ABSTRACT
The scientific community and decision-makers are increasingly concerned about transparency and reproducibility of epidemiologic studies using longitudinal healthcare databases. We explored the extent to which published pharmacoepidemiologic studies using commercially available databases could be reproduced by other investigators. We identified a nonsystematic sample of 38 descriptive or comparative safety/effectiveness cohort studies. Seven studies were excluded from reproduction, five because of violation of fundamental design principles, and two because of grossly inadequate reporting. In the remaining studies, >1,000 patient characteristics and measures of association were reproduced with a high degree of accuracy (median differences between original and reproduction <2% and <0.1). An essential component of transparent and reproducible research with healthcare databases is more complete reporting of study implementation. Once reproducibility is achieved, the conversation can be elevated to assess whether suboptimal design choices led to avoidable bias and whether findings are replicable in other data sources.
Subject(s)
Access to Information , Databases, Factual , Observational Studies as Topic/standards , Pharmacoepidemiology/standards , Cohort Studies , Humans , Reproducibility of ResultsABSTRACT
Cooling of the skin has long been thought to be beneficial in pain states but intense cold is clearly noxious. Does cooling lead to pain or gain? Rapid progress in this controversy has been made since the discovery of specific ion channels of the transient receptor potential (TRP) family that are activated by cooling of sensory nerve cells to below body temperature. This review focuses on the role of one of these, TRPM8, which has been implicated in cool sensation and cold pain by recent knockout mouse studies, but remarkably also appears capable of eliciting a novel analgesic gating control over noxious inputs in chronic pain states. We discuss hypothetical mechanisms that could bring about this composite profile. It is clear that new and highly selective agents will need to be developed to further evaluate the potential therapeutic opportunities offered by low temperature sensitive TRP channels.
Subject(s)
Cold Temperature , Pain Management , Animals , Calcium Channels/physiology , Humans , Membrane Proteins/physiology , Nerve Tissue Proteins/physiology , Pain/physiopathology , Sensation , TRPA1 Cation Channel , TRPM Cation Channels/physiology , TRPV Cation Channels/physiology , Transient Receptor Potential ChannelsABSTRACT
Activation of intracellular signaling pathways involving p38 and p42/44 MAP kinases may contribute importantly to synaptic plasticity underlying spinal neuronal sensitization. Inhibitors of p38 or p42/44 pathways moderately attenuated responses of dorsal horn neurons evoked by mustard oil but not brush and alleviated the behavioral reflex sensitization seen following nerve injury. Activation of p38 and p42/44 MAP kinases in spinal cord ipsilateral to constriction injury was reduced by antagonists of NMDA, VPAC2 and NK2 (but not related) receptors, the glial inhibitor propentofylline and inhibitors of TNF-alpha. A VPAC2 receptor agonist enhanced p38 phosphorylation and caused behavioral reflex sensitization in naïve animals that could be blocked by co-administration of p38 inhibitor. Conversely, an NK2 receptor agonist activated p42/44 and caused behavioral sensitization that could be prevented by co-administration of p42/44 inhibitor. Thus, spinal p38 and p42/44 MAP kinases are activated in neuropathic pain states by mechanisms involving VPAC2, NK2, NMDA receptors and glial cytokine production.
Subject(s)
MAP Kinase Signaling System/physiology , Neuroglia/metabolism , Peripheral Nervous System Diseases/metabolism , Posterior Horn Cells/metabolism , Receptors, Neurokinin-2/metabolism , Receptors, Vasoactive Intestinal Peptide, Type II/metabolism , Animals , Disease Models, Animal , Enzyme Activation/drug effects , Enzyme Activation/physiology , Enzyme Inhibitors/pharmacology , Inflammation Mediators/pharmacology , MAP Kinase Signaling System/drug effects , Male , Mitogen-Activated Protein Kinase 1/drug effects , Mitogen-Activated Protein Kinase 1/metabolism , Neuralgia/metabolism , Neuralgia/physiopathology , Neuroglia/drug effects , Neuroprotective Agents/pharmacology , Peripheral Nerve Injuries , Peripheral Nerves/metabolism , Peripheral Nerves/physiopathology , Peripheral Nervous System Diseases/physiopathology , Phosphorylation/drug effects , Physical Stimulation , Posterior Horn Cells/drug effects , Rats , Rats, Wistar , Receptors, N-Methyl-D-Aspartate/drug effects , Receptors, N-Methyl-D-Aspartate/metabolism , Receptors, Neurokinin-2/drug effects , Receptors, Vasoactive Intestinal Peptide, Type II/drug effects , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/metabolism , Xanthines/pharmacology , p38 Mitogen-Activated Protein Kinases/drug effects , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
The Prx gene in Schwann cells encodes L- and S-periaxin, two abundant PDZ domain proteins thought to have a role in the stabilization of myelin in the peripheral nervous system (PNS). Mice lacking a functional Prx gene assemble compact PNS myelin. However, the sheath is unstable, leading to demyelination and reflex behaviors that are associated with the painful conditions caused by peripheral nerve damage. Older Prx-/- animals display extensive peripheral demyelination and a severe clinical phenotype with mechanical allodynia and thermal hyperalgesia, which can be reversed by intrathecal administration of a selective NMDA receptor antagonist We conclude that the periaxins play an essential role in stabilizing the Schwann cell-axon unit and that the periaxin-deficient mouse will be an important model for studying neuropathic pain in late onset demyelinating disease.
