Handbook of Pain Assessment

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a 38-amino acid peptide that was first isolated from ovine hypothalamic extracts on the basis of its ability to stimulate cAMP formation in anterior pituitary cells. PACAP belongs to the vasoactive intestinal polypeptide (VIP)-glucagon-growth hormone releasing factor-secretin superfamily. The sequence of PACAP has been remarkably well conserved during the evolution from protochordate to mammals, suggesting that PACAP is involved in the regulation of important biological functions. PACAP is widely distributed in the brain and peripheral organs, notably in the endocrine pancreas, gonads, and respiratory and urogenital tracts. Characterization of the PACAP precursor has revealed the existence of a PACAP-related peptide whose activity remains unknown. Two types of PACAP binding sites have been characterized. Type I binding sites exhibit a high affinity for PACAP and a much lower affinity for VIP whereas type II binding sites have similar affinity for PACAP and VIP. Molecular cloning of PACAP receptors has shown the existence of three distinct receptor subtypes, the PACAP-specific PAC1 receptor, which is coupled to several transduction systems, and the two PACAP/VIP-indifferent VPAC1 and VPAC2 receptors, which are primarily coupled to adenylyl cyclase. PAC1 receptors are particularly abundant in the brain and pituitary and adrenal glands whereas VPAC receptors are expressed mainly in the lung, liver, and testis. The wide distribution of PACAP and PACAP receptors has led to an explosion of studies aimed at determining the pharmacological effects and biological functions of the peptide. This report reviews the current knowledge concerning the multiple actions of PACAP in the central nervous system and in various peripheral organs including the endocrine glands, the airways, and the cardiovascular and immune systems, as well as the different effects of PACAP on a number of tumor cell types.

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: From Structure to Functions

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a 38-amino acid C-terminally alpha-amidated peptide that was first isolated 20 years ago from an ovine hypothalamic extract on the basis of its ability to stimulate cAMP formation in anterior pituitary cells (Miyata et al., 1989. PACAP belongs to the vasoactive intestinal polypeptide (VIP)-secretin-growth hormone-releasing hormone-glucagon superfamily. The sequence of PACAP has been remarkably well conserved during evolution from protochordates to mammals, suggesting that PACAP is involved in the regulation of important biological functions. PACAP is widely distributed in the brain and peripheral organs, notably in the endocrine pancreas, gonads, respiratory and urogenital tracts. Characterization of the PACAP precursor has revealed the existence of a PACAP-related peptide, the activity of which remains unknown. Two types of PACAP binding sites have been characterized: type I binding sites exhibit a high affinity for PACAP and a much lower affinity for VIP, whereas type II binding sites have similar affinity for PACAP and VIP. Molecular cloning of PACAP receptors has shown the existence of three distinct receptor subtypes: the PACAP-specific PAC1-R, which is coupled to several transduction systems, and the PACAP/VIP-indifferent VPAC1-R and VPAC2-R, which are primarily coupled to adenylyl cyclase. PAC1-Rs are particularly abundant in the brain, the pituitary and the adrenal gland, whereas VPAC receptors are expressed mainly in lung, liver, and testis. The development of transgenic animal models and specific PACAP receptor ligands has strongly contributed to deciphering the various actions of PACAP. Consistent with the wide distribution of PACAP and its receptors, the peptide has now been shown to exert a large array of pharmacological effects and biological functions. The present report reviews the current knowledge concerning the pleiotropic actions of PACAP and discusses its possible use for future therapeutic applications.

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery

Overuse tendinopathy is problematic to manage clinically. People of different ages with tendons under diverse loads present with varying degrees of pain, irritability, and capacity to function. Recovery is similarly variable; some tendons recover with simple interventions, some remain resistant to all treatments. The pathology of tendinopathy has been described as degenerative or failed healing. Neither of these descriptions fully explains the heterogeneity of presentation. This review proposes, and provides evidence for, a continuum of pathology. This model of pathology allows rational placement of treatments along the continuum. A new model of tendinopathy and thoughtful treatment implementation may improve outcomes for those with tendinopathy. This model is presented for evaluation by clinicians and researchers.

https://bjsm.bmj.com/content/bjsports/43/6/409.full.pdf

Is tendon pathology a continuum? A pathology model to explain the clinical presentation of load-induced tendinopathy

https://espace.library.uq.edu.au/view/UQ:225158/UQ225158_OA.pdf

Efficacy and safety of corticosteroid injections and other injections for management of tendinopathy: a systematic review of randomised controlled trials

Overuse tendon injury is one of the most common injuries in sports. The etiology as well as the pathophysiological mechanisms leading to tendinopathy are of crucial medical importance. At the moment intrinsic and extrinsic factors are assumed as mechanisms of overuse tendon injury. Except for the acute, extrinsic trauma, the chronic overuse tendon injury is a multifactorial process. There are many other factors, such as local hypoxia, less of nutrition, impaired metabolism and local inflammatory that may also contribute to the development of tissue damage. The exact interaction of these factors cannot be explained entirely at the moment. Further studies will be necessary in order to get more information.

Pathophysiology of overuse tendon injury

Study design Register study. Objective The purpose of this study was to assess the safety of lumbar spine surgery for degenerative disorders and to assess the predictive factors for mortality and causes of death. Summary of background data Growing numbers and relative indications of spine surgery emphasize the importance of patient safety. We assessed the incidence of mortality related to surgery, overall case fatality and factors predicting mortality in elective spinal surgery. Methods A national database was utilized to assess patient characteristics, surgical procedures, and outcomes of degenerative spinal surgery in Finland. Patients were classified into four diagnostic categories: disc herniation, spinal stenosis, degenerative disc disease, and spondylolysis and spondylolisthesis. The mortality related to surgery and overall mortality in each diagnostic group was analyzed at 7 days, 30 days, 90 days, and 1 year after surgery. We categorized the deaths into medical errors, sequelae of surgery, surgery probably a contributing factor, and deaths not associated with surgery. Age, sex, comorbid conditions, and hospital characteristics were considered as potential risk factors for mortality. Results Out of 408 deaths (0.67% of total of 61,166 patients) deaths that occurred during the 1-year follow up, 49 deaths (12% of deaths, 0.08% of patients) were classified as having an association with surgery: two deaths by medical errors, 28 deaths by complications after surgery and 19 deaths related to the surgery. The surgery-related 1-year mortality was 0.08%. Age >75 years, male sex, diabetes, and hypertension showed an association with increased risk of death related to surgery. Conclusion Mortality caused by elective spinal surgery is rare. Cardiovascular incidents are the most common reasons for deaths occurring soon after surgery. Consideration of expected gains and risks of surgery, prevention of unintended errors during surgery and recognition and treatment of complications once they occur are recommended. Level of evidence 3.

Mortality Caused by Surgery for Degenerative Lumbar Spine

OBJECTIVE
Controversial and misleading interpretation of data from randomized trials is common. How to avoid misleading interpretation has received little attention. Herein, we describe two applications of an approach that involves blinded interpretation of the results by study investigators.


STUDY DESIGN AND SETTINGS
The approach involves developing two interpretations of the results on the basis of a blinded review of the primary outcome data (experimental treatment A compared with control treatment B). One interpretation assumes that A is the experimental intervention and another assumes that A is the control. After agreeing that there will be no further changes, the investigators record their decisions and sign the resulting document. The randomization code is then broken, the correct interpretation chosen, and the manuscript finalized. Review of the document by an external authority before finalization can provide another safeguard against interpretation bias.


RESULTS
We found the blinded preparation of a summary of data interpretation described in this article practical, efficient, and useful.


CONCLUSIONS
Blinded data interpretation may decrease the frequency of misleading data interpretation. Widespread adoption of blinded data interpretation would be greatly facilitated were it added to the minimum set of recommendations outlining proper conduct of randomized controlled trials (eg, the Consolidated Standards of Reporting Trials statement).

Blinded interpretation of study results can feasibly and effectively diminish interpretation bias

Background and purpose Little is known about the effect of the learning curve for different types of total hip arthroplasties (THAs). We investigated the prostheses survival of THAs just after the implementation of a model new to the hospital, and compared these results with the results of THAs done when more than 100 implantations had been undertaken. In addition, we investigated whether differences exist between different types of femoral stems and acetabular cups at the early implementation phase. Patients and methods We used comprehensive registry data from all units (n = 76) that performed THAs for primary osteoarthritis in Finland between 1998 and 2007. Complete data including follow-up data to December 31, 2010 or until death were available for 33,819 patients (39,125 THAs). The stems and cups used were given order numbers in each hospital and classified into 5 groups: operations with order number (a) 1–15, (b) 16–30, (c) 31–50, (d) 51–100, and (e) > 100. We used Cox’s proportional hazards modeling...

Hip prosthesis introduction and early revision risk. A nationwide population-based study covering 39,125 operations.

Background The risk of early revision is increased for the first patients operatively treated with a newly introduced knee prosthesis. In this study, we explored the learning curves associated with ten knee implant models to determine their effect on early revision risk. Methods We studied register data from all seventy-five surgical units that performed knee arthroplasty in Finland from 1998 to 2007. Of 54,925 patients (66,098 knees), 39,528 patients (46,363 knees) underwent arthroplasty for osteoarthritis of the knee with the ten most common total knee implants and were followed with complete data until December 31, 2010, or the time of death. We used a Cox proportional-hazards regression model for calculating the hazard ratios for early revision for the first fifteen arthroplasties and subsequent increments of numbers of arthroplasties. Results We found large differences among knee implants at the introduction with regard to the risk of early revision, as well as for the overall risk of early revision. A learning curve was found for four implant models, while six models did not show a learning effect on the risk of early revision. The survivorship of the studied prostheses showed substantial differences. Conclusions Knee implants have model-specific learning curves and early revision risks. Some models are more difficult to implement than others. The manufacturers should consider the learning effect when designing implants and instrumentation. The surgeons should thoroughly familiarize themselves with the new knee implants before use.

Mika Paavola

Papers

Pathophysiology of overuse tendon injury

Mortality Caused by Surgery for Degenerative Lumbar Spine

Blinded interpretation of study results can feasibly and effectively diminish interpretation bias

Hip prosthesis introduction and early revision risk. A nationwide population-based study covering 39,125 operations.

Learning curve for new technology?: a nationwide register-based study of 46,363 total knee arthroplasties.