can lay the groundwork for the successful clinical application of a new compound, while contributing to understanding of pain pathophysiology. This selection of pioneering work from 2014 represents the dynamism, variety, and efficacy in pain research and gives us reason to look forward with confidence to exciting future endeavours. Nurcan Üçeyler, *Claudia Sommer Department of Neurology, University of Würzburg, 97080 Würzburg, Germany [email protected] NÜ has received speaker’s fees from Astellas and consulting fees from Grünenthal GmbH. CS has received consulting fees and speaker’s fees from Astellas and Pfizer. 1 2 3
4
5 6
Üçeyler N, Zeller D, Kahn AK, et al. Small fibre pathology in patients with fibromyalgia syndrome. Brain 2013; 136: 1857–67. Serra J, Collado A, Sola R, et al. Hyperexcitable C nociceptors in fibromyalgia. Ann Neurol 2014; 75: 196–208. Sorge RE, Martin LJ, Isbester KA, et al. Olfactory exposure to males, including men, causes stress and related analgesia in rodents. Nat Methods 2014; 11: 629–32. Iyer SM, Montgomery KL, Towne C, et al. Virally mediated optogenetic excitation and inhibition of pain in freely moving nontransgenic mice. Nat Biotechnol 2014; 32: 274–78. Wright BD, Loo L, Street SE, et al. The lipid kinase PIP5K1C regulates pain signaling and sensitization. Neuron 2014; 82: 836–47. Rice AS, Dworkin RH, McCarthy TD, et al. EMA401, an orally administered highly selective angiotensin II type 2 receptor antagonist, as a novel treatment for postherpetic neuralgia: a randomised, double-blind, placebo-controlled phase 2 clinical trial. Lancet 2014; 383: 1637–47.
23
