Neck pain is the fourth leading cause of disability, with an annual prevalence rate exceeding 30%. Most episodes of acute neck pain will resolve with or without treatment, but nearly 50% of ...individuals will continue to experience some degree of pain or frequent occurrences. History and physical examination can provide important clues as to whether the pain is neuropathic or mechanical and can also be used to identify "red flags" that may signify serious pathology, such as myelopathy, atlantoaxial subluxation, and metastases. Magnetic resonance imaging is characterized by a high prevalence of abnormal findings in asymptomatic individuals but should be considered for cases involving focal neurologic symptoms, pain refractory to conventional treatment, and when referring a patient for interventional treatment. Few clinical trials have evaluated treatments for neck pain. Exercise treatment appears to be beneficial in patients with neck pain. There is some evidence to support muscle relaxants in acute neck pain associated with muscle spasm, conflicting evidence for epidural corticosteroid injections for radiculopathy, and weak positive evidence for cervical facet joint radiofrequency denervation. In patients with radiculopathy or myelopathy, surgery appears to be more effective than nonsurgical therapy in the short term but not in the long term for most people.
Nociplastic pain is the semantic term suggested by the international community of pain researchers to describe a third category of pain that is mechanistically distinct from nociceptive pain, which ...is caused by ongoing inflammation and damage of tissues, and neuropathic pain, which is caused by nerve damage. The mechanisms that underlie this type of pain are not entirely understood, but it is thought that augmented CNS pain and sensory processing and altered pain modulation play prominent roles. The symptoms observed in nociplastic pain include multifocal pain that is more widespread or intense, or both, than would be expected given the amount of identifiable tissue or nerve damage, as well as other CNS-derived symptoms, such as fatigue, sleep, memory, and mood problems. This type of pain can occur in isolation, as often occurs in conditions such as fibromyalgia or tension-type headache, or as part of a mixed-pain state in combination with ongoing nociceptive or neuropathic pain, as might occur in chronic low back pain. It is important to recognise this type of pain, since it will respond to different therapies than nociceptive pain, with a decreased responsiveness to peripherally directed therapies such as anti-inflammatory drugs and opioids, surgery, or injections.
Neuropathic pain can develop after nerve injury, when deleterious changes occur in injured neurons and along nociceptive and descending modulatory pathways in the central nervous system. The myriad ...neurotransmitters and other substances involved in the development and maintenance of neuropathic pain also play a part in other neurobiological disorders. This might partly explain the high comorbidity rates for chronic pain, sleep disorders, and psychological conditions such as depression, and why drugs that are effective for one condition may benefit others. Neuropathic pain can be distinguished from non-neuropathic pain by two factors. Firstly, in neuropathic pain there is no transduction (conversion of a nociceptive stimulus into an electrical impulse). Secondly, the prognosis is worse: injury to major nerves is more likely than injury to non-nervous tissue to result in chronic pain. In addition, neuropathic pain tends to be more refractory than non-neuropathic pain to conventional analgesics, such as non-steroidal anti-inflammatory drugs and opioids. However, because of the considerable overlap between neuropathic and nociceptive pain in terms of mechanisms and treatment modalities, it might be more constructive to view these entities as different points on the same continuum. This review focuses on the mechanisms of neuropathic pain, with special emphasis on clinical implications.
Protein phosphorylation regulates most aspects of cell life, whereas abnormal phosphorylation is a cause or consequence of disease. A growing interest in developing orally active protein-kinase ...inhibitors has recently culminated in the approval of the first of these drugs for clinical use. Protein kinases have now become the second most important group of drug targets, after G-protein-coupled receptors. Here, I give a personal view of some of the most important advances that have shaped this field.
Introduction
To evaluate the possibility that switching from reference biologic medicines to biosimilars could lead to altered clinical outcomes, including enhanced immunogenicity, compromised ...safety, or diminished efficacy for patients, a systematic literature review was conducted of all switching studies between related biologics (including biosimilars).
Methods
A systematic search was conducted using the Medline
®
and Embase
®
databases up to 30 June 2017 employing specific medical subject heading terms. Additionally, the snowball method and a hand search were also applied. Publications were considered if they contained efficacy or safety information related to a switch from a reference medicine to a biosimilar. Non-English, non-human studies, editorials, notes, and short surveys were excluded.
Results
Primary data were available from 90 studies that enrolled 14,225 unique individuals. They included protein medicines used in supportive care as well as those used as therapeutic agents. The medicines contained seven different molecular entities that were used to treat 14 diseases. The great majority of the publications did not report differences in immunogenicity, safety, or efficacy. The nature and intensity of safety signals reported after switching from reference medicines to biosimilars were the same as those already known from continued use of the reference medicines alone. Three large multiple switch studies with different biosimilars did not show differences in efficacy or safety after multiple switches between reference medicine and biosimilar. Two publications reported a loss of efficacy or increased dropout rates.
Conclusions
While use of each biologic must be assessed individually, these results provide reassurance to healthcare professionals and the public that the risk of immunogenicity-related safety concerns or diminished efficacy is unchanged after switching from a reference biologic to a biosimilar medicine.
Sacroiliac (SI) joint pain is a challenging condition affecting 15% to 25% of patients with axial low back pain, for which there is no standard long-term treatment. Recent studies have demonstrated ...that historical and physical examination findings and radiological imaging are insufficient to diagnose SI joint pain. The most commonly used method to diagnose the SI joint as a pain generator is with small-volume local anesthetic blocks, although the validity of this practice remains unproven. In the present review I provide a comprehensive review of the anatomy, function, and mechanisms of injury of the SI joint, along with a systematic assessment of its diagnosis and treatment.
Lumbar zygapophysial joint arthropathy is a challenging condition affecting up to 15% of patients with chronic low back pain. The onset of lumbar facet joint pain is usually insidious, with ...predisposing factors including spondylolisthesis, degenerative disc pathology, and old age. Despite previous reports of a "facet syndrome," the existing literature does not support the use of historic or physical examination findings to diagnose lumbar zygapophysial joint pain. The most accepted method for diagnosing pain arising from the lumbar facet joints is with low-volume intraarticular or medial branch blocks, both of which are associated with high false-positive rates. Standard treatment modalities for lumbar zygapophysial joint pain include intraarticular steroid injections and radiofrequency denervation of the medial branches innervating the joints, but the evidence supporting both of these is conflicting. In this article, the authors provide a comprehensive review of the anatomy, biomechanics, and function of the lumbar zygapophysial joints, along with a systematic analysis of the diagnosis and treatment of facet joint pain.
The phosphorylation of a protein can alter its behaviour in almost every conceivable way. These include modulation of its intrinsic biological activity, subcellular location, half-life and docking ...with other proteins. ‘Multisite phosphorylation can enable several such effects to operate in the same protein. It can also determine the extent and duration of a response and is the key to signal integration.
Understanding the etiology of metastasis is very important in clinical perspective, since it is estimated that metastasis accounts for 90% of cancer patient mortality. Metastasis results from a ...sequence of multiple steps including invasion and migration. The early stages of metastasis are tightly controlled in normal cells and can be drastically affected by malignant mutations; therefore, they might constitute the principal determinants of the overall metastatic rate even if the later stages take long to occur. To elucidate the role of individual mutations or their combinations affecting the metastatic development, a logical model has been constructed that recapitulates published experimental results of known gene perturbations on local invasion and migration processes, and predict the effect of not yet experimentally assessed mutations. The model has been validated using experimental data on transcriptome dynamics following TGF-β-dependent induction of Epithelial to Mesenchymal Transition in lung cancer cell lines. A method to associate gene expression profiles with different stable state solutions of the logical model has been developed for that purpose. In addition, we have systematically predicted alleviating (masking) and synergistic pairwise genetic interactions between the genes composing the model with respect to the probability of acquiring the metastatic phenotype. We focused on several unexpected synergistic genetic interactions leading to theoretically very high metastasis probability. Among them, the synergistic combination of Notch overexpression and p53 deletion shows one of the strongest effects, which is in agreement with a recent published experiment in a mouse model of gut cancer. The mathematical model can recapitulate experimental mutations in both cell line and mouse models. Furthermore, the model predicts new gene perturbations that affect the early steps of metastasis underlying potential intervention points for innovative therapeutic strategies in oncology.
PDF
