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Concept: Eric Kandel


PURPOSE OF REVIEW: Nonspecific lipid transfer protein (LTP) is the main cause of primary food allergy in adults living in the Mediterranean area. The way allergic patients get sensitized to this protein is all but established, and the clinical expression of sensitization is extremely variable, ranging from long-lasting symptomless sensitization to severe anaphylaxis. Such variability is seemingly due to the presence/absence of a number of cofactors. RECENT FINDINGS: The possibility that LTP sensitization occurs via the inhalation of LTP-containing pollen particles seems unlikely; in contrast, peach particles containing the protein seem able to sensitize both via the airways and the skin. Cosensitization to pollen allergens as well as to labile plant food allergens makes LTP allergy syndrome less severe. In some LTP sensitized subjects clinical food allergy occurs only in the presence of cofactors such as exercise, NSAIDs, or chronic urticaria. SUMMARY: Lipid transfer protein allergy syndrome shows some peculiarities that are unique in the primary food allergy panorama: geographical distribution, frequent asymptomatic sensitization, frequent need for cofactors, and reduced severity when pollen allergy is present. Future studies will have to address these points as the results may have favorable effects on other, more severe, types of food allergy.

Concepts: Asthma, Allergy, Food allergy, Eczema, Allergology, Allergen immunotherapy, Sensitization, Eric Kandel


Radiographic measures of the pathologic changes of knee osteoarthritis (OA) have shown modest associations with clinical pain. We sought to evaluate possible differences in quantitative sensory testing (QST) results and psychosocial distress profiles between knee OA patients with discordant versus congruent clinical pain reports relative to radiographic severity measures.

Concepts: Osteoarthritis, Sensitization, Eric Kandel


Patellofemoral Pain (PFP) is highly prevalent among adults and adolescents. Localized mechanical hyperalgesia around the knee and tibialis anterior have been observed in people with PFP, but limited knowledge of potential manifestations of central sensitisation exists. The aims of this study were to study conditioned pain modulation (CPM) and wide-spread hyperalgesia in adults with PFP. This assessor-blinded cross-sectional study design compared CPM and mechanical pressure pain thresholds (PPT) between 33 adults (23 females) diagnosed with PFP and 32 age and sex matched pain-free controls. The investigator taking the PPT measurements was blinded to which participants had PFP. PPTs were reliably measured using a Somedic hand-held pressure algometer at three sites: 1) The centre of the patella, 2) the tibialis anterior muscle and 3) a remote site on the lateral epicondyle. For the assessment of CPM, experimental pain was induced to the contralateral hand by immersion into a cold water bath (conditioning stimulus), and assessment of PPTs (the test stimulus) was performed before and immediately after the conditioning stimulation. On average, the CPM paradigm induced a significant increase in PPTs across the three sites (6.3-13.5%, P<0.05), however there was no difference in CPM between young adults with PFP compared to the control group, (F(1,189) = 0.39, P = 0.89). There was no difference in mechanical PPTs between the two groups (F(1,189) = 0.03, P = 0.86). Contrary to our a-priori hypothesis, we found no difference in CPM or PPT between young adults with PFP and age and sex matched pain-free controls.

Concepts: Scientific method, Cross-sectional study, Tibialis anterior muscle, Tibialis posterior muscle, Sensitization, Eric Kandel


In recent years, there has been an increased interest in pain neuroscience education (PNE) in physical therapy. There is growing evidence for the efficacy of PNE to decrease pain, disability, fear-avoidance, pain catastrophization, limited movement, and health care utilization in people struggling with pain. PNE teaches people in pain more about the biology and physiology of their pain experience including processes such as central sensitization, peripheral sensitization, allodynia, inhibition, facilitation, neuroplasticity and more. PNE’s neurobiological model often finds itself at odds with traditional biomedical models used in physical therapy. Traditional biomedical models, focusing on anatomy, pathoanatomy, and biomechanics have been shown to have limited efficacy in helping people understand their pain, especially chronic pain, and may in fact even increase a person’s pain experience by increasing fear-avoidance and pain catastrophization. An area of physical therapy where the biomedical model is used a lot is manual therapy. This contrast between PNE and manual therapy has seemingly polarized followers from each approach to see PNE as a ‘hands-off’ approach even having clinicians categorize patients as either in need of receiving PNE (with no hands-on), or hands-on with no PNE. In this paper, we explore the notion of PNE and manual therapy co-existing. PNE research has shown to have immediate effects of various clinical signs and symptoms associated with central sensitization. Using a model of sensitization (innocuous, noxious, and allodynia), we argue that PNE can be used in a manual therapy model, especially treating someone where the nervous system has become increasingly hypervigilant. Level of Evidence: VII.

Concepts: Central nervous system, Nervous system, Medicine, Biology, Neuroscience, Medical diagnosis, Pain, Eric Kandel


Traditional understanding of osteoarthritis-related pain has recently been challenged in light of evidence supporting a key role of central sensitization in a subgroup of this population. This fact may erroneously lead musculoskeletal therapists to conclude that hands-on interventions have no place in OA management, and that hands-off interventions must be applied exclusively. The aim of this paper is to encourage clinicians in finding an equilibrium between hands-on and hands-off interventions in patients with osteoarthritis-related pain dominated by central sensitization. The theoretical rationale for simultaneous application of manual therapy and pain neuroscience education is presented. Practical problems when combining these interventions are also addressed. Future studies should explore the combined effects of these treatment strategies to examine whether they increase therapeutic outcomes against current approaches for chronic osteoarthritis-related pain.

Concepts: Medicine, Therapy, Physical therapy, Sensitization, Eric Kandel, Manual therapy


Despite growing awareness of the contribution of central pain mechanisms to knee osteoarthritis pain in a subgroup of patients, routine evaluation of central sensitization is yet to be incorporated into clinical practice.

Concepts: Clinical trial, Osteoarthritis, Pain, Sensitization, Eric Kandel


Caloric restriction (CR) is proposed to decrease tumorigenesis through a variety of mechanisms including effects on glycolysis. However, understanding how CR affects the response to cancer therapy is still rudimentary. Here, using the Eμ-Myc transgenic mouse model of B-cell lymphoma, we report that CR by reducing protein translation, can reduce expression of the pro-survival Bcl-2-family member, Mcl-1 and sensitize lymphomas to ABT-737-induced death in vivo. Using Eμ-Myc lymphoma cells lacking p53, we showed that CR mimetics, such as 2-deoxyglucose, led to a decrease in Mcl-1 expression and sensitized lymphoma cells to ABT-737-induced death independently of p53. In keeping with this, Eμ-Myc lymphoma cells lacking either the BH3-only pro-apoptotic members, Noxa, Puma or Bim were also sensitized by CR mimetics to ABT-737-induced death. Remarkably, neither the loss of both Puma and Noxa, the loss of both Puma and Bim nor the loss of all three BH3-only proteins prevented sensitization to ABT-737 induced by CR mimetics. Thus, CR can influence Mcl-1 expression and sensitize cells to BH3-mimetic-induced apoptosis, independently of the main BH3-only proteins and of p53. Exploiting this may improve the efficiency of, or prevent resistance to, cancer therapy.

Concepts: Protein, Gene, Cancer, Molecular biology, B cell, Lymphoma, Sensitization, Eric Kandel


Study Design Case report. Background Aggressive PT in the freezing stage of frozen shoulder (FS) may prolong the course of recovery. Central sensitization (CS) may play a role in the early stages of FS. Pain neuroscience education (PNE), tactile discrimination (TD) and graded motor imagery (GMI) have been used in a number of conditions with CS. The purpose of this case report is to describe the examination and treatment of a patient in the freezing stage of FS using PNE, TD and GMI. Case Description A 54-year-old female with a diagnosis of FS was referred by an orthopedic surgeon following a failed bout of 4 weeks of intensive daily physical therapy (PT). Pain at rest was 7/10 and her Shoulder Pain and Disability Index (SPADI) score was 62%. She had painful and limited active range of motion (AROM) and elevated fear avoidance beliefs. TD and limb laterality were impaired with signs of CS. A “top-down” approach using PNE, TD, and GMI was used for the first 6 weeks followed by a “bottom-up” impairment based approach. Outcomes The patient was seen for 20 sessions over 12 weeks. At discharge, her SPADI was 22%, resting pain was 0/10, and fear avoidance beliefs improved. Improvements in AROM, laterality and TD were also noted. Discussion Intensive PT in the freezing stage of FS may be detrimental to long term outcomes. This case report suggests a “top-down approach” may allow a quicker transition through the freezing stage of FS. Level of Evidence Therapy, level 5. J Orthop Sports Phys Ther, Epub 19 Dec 2017. doi:10.2519/jospt.2018.7716.

Concepts: Neuroscience, Pain, Orthopedic surgery, Neuropsychology, Stage, Term, Shoulder, Eric Kandel


Modern pain neuroscience has substantially improved our understanding of the (development of) chronic musculoskeletal pain. The time has come for orthopaedic and sports physical therapists to implement modern pain neuroscience in specialized, but definitely also in primary, care settings, including the role of central sensitization (CS) in amplifying and explaining the presence of the pain experience. Central sensitization dominates the clinical picture in a subgroup of the musculoskeletal pain population, ranging from tennis elbow over shoulder pain to osteoarthritis and whiplash. Applying modern pain neuroscience to clinical practice implies (1) recognizing those patients having predominant CS pain, and (2) accounting for CS when designing the treatment plan in those with predominant CS pain. Future work in this area should (1) examine the validity of the proposed clinical classification algorithm for identifying CS pain in patients with orthopaedic and sports injuries, and (2) explore evidence-based treatment options for patients having predominant CS pain. J Orthop Sports Phys Ther 2016;46(12):1024-1028. doi:10.2519/jospt.2016.0612.

Concepts: Medicine, Evidence-based medicine, Pain, Injuries, Acupuncture, Chronic pain, Eric Kandel, Overuse injuries


Inflammation is a part of the body’s natural response to tissue injury which initiates the healing process. Unfortunately, inflammation is frequently painful and leads to hypersensitivity to mechanical stimuli, which is difficult to treat clinically. While it is well established that altered sensory processing in the spinal cord contributes to mechanical hypersensitivity (central sensitization), it is still debated whether primary afferent neurons become sensitized to mechanical stimuli after tissue inflammation. We induced inflammation in C57BL/6 mice via intraplantar injection of Complete Freund’s Adjuvant. Cutaneous C fibers exhibited increased action potential firing to suprathreshold mechanical stimuli. We found that abnormal responses to intense mechanical stimuli were completely suppressed by acute incubation of the receptive terminals with the TRPA1 inhibitor, HC-030031. Further, elevated responses were predominantly exhibited by a specific subgroup of C fibers, which we determined to be C-Mechano Cold sensitive fibers. Thus, in the presence of HC-030031, C fiber mechanical responses in inflamed mice were not different than responses in saline-injected controls. We also demonstrate that injection of the HC-030031 compound into the hind paw of inflamed mice alleviates behavioral mechanical hyperalgesia without affecting heat hyperalgesia. Further, we pharmacologically anesthetized the TRPA1-expressing fibers in vivo by co-injecting the membrane-impermeable sodium channel inhibitor QX-314 and the TRPA1 agonist cinnamaldehyde into the hind paw. This approach also alleviated behavioral mechanical hyperalgesia in inflamed mice but left heat hypersensitivity intact. Our findings indicate that C-Mechano Cold sensitive fibers exhibit enhanced firing to suprathreshold mechanical stimuli in a TRPA1-dependent manner during inflammation, and that input from these fibers drives mechanical hyperalgesia in inflamed mice.

Concepts: Immune system, Inflammation, Neuron, Asthma, Action potential, Behaviorism, Sensitization, Eric Kandel