The human μ-opioid receptor gene polymorphism (A118G) is associated with head pain severity in a clinical cohort of female migraine with aura patients

Migraine is a painful and debilitating, neurovascular disease. Current migraine head pain treatments work with differing efficacies in migraineurs. The opioid system plays an important role in diverse biological functions including analgesia, drug response and pain reduction. The A118G single nucleotide polymorphism (SNP) in exon 1 of the μ-opioid receptor gene (OPRM1) has been associated with elevated pain responses and decreased pain threshold in a variety of populations. The aim of the current preliminary study was to test whether genotypes of the OPRM1 A118G SNP are associated with head pain severity in a clinical cohort of female migraineurs. This was a preliminary study to determine whether genotypes of the OPRM1 A118G SNP are associated with head pain severity in a clinical cohort of female migraineurs. A total of 153 chronic migraine with aura sufferers were assessed for migraine head pain using the Migraine Disability Assessment Score instrument and classified into high and low pain severity groups. DNA was extracted and genotypes obtained for the A118G SNP. Logistic regression analysis adjusting for age effects showed the A118G SNP of the OPRM1 gene to be significantly associated with migraine pain severity in the test population (P = 0.0037). In particular, G118 allele carriers were more likely to be high pain sufferers compared to homozygous carriers of the A118 allele (OR = 3.125, 95 % CI = 1.41, 6.93, P = 0.0037). These findings suggest that A118G genotypes of the OPRM1 gene may influence migraine-associated head pain in females. Further investigations are required to fully understand the effect of this gene variant on migraine head pain including studies in males and in different migraine subtypes, as well as in response to head pain medication.

Results of a phase IIa clinical trial of an anti-inflammatory molecule, chaperonin 10, in multiple sclerosis

Background Chaperonin 10 (Cpn10) is a mitochondrial molecule involved in protein folding. The aim of this study was to determine the safety profile of Cpn10 in patients with multiple sclerosis (MS). Methods A total of 50 patients with relapse-remitting or secondary progressive MS were intravenously administered 5 mg or 10 mg of Cpn10 weekly for 12 weeks in a double-blind, randomized, placebo controlled, phase II trial. Clinical reviews, including Expanded Disability Status Scale and magnetic resonance imaging (MRI) with Gadolinium, were undertaken every 4 weeks. Stimulation of patient peripheral blood mononuclear cells with lipopolysaccharide ex vivo was used to measure the in vivo activity of Cpn10. Results No significant differences in the frequency of adverse events were seen between treatment and placebo arms. Leukocytes from both groups of Cpn10-treated patients produced significantly lower levels of critical proinflammatory cytokines. A trend toward improvement in new Gadolinium enhancing lesions on MRI was observed, but this difference was not statistically significant. No differences in clinical outcome measures were seen. Conclusions Cpn10 is safe and well tolerated when administered to patients with MS for 3 months, however, a further extended phase II study primarily focused on efficacy is warranted.

Common PPARγ variants C161T and Pro12Ala are not associated with inflammatory bowel disease in an Australian cohort

Background & Aims: Peroxisome proliferator-activated receptor (PPAR) γ is a transcription factor, highly expressed in colonic epithelial cells, adipose tissue and macrophages, with an important role in the regulation of inflammatory pathways. The common PPARγ variants C161T and Pro12Ala have recently been associated with Ulcerative Colitis (UC) and an extensive UC phenotype respectively, in a Chinese population. PPARγ Pro12Ala variant homozygotes appear to be protected from the development of Crohn's disease (CD) in European Caucasians. Methods: A case-control study was performed for both variants (CD n=575, UC n=306, Controls n=360) using a polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis in an Australian IBD cohort. A transmission disequilibrium test was also performed using CD trios for the PPARγ C161T variant. Genotype-phenotype analyses were also undertaken. Results: There was no significant difference in genotype distribution data or allele frequency between CD and UC patients and controls. There was no difference in allele transmission for the C161T variant. No significant relationship between the variants and disease location was observed. Conclusions: We were unable to replicate in a Caucasian cohort the recent association between PPARγ C161T and UC or between PPARγ Pro12Ala and an extensive UC phenotype in a Chinese population. There are significant ethnic differences in genetic susceptibility to IBD and its phenotypic expression.

Packed red blood cells suppress myeloid dendritic cell and monocyte inflammatory responses in a whole blood model of transfusion

Purpose/Objective: The basis for poor outcomes in some patients post transfusion remains largely unknown. Despite leukodepletion, there is still evidence of immunomodulatory effects of transfusion that require further study. In addition, there is evidence that the age of blood components transfused significantly affects patient outcomes. Myeloid dendritic cell (DC) and monocyte immune function were studied utilising an in vitro whole blood model of transfusion. Materials and methods: Freshly collected (‘recipient’) whole blood was cultured with ABO compatible leukodepleted PRBC at 25% blood replacement-volume (6hrs). PRBC were assayed at [Day (D) 2, 14, 28and 42 (date-of expiry)]. In parallel, LPS or Zymosan (Zy) were added to mimic infection. Recipients were maintained for the duration of the time course (2 recipients, 4 PRBC units, n = 8).Recipient DC and monocyte intracellular cytokines and chemokines (IL-6, IL-10, IL-12,TNF-a, IL-1a, IL-8, IP-10, MIP-1a, MIP-1b, MCP-1) were measured using flow cytometry. Changes in immune response were calculated by comparison to a parallel no transfusion control (Wilcoxin matched pairs). Influence of storage age was calculated using ANOVA. Results: Significant suppression of DC and monocyte inflammatory responses were evident. DC and monocyte production of IL-1a was reduced following exposure to PRBC regardless of storage age (P < 0.05 at all time points). Storage independent PRBC mediated suppression of DC and monocyte IL-1a was also evident in cultures costimulated with Zy. In cultures co-stimulated with either LPS or Zy, significant suppression of DC and monocyte TNF-a and IL-6 was also evident. PRBC storage attenuated monocyte TNF-a production when co-cultured with LPS (P < 0.01 ANOVA). DC and monocyte production of MIP-1a was significantly reduced following exposure to PRBC (DC: P < 0.05 at D2, 28, 42; Monocyte P < 0.05 all time points). In cultures co-stimulated with LPS and zymosan, a similar suppression of MIP-1a production was also evident, and production of both DC and monocyte MIP-1b and IP-10 were also significantly reduced. Conclusions: The complexity of the transfusion context was reflected in the whole blood approach utilised. Significant suppression of these key DC and monocyte immune responses may contribute to patient outcomes, such as increased risk of infection and longer hospital stay, following blood transfusion.

Bridging the biology of the ovine TRALI model – human inflammatory cell responses to TRALI inducing supernatants

Background Transfusion-related acute lung injury (TRALI) is a serious and potentially fatal consequence of transfusion. A two-event TRALI model demonstrated date-of-expiry - day (D) 5 platelet (PLT) and D42 packed red blood cell (PRBC) supernatants (SN) induced TRALI in LPS-treated sheep. We have adapted a whole blood transfusion culture model as an investigative bridge between the ovine TRALI model human responses to transfusion. Methods A whole blood transfusion model was adapted to replicate the ovine model - specifically +/- 0.23μg/mL LPS as the first event and 10% SN volume (transfusion) as the second event. Four pooled SN from blood products, previously used in the TRALI ovine model, were investigated: D1-PLT, D5-PLT, D1-PRBC, and D42-PRBC. Fresh human whole blood (recipient) was mixed with combinations of LPS and BP-SN stimuli and incubated in vitro for 6 hrs. Addition of golgi plug enabled measurement of monocyte cytokine production (IL-6, IL-8, IL-10, IL-12, TNF-α, IL-1α, CXCL-5, IP-10, MIP-1α, MCP-1) using multi-colour flow cytometry. Responses for 6 recipients were assessed. Results In the presence of LPS, D42-PRBC-SN significantly increased monocyte IL-6 (P=0.031), IL-8 (P=0.016) and IL-1α (P=0.008) production compared to D1-PRBC-SN. This response to D42-PRBC-SN was LPS-dependent, and was not evident in non-LPSstimulated controls. This response was also specific to D42-PRBC-SN, as similar changes were not evident for the D5-PLT-SN, compared to the D1-PLT-SN, regardless of the presence of LPS. D5-PLT-SN significantly increased IL-12 production (P=0.024) compared to D1-PLT-SN. This response was again LPS-dependent. Conclusions These data demonstrate a novel two-event mechanism of monocyte inflammatory response that was dependent upon both the presence of date-of-expiry blood product SN and LPS. Further, these results demonstrate different cytokines responses induced by date-of-expiry PLT-SN and PRBC-SN. These data are consistent with the evidence from the ovine TRALI model, and enhancing its relevance to transfusion related changes in humans.

How Can Models of Motor Control Be Useful for Understanding Low Back Pain?

Introduction. The purpose of this chapter is to address the question raised in the chapter title. Specifically, how can models of motor control help us understand low back pain (LBP)? There are several classes of models that have been used in the past for studying spinal loading, stability, and risk of injury (see Reeves and Cholewicki (2003) for a review of past modeling approaches), but for the purpose of this chapter we will focus primarily on models used to assess motor control and its effect on spine behavior. This chapter consists of 4 sections. The first section discusses why a shift in modeling approaches is needed to study motor control issues. We will argue that the current approach for studying the spine system is limited and not well-suited for assessing motor control issues related to spine function and dysfunction. The second section will explore how models can be used to gain insight into how the central nervous system (CNS) controls the spine. This segues segue nicely into the next section that will address how models of motor control can be used in the diagnosis and treatment of LBP. Finally, the last section will deal with the issue of model verification and validity. This issue is important since modelling accuracy is critical for obtaining useful insight into the behavior of the system being studied. This chapter is not intended to be a critical review of the literature, but instead intended to capture some of the discussion raised during the 2009 Spinal Control Symposium, with some elaboration on certain issues. Readers interested in more details are referred to the cited publications.

Understanding chronic pain complicating disability: Finding meaning through focus group methodology

Over the past few decades a major paradigm shift has occurred in the conceptualisation of chronic pain as a complex multidimensional phenomenon. Yet, pain experienced by individuals with a primary disability continues to be understood largely from a traditional biomedical model, despite its inherent limitations. This is reflected in the body of literature on the topic that is primarily driven by positivist assumptions and the search for etiologic pain mechanisms. Conversely, little is known about the experiences of and meanings attributed to, disability-related pain. Thus the purpose of this paper is to discuss the use of focus group methodology in elucidating the meanings and experiences of this population. Here, a distinction is made between the method of the focus group and focus group research as methodology. Typically, the focus group is presented as a seemingly atheoretical method of research. Drawing on research undertaken on the impact of chronic pain in people with multiple sclerosis, this paper seeks to theorise the focus group in arguing the methodological congruence of focus group research and the study of pain experience. It is argued that the contributions of group interaction and shared experiences in focus group discussions produce data and insights less accessible through more structured research methods. It is concluded that a biopsychosocial perspective of chronic pain may only ever be appreciated when the person-in-context is the unit of investigation.

A comparative analysis of risk stratification tools for emergency department patients with chest pain

Background: Appropriate disposition of emergency department (ED) patients with chest pain is dependent on clinical evaluation of risk. A number of chest pain risk stratification tools have been proposed. The aim of this study was to compare the predictive performance for major adverse cardiac events (MACE) using risk assessment tools from the National Heart Foundation of Australia (HFA), the Goldman risk score and the Thrombolysis in Myocardial Infarction risk score (TIMI RS). Methods: This prospective observational study evaluated ED patients aged ≥30 years with non-traumatic chest pain for which no definitive non-ischemic cause was found. Data collected included demographic and clinical information, investigation findings and occurrence of MACE by 30 days. The outcome of interest was the comparative predictive performance of the risk tools for MACE at 30 days, as analyzed by receiver operator curves (ROC). Results: Two hundred eighty-one patients were studied; the rate of MACE was 14.1%. Area under the curve (AUC) of the HFA, TIMI RS and Goldman tools for the endpoint of MACE was 0.54, 0.71 and 0.67, respectively, with the difference between the tools in predictive ability for MACE being highly significant [chi2 (3) = 67.21, N = 276, p < 0.0001]. Conclusion: The TIMI RS and Goldman tools performed better than the HFA in this undifferentiated ED chest pain population, but selection of cutoffs balancing sensitivity and specificity was problematic. There is an urgent need for validated risk stratification tools specific for the ED chest pain population.

Visual analog scale and pressure pain threshold for delayed onset muscle soreness assessment

Objectives: To investigate the relationship between two assessments to quantify delayed onset muscle soreness [DOMS]: visual analog scale [VAS] and pressure pain threshold [PPT]. Methods: Thirty-one healthy young men [25.8 ± 5.5 years] performed 10 sets of six maximal eccentric contractions of the elbow flexors with their non-dominant arm. Before and one to four days after the exercise, muscle pain perceived upon palpation of the biceps brachii at three sites [5, 9 and 13 cm above the elbow crease] was assessed by VAS with a 100 mm line [0 = no pain, 100 = extremely painful], and PPT of the same sites was determined by an algometer. Changes in VAS and PPT over time were compared amongst three sites by a two-way repeated measures analysis of variance, and the relationship between VAS and PPT was analyzed using a Pearson product-moment correlation. Results: The VAS increased one to four days after exercise and peaked two days post-exercise, while the PPT decreased most one day post-exercise and remained below baseline for four days following exercise [p < 0.05]. No significant difference among the three sites was found for VAS [p = 0.62] or PPT [p = 0.45]. The magnitude of change in VAS did not significantly correlate with that of PPT [r = −0.20, p = 0.28]. Conclusion: These results suggest that the level of muscle pain is not region-specific, at least among the three sites investigated in the study, and VAS and PPT provide different information about DOMS, indicating that VAS and PPT represent different aspects of pain.

Mathematical investigation of the interactions between the inflammatory response and mechanical aspects of dermal wound repair

Dermal wound repair involves complex interactions between cells, cytokines and mechanics to close injuries to the skin. In particular, we investigate the contribution of fibroblasts, myofibroblasts, TGFβ, collagen and local tissue mechanics to wound repair in the human dermis. We develop a morphoelastic model where a realistic representation of tissue mechanics is key, and a fibrocontractive model that involves a reasonable approximation to the true kinetics of the important bioactive species. We use each of these descriptions to elucidate the mechanisms that generate pathologies such as hypertrophic scars, contractures and keloids. We find that for hypertrophic scar and contracture development, factors regulating the myofibroblast phenotype are critical, with heightened myofibroblast activation, reduced myofibroblast apoptosis or prolonged inflammation all predicted as mediators for scar hypertrophy and contractures. Prevention of these pathologies is predicted when myofibroblast apoptosis is induced, myofibroblast activation is blocked or TGFβ is neutralised. To investigate keloid invasion, we develop a caricature representation of the fibrocontractive model and find that TGFβ spread is the driving factor behind keloid growth. Blocking activation of TGFβ is found to cause keloid regression. Thus, we recommend myofibroblasts and TGFβ as targets for clinicians when developing intervention strategies for prevention and cure of fibrotic scars.

Advancing Nursing Practice in Pain Management

This book showcases the development and evaluation of innovative examples of pain management initiatives by advanced practitioners. It considers each service development or community initiative both in terms of advanced practice nursing and pain management. There is a wide range of examples of innovation in pain management included - from the introduction of ketamine use in one trust, to wider issues around meeting the needs of pain management in the community. The book considers issues including use of research, education and interprofessional working in the advanced practitioner role. Each chapter looks at development of the service, challenges of implementation, evaluation of the service's success and justifying the importance of the advanced nurse in the service's achievements.

Introduction to Advancing Practice in Pain Management

This chapter contains sections titled: Introduction Advanced practice The context of pain management: definitions and prevalence Advancing practice in pain management Bringing together advanced practice and pain management Conclusions References

Nurse Prescribing in Acute and Chronic Pain Management

This chapter contains sections titled: Introduction Acute pain Chronic pain Rationale for service development Evaluation use of audit and CPD Justifying the advanced nursing contribution to develop nurse prescribing in pain management Conclusions References